"KEGG_Id","Name","Description","Class"
"map00010","Glycolysis / Gluconeogenesis","Glycolysis is the process of converting glucose into pyruvate and generating small amounts of ATP (energy) and NADH (reducing power). It is a central pathway that produces important precursor metabolites: six-carbon compounds of glucose-6P and fructose-6P and three-carbon compounds of glycerone-P, glyceraldehyde-3P, glycerate-3P, phosphoenolpyruvate, and pyruvate [MD:M00001]. Acetyl-CoA, another important precursor metabolite, is produced by oxidative decarboxylation of pyruvate [MD:M00307]. When the enzyme genes of this pathway are examined in completely sequenced genomes, the reaction steps of three-carbon compounds from glycerone-P to pyruvate form a conserved core module [MD:M00002], which is found in almost all organisms and which sometimes contains operon structures in bacterial genomes. Gluconeogenesis is a synthesis pathway of glucose from noncarbohydrate precursors. It is essentially a reversal of glycolysis with minor variations of alternative paths [MD:M00003].","Metabolism; Carbohydrate metabolism"
"map00020","Citrate cycle (TCA cycle)","The citrate cycle (TCA cycle, Krebs cycle) is an important aerobic pathway for the final steps of the oxidation of carbohydrates and fatty acids. The cycle starts with acetyl-CoA, the activated form of acetate, derived from glycolysis and pyruvate oxidation for carbohydrates and from beta oxidation of fatty acids. The two-carbon acetyl group in acetyl-CoA is transferred to the four-carbon compound of oxaloacetate to form the six-carbon compound of citrate. In a series of reactions two carbons in citrate are oxidized to CO2 and the reaction pathway supplies NADH for use in the oxidative phosphorylation and other metabolic processes. The pathway also supplies important precursor metabolites including 2-oxoglutarate. At the end of the cycle the remaining four-carbon part is transformed back to oxaloacetate. According to the genome sequence data, many organisms seem to lack genes for the full cycle [MD:M00009], but contain genes for specific segments [MD:M00010 M00011].","Metabolism; Carbohydrate metabolism"
"map00030","Pentose phosphate pathway","The pentose phosphate pathway is a process of glucose turnover that produces NADPH as reducing equivalents and pentoses as essential parts of nucleotides. There are two different phases in the pathway. One is irreversible oxidative phase in which glucose-6P is converted to ribulose-5P by oxidative decarboxylation, and NADPH is generated [MD:M00006]. The other is reversible non-oxidative phase in which phosphorylated sugars are interconverted to generate xylulose-5P, ribulose-5P, and ribose-5P [MD:M00007]. Phosphoribosyl pyrophosphate (PRPP) formed from ribose-5P [MD:M00005] is an activated compound used in the biosynthesis of histidine and purine/pyrimidine nucleotides. This pathway map also shows the Entner-Doudoroff pathway where 6-P-gluconate is dehydrated and then cleaved into pyruvate and glyceraldehyde-3P [MD:M00008].","Metabolism; Carbohydrate metabolism"
"map00040",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00051",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00052",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00053",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00061",nothing,nothing,"Metabolism; Lipid metabolism"
"map00062",nothing,nothing,"Metabolism; Lipid metabolism"
"map00071",nothing,nothing,"Metabolism; Lipid metabolism"
"map00073",nothing,nothing,"Metabolism; Lipid metabolism"
"map00100",nothing,nothing,"Metabolism; Lipid metabolism"
"map00120","Primary bile acid biosynthesis","Bile acids are steroid carboxylic acids derived from cholesterol in vertebrates. The primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the liver and conjugated with taurine or glycine before secretion via bile into the intestine. The conversion from cholesterol to cholic and chenodeoxycholic acids involves four steps: 1) the initiation of synthesis by 7alpha-hydroxylation of sterol precursors, 2) further modifications to the ring structures, 3) side-chain oxidation and shortening (cleavage) by three carbons, and 4) conjugation of the bile acid with taurine or glycine.","Metabolism; Lipid metabolism"
"map00121","Secondary bile acid biosynthesis","The secondary bile acids are derived from the primary bile acids by the enzymatic action of intestinal bacteria through the process of deconjugation and dehydroxylation. The secondary bile acids in humans include deoxycholic acid and lithocholic acid, formed from the 7alpha-dehydroxylation of cholic acid and chenodeoxycholic acid, respectively.","Metabolism; Lipid metabolism"
"map00130","Ubiquinone and other terpenoid-quinone biosynthesis","Ubiquinone (UQ), also called coenzyme Q, and plastoquinone (PQ) are electron carriers in oxidative phosphorylation and photosynthesis, respectively. The quinoid nucleus of ubiquinone is derived from the shikimate pathway; 4-hydroxybenzoate is directly formed from chorismate in bacteria, while it can be formed from either chorismate or tyrosine in yeast. The following biosynthesis of terpenoid moiety involves reactions of prenylation, decarboxylation, and three hydroxylations alternating with three methylations. The order of these reactions are somewhat different between bacteria and yeast. Phylloquinone (vitamin K1), menaquinone (vitamin K2), and tocopherol (vitamin E) are fat-soluble vitamins. Phylloquinone is a compound present in all photosynthetic plants serving as a cofactor for photosystem I-mediated electron transport. Menaquinone is an obligatory component of the electron-transfer pathway in bacteria.","Metabolism; Metabolism of cofactors and vitamins"
"map00140","Steroid hormone biosynthesis","Steroid hormones derived from cholesterol are a class of biologically active compounds in vertebrates. The cholesterol side-chain cleavage enzyme CYP11A1 catalyzes conversion of cholesterol, a C27 compound, to the first C21 steroid, pregnenolone, which is converted by a bifunctional enzyme complex to the gestagen hormone, progesterone [MD:M00107]. Pregnenolone and progesterone are the starting materials for the three groups of steroids: C21 steroids of glucocorticoids and mineralocorticoids, C19 steroids of androgens, and C18 steroids of estrogens. (i) Progesterone is converted by hydroxylations at carbons 21 and 11 to corticosterone, which is further modified by hydroxylation and oxydoreduction at carbon 18 to yield aldosterone, a mineralcorticoid [MD:M00108]. Cortisol, the main glucocorticoid, is formed from 17alpha-hydroxyprogesterone with 11-deoxycortisol as an intermediate [MD:M00109]. (ii) Male hormone testosterone is formed from pregnenolone by two pathways, delta5 pathway via dehydroepiandrosterone and delta4 pathway via androstenedione [MD:M00110]. The enzyme CYP17A1 is responsible for the 17,20 lyase and 17alpha-hydroxylase activities in respective pathways. (iii) Female hormones estrone and estradiol are formed from testosterone and 4-androstene-3,17-dione by oxidative removal of the C19 methyl group and subsequent aromatization of ring A [MD:M00111]. In addition to these three groups, recent studies show that there is another group, termed neurosteroids, synthesized in the brain rather than the peripheral endocrine gland.","Metabolism; Lipid metabolism"
"map00190",nothing,nothing,"Metabolism; Energy metabolism"
"map00195","Photosynthesis","Photosynthesis in green plants and specialized bacteria is the process of utilizing light energy to synthesize organic compounds from carbon dioxide and water. It consists of the light dependent part (light reaction) and the light independent part (dark reaction, carbon fixation). The light reaction takes place in thylakoid, a membrane-bound compartment inside chloroplasts and cyanobacteria. The light energy is used by photosystems I and II to generate proton motive force and reducing power (NADPH or NADH). The proton motive force is used by ATP synthase to generate ATP, essentially in the same way as the mitochondrial respiratory chain. The supplies of ATP and NAD(P)H are then used to fix carbon dioxide.","Metabolism; Energy metabolism"
"map00196","Photosynthesis - antenna proteins","The chlorophyll-binding subunits of photosystems I and II are internal antenna light-harvesting proteins of oxygenic photosynthesis. The antenna proteins that exist in phycobilisomes in cyanobacteria and light-harvesting chlorophyll protein complexes in green plants act as peripheral antenna systems, enabling more efficient absorption of light energy.","Metabolism; Energy metabolism"
"map00220",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00230",nothing,nothing,"Metabolism; Nucleotide metabolism"
"map00232",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00240",nothing,nothing,"Metabolism; Nucleotide metabolism"
"map00250",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00253","Tetracycline biosynthesis","Tetracyclines are aromatic polyketide antibiotics produced by Streptomyces species via type II polyketide synthases (PKSs). Tetracyclines contain a linear tetracyclic skeleton, which is formed from a malonamate starter unit and malonyl-CoA extender units through a common polyketide pathway [MD:M00778]. This diagram shows biosynthesis of naturally occurring tetracyclines (tetracycline, oxytetracycline and chlortetracycline) via a common intermediate anhydrotetracycline [MD:M00780 M00823].","Metabolism; Metabolism of terpenoids and polyketides"
"map00254",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00260","Glycine, serine and threonine metabolism","Serine is derived from 3-phospho-D-glycerate, an intermediate of glycolysis [MD:M00020], and glycine is derived from serine. Threonine is an essential amino acid, which animals cannot synthesize. In bacteria and plants, threonine is derived from aspartate [MD:M00018].","Metabolism; Amino acid metabolism"
"map00261","Monobactam biosynthesis","Monobactams are beta-lactam antibiotics containing a monocyclic beta-lactam nucleus, which is structurally different from penicillin and cephalosporin core structures with another fused ring. This diagram shows biosynthesis of nocardicin A, a naturally occurring monobactam, via the pentapeptide formed by condensation of L-4-hydroxyphenylglycine (L-pHPG), L-arginine and L-serine [MD:M00736]. Other naturally occurring monobactams are also shown but the biosynthetic pathway is not yet fully characterized. Sulfazecin and other 3-aminomonobactamic acid derivatives are derived from serine or threonine, and tabtoxinine-beta-lactam is a phytotoxin. Aztreonam, a synthetic monobactam originally isolated as SQ 26,180 from Chromobacterium violaceum, is the first clinically used monobactam.","Metabolism; Biosynthesis of other secondary metabolites"
"map00270","Cysteine and methionine metabolism","Cysteine and methionine are sulfur-containing amino acids. Cysteine is synthesized from serine through different pathways in different organism groups. In bacteria and plants, cysteine is converted from serine (via acetylserine) by transfer of hydrogen sulfide [MD:M00021]. In animals, methionine-derived homocysteine is used as sulfur source and its condensation product with serine (cystathionine) is converted to cysteine [MD:M00338]. Cysteine is metabolized to pyruvate in multiple routes. Methionine is an essential amino acid, which animals cannot synthesize. In bacteria and plants, methionine is synthesized from aspartate [MD:M00017]. S-Adenosylmethionine (SAM), synthesized from methionine and ATP, is a methyl group donor in many important transfer reactions including DNA methylation for regulation of gene expression. SAM may also be used to regenerate methionine in the methionine salvage pathway [MD:M00034].","Metabolism; Amino acid metabolism"
"map00280",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00281",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map00290",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00300",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00310",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00311","Penicillin and cephalosporin biosynthesis","Penicillins (Penams) and cephalosporins (cephems) are beta-lactam antibiotics containing 6-aminopenicillanate (6-APA) and 7-aminocephalosporanate (7-ACA) nuclei, respectively. 6-APA and 7-ACA are key intermediates for a variety of semisynthetic penicillin and cephalosporin derivatives. Penicillins are produced only by fungi, while cephalosporins (including cephamycins) are produced by fungi and bacteria. Both antibiotics are synthesized from L-2-aminoadipate, L-cysteine and L-valine through a common pathway. It starts with the condensation of these three amino acids by the non-ribosomal peptide synthetase to form the tripeptide delta-(L-2-aminoadipyl)-L-cysteinyl-D-valine (ACV). The linear ACV tripeptide is then converted to bicyclic isopenicillin N by isopenicillin N synthase, in which the beta-lactam ring is formed. Isopenicillin N is the branch point of penicillin [MD:M00672] and cephalosporin [MD:M00673] pathways.","Metabolism; Biosynthesis of other secondary metabolites"
"map00330",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00331",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00332","Carbapenem biosynthesis","Carbapenems are broad-spectrum beta-lactam antibiotics, which are often considered as the antibiotics of last resort. A naturally occurring carbapenem, thienamycin, was first discovered in Streptomyces cattleya. This diagram shows how a simple carbapenem, carbapenem-3-carboxylate, is synthesized from malonyl-CoA and pyrroline-5-carboxylate [MD:M00675]. For structurally complex carbapenems, such as thienamycin, olivanic acid, epi-thienamycin and carbapenems of the OA-6129 group, uncertainty remains about the mechanism and timing for the inversion of the C-5 carbapenam bridgehead, the desaturation of the C-2/C-3 bond and the attachment of the C-2 and C-6 side chains.","Metabolism; Biosynthesis of other secondary metabolites"
"map00333","Prodigiosin biosynthesis","Prodiginines are red-pigmented natural antibiotics that are produced as secondary metabolites and have received renewed attention because of potential clinical interests. In Serratia sp. or actinomycetes such as Streptomyces coelicolor, the tripyrrole molecules of prodigiosin and undecylprodigiosin are formed by the condensation of 4-methoxy-2,2'-bipyrrole-5-carbaldehyde and either 2-methyl-3-n-amyl-pyrrole [MD:M00837] or 2-undecylpyrrole [MD:M00838]. The Serratia pig gene cluster and the Streptomyces red gene cluster responsible for these biosynthesis pathways have been identified.","Metabolism; Biosynthesis of other secondary metabolites"
"map00340",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00350",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00360",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00361",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00362",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00363",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00364",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00365",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00380",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00400",nothing,nothing,"Metabolism; Amino acid metabolism"
"map00401",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00402","Benzoxazinoid biosynthesis","Benzoxazinoids (hydroxamic acids) are plant secondary metabolites that serve as important factors for host resistance against microbial pathogens and insects and for allelopathic effects. They are found in grass family and some eudicot families. The predominant benzoxazinoids are DIBOA and its 7-methoxy derivative DIMBOA, which are stored as glucosides in vacuoles. In maize, benzoxazinoid biosynthesis branches off from tryptophan biosynthesis at indole-3-glycerol phosphate, which is converted to indole by indole-3-glycerol phosphate lyase, BX1. Subsequently four cytochrome P450 monooxygenases (BX2-BX5) catalyze the introduction of four oxygen atoms into the indole moiety, yielding DIBOA. After glucosylation by UDP-glucosyltransferase (BX8/BX9), the glucoside is further modified by hydroxylation and O-methylation at C-7 to form DIMBOA-glucoside.","Metabolism; Biosynthesis of other secondary metabolites"
"map00403","Indole diterpene alkaloid biosynthesis","Indole diterpene alkaloids are a group of meroterpenoids consisting of a partial diterpene structure with four isoprene units and an indole moiety. The common cyclic diterpene skeleton is derived from geranylgeranyl diphosphate (GGPP) and an indole moiety is derived from tryptophan or a tryptophan precursor. They are combined in the initial step of biosynthetic reactions that generate paspaline, the first stable and less modified form required for other forms. Most indole diterpene alkaloids have potent mammalian tremorgenic activities, such as ryegrass staggers in livestock, and some have anti-insect properties. This map shows examples of indole diterpene alkaloids isolated from filamentous fungi.","Metabolism; Biosynthesis of other secondary metabolites"
"map00404",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00405",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00410",nothing,nothing,"Metabolism; Metabolism of other amino acids"
"map00430",nothing,nothing,"Metabolism; Metabolism of other amino acids"
"map00440","Phosphonate and phosphinate metabolism","Natural products containing carbon-phosphorous bonds, so-called C-P compounds, are derivatives of phosphonate and phosphinate with substitution of alkyl group for hydrogen of phosphorus-hydrogen bonds. C-P compounds have been found in many organisms, but only protists and bacteria, mostly Actinobacteria, have biosynthetic capacity. A common reaction in the biosynthetic pathway is C-P bond forming reaction from phosphoenolpyruvate (PEP) to phosphonopyruvate (PnPy) catalyzed by PEP phosphomutase. 2-Aminoethylphosphonate (AEP) is the most abundant C-P compound in the natural world. AEP derivatives include phosphonoprotein, phosphonoglycan, and phosphonolipid. Other known C-P compounds are bioactive substances used in medicine (antibiotics) and agriculture (herbicide) such as fosfomycin, FR-33289, rhizocticin, and bialaphos.","Metabolism; Metabolism of other amino acids"
"map00450",nothing,nothing,"Metabolism; Metabolism of other amino acids"
"map00460",nothing,nothing,"Metabolism; Metabolism of other amino acids"
"map00470",nothing,nothing,"Metabolism; Metabolism of other amino acids"
"map00480",nothing,nothing,"Metabolism; Metabolism of other amino acids"
"map00500",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00510","N-Glycan biosynthesis","N-glycans or asparagine-linked glycans are major constituents of glycoproteins in eukaryotes. N-glycans are covalently attached to asparagine with the consensus sequence of Asn-X-Ser/Thr by an N-glycosidic bond, GlcNAc b1- Asn. Biosynthesis of N-glycans begins on the cytoplasmic face of the ER membrane with the transferase reaction of UDP-GlcNAc and the lipid-like precursor P-Dol (dolichol phosphate) to generate GlcNAc a1- PP-Dol. After sequential addition of monosaccharides by ALG glycosyltransferases [MD:M00055], the N-glycan precursor is attached by the OST (oligosaccharyltransferase) complex to the polypeptide chain that is being synthesized and translocated through the ER membrane. The protein-bound N-glycan precursor is subsequently trimmed, extended, and modified in the ER and Golgi by a complex series of reactions catalyzed by membrane-bound glycosidases and glycosyltransferases. N-glycans thus synthesized are classified into three types: high-mannose type, complex type, and hybrid type. Defects in N-glycan biosynthesis lead to a variety of human diseases known as congenital disorders of glycosylation [DS:H00118 H00119].","Metabolism; Glycan biosynthesis and metabolism"
"map00511",nothing,nothing,"Metabolism; Glycan biosynthesis and metabolism"
"map00512","Mucin type O-glycan biosynthesis","O-glycans are a class of glycans that modify serine or threonine residues of proteins. Biosynthesis of O-glycans starts from the transfer of N-acetylgalactosamine (GalNAc) to serine or threonine. The first GalNAc may be extended with sugars including galactose, N-acetylglucosamine, fucose, or sialic acid, but not mannose, glucose, or xylose. Depending on the sugars added, there are four common O-glycan core structures, cores 1 through 4, and an additional four, cores 5 though 8. Mucins are highly O-glycosylated glycoproteins ubiquitous in mucous secretions on cell surfaces and in body fluids. Mucin O-glycans can be branched, and many sugars or groups of sugars are antigenic. Important modifications of mucin O-glycans include O-acetylation of sialic acid and O-sulfation of galactose and N-acetylglucosamine.","Metabolism; Glycan biosynthesis and metabolism"
"map00513",nothing,nothing,"Metabolism; Glycan biosynthesis and metabolism"
"map00514","Other types of O-glycan biosynthesis","O-linked glycosylation is the attachment of monosaccharides to the hydroxyl groups of amino acids, mostly serine and threonine, and is found in eukaryotes, archaea and bacteria. O-glycans exhibit diverse types of modifications where the innermost monosaccharide is N-acetylgalactosamine (map00512), mannose in mammals (map00515), and others (this map) including N-acetylglucosamine, fucose, glucose, galactose, mannose in yeast and arabinose in plants.","Metabolism; Glycan biosynthesis and metabolism"
"map00515","Mannose type O-glycan biosynthesis","Biosynthesis of mammalian O-mannosyl glycans is initiated by the transfer of mannose from mannose-P-Dol to serine or threonine residue, followed by extensions with N-acetylglucosamine (GlcNAc) and galactose (Gal) to generate core M1, M2 and M3 glycans. Core M1 and M2 glycans can then be further attached by fucose residues, sialic acid terminals and sulfatded glucuroinc acid terminals. Core M3 glycan is involved in the synthesis of alpha-dystroglycan, a heavily glycosylated protein found in muscle and brain tissues. Core M3 glycan contains a tandem repeat of ribitol 5-phosphate (Rbo5P) and -alpha3-GlcA-beta3-Xyl- repeating structures. Defects of genes encoding core glycans and modified core M3 glycans are associated with various congenital diseases, such as muscular dystrophies caused by reduced O-mannosylation of alpha-dystroglycan in skeletal muscles [DS:H00120].","Metabolism; Glycan biosynthesis and metabolism"
"map00520",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00521","Streptomycin biosynthesis","Streptomycin is an aminocyclitol-aminoglycoside antibiotic produced by Streptomyces griseus. Streptomycin consists of aminocyclitol (streptidine), 6-deoxyhexose (streptose), and N-methyl-L-glucosamine moieties, which are formed by independent biosynthetic pathways. All of the moieties are derived from D-glucose. The streptidine moiety is synthesized via myo-inositol, which is then oxidized at C-1 and transaminated to give scyllo-inosamine. After phosphorylation, the compound is transamidinated by arginine. The same procedure is repeated at the C-3 position. The streptose moiety is made from D-glucose via a dTDP-glucose pathway. The exact biosynthetic route for the N-methyl-L-glucosamine moiety is unknown, though the biosynthetic gene cluster have been proposed.","Metabolism; Biosynthesis of other secondary metabolites"
"map00522",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map00523",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map00524",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00525",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00531",nothing,nothing,"Metabolism; Glycan biosynthesis and metabolism"
"map00532","Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate","Glycosaminoglycans (GAGs) are linear polysaccharide chains consisting of repeating disaccharide units and form proteglycans by covalently attaching to their core proteins. Chondroitin sulfate (CS) is a glycosaminoglycan with the disaccharide unit of beta-D-galactosamine (GalNAc) and beta-D-glucuronic acid (GlcA), and often modified with ester-linked sulfate at certain positions. Dermatan sulfate (DS) is a modified form of CS, in which a portion of D-glucuronate residues is epimerized to L-iduronates (IdoA). CS and DS are linked to serine residues in core proteins via a linkage tetrasaccharide formed by the transfer of xylose and three more residues [MD:M00057]. The assembly process of CS is initiated by transferring GalNAc residue to the linkage tetrasaccharide. The polymerization is catalyzed by bifunctional enzymes (chondroitin synthases) possessing both beta 1,3 glucuronosyltransferase and beta 1,4 N-acetylgalactosaminyltransferase activities [MD:M00058]. Chondroitin polymerization also requires the action of the chondroitin polymerizing factor. There are various O-sulfation patterns in CS and DS, where 4-O sulfation and 6-O sulfation of GalNAc and 2-O-sulfation of the uronic acids (GlcA / IdoA) are mainly found.","Metabolism; Glycan biosynthesis and metabolism"
"map00533","Glycosaminoglycan biosynthesis - keratan sulfate","Keratan sulfate (KS) is a glycosaminoglycan with the basic disaccharide unit of N-acetyllactosamine, Gal(b1-4)GlcNAc(b1-3), with sulfate esters at C-6 of GlcNAc and Gal residues. There are two types of KS distinguished by the protein linkage: type I for N-linked via the N-glycan core structure and type II for O-linked via the O-glycan core 2 structure.","Metabolism; Glycan biosynthesis and metabolism"
"map00534","Glycosaminoglycan biosynthesis - heparan sulfate / heparin","Heparan sulfate (HS) and heparin (Hep) are glycosaminoglycans with repeating disaccharide units that consist of alternating residues of alpha-D-glucosamine (GlcN) and uronic acid, the latter being either beta-D-glucuronic acid (GlcA) or alpha-L-iduronic acid (IdoA). In these sugar residues, sulfation modification may be performed at various positions. Structural studies show that Hep possesses a higher degree of sulfation than HS. The biosynthesis of HS/Hep occurs with the addition of the first GlcNAc residue by EXTL3 glycosyltransferase after completion of tetrasaccharide linkage region attached to serine residue of a core protein. The chain polymeraization is then catalyzed by EXT1 and EXT2 transferases. As the chain polymerizes, HS/Hep undergoes a series of modification reactions including N-deacetylation, N-sulfation, epimerization, and subsequently O-sulfation. As final products of biosynthesis, HS is present in the form of hepran sulfate proteoglycan (HSPG) whereas Hep exists as a sugar chain without a core protein. The proteoglycan families with HS, as well as CS (chondroitin sulfate), DS (dermatan sulfate), and KS (keratan sulfate), are composed of two main types depending on the subcellular locations: cell membrane and extracellular matrix [BR:ko00535]. HS/Hep has been shown to bind to a variety of molecules, such as growth factors, chemokines, morphogens, and extracellular matrix components [BR:ko00536].","Metabolism; Glycan biosynthesis and metabolism"
"map00540","Lipopolysaccharide biosynthesis","Lipopolysaccharide (LPS) is the major component of the outer membrane of Gram-negative bacteria consisting of three domains: a hydrophobic anchor called lipid A, a non-repeating core oligosaccharide (OS) and a repetitive glycan polymer called O-antigen or O-polysaccharide (O-PS). The enzymes for the biosynthesis of lipid A are well conserved among Gram-negative bacterial species [MD:M00060 M00866]. The core OS connecting lipid A with O-antigen is divided into inner and outer parts. Five core types, K-12 and R1-R4, are identified in Escherichia coli, with the common inner part composed of Kdo (ketodeoxyoctulosonic acid) and Hep (heptose) residues and the outer part made of various sugar residues. O-antigen is the most variable part used for serotyping of pathogenic Escherichia coli, where about 170 types are known. All three domains are involved in toxicity, pathogenicity, antimicrobial resistance and other activities.","Metabolism; Glycan biosynthesis and metabolism"
"map00541","O-Antigen nucleotide sugar biosynthesis","The O-antigen is a repetitive glycan polymer with a repeat unit of two to six sugar residues, and comprises the outermost and immunogenic domain of the lipopolysaccharide (map00540). Most of the sugar residues are derived from nucleotide sugars and the genes for their biosynthesis seem to be well conserved among Gram-negative bacterial species. They include UDP-sugars synthesized from Glc-1P via UDP-Glc or from GlcNAc-1P via UDP-GlcNAc, GDP-sugars synthesized from Fru-6P via GDP-Man, and dTDP-sugars and CDP-sugars synthesized from Glc-1P via dTDP-Glc and CDP-Glc, respectively. CMP-sugars are also synthesized from UDP-GlcNAc. The O-antigen nucleotide sugar biosynthesis genes often form gene clusters with glycosyltransferase genes and other processing genes such as for translocation and polymerization.","Metabolism; Glycan biosynthesis and metabolism"
"map00542","O-Antigen repeat unit biosynthesis","O-antigen is a repetitive glycan polymer synthesized as the most variable part in the lipopolysaccharide (LPS) biosynthesis (map00541). Structural diversity of O-antigen repeat units results from genetic diversity as summarized here for completely sequenced Escherichia coli genomes, many of which are for pathogenic strains.","Metabolism; Glycan biosynthesis and metabolism"
"map00550","Peptidoglycan biosynthesis","Peptidoglycan is a macromolecule made of long aminosugar strands cross-linked by short peptides. It forms the cell wall in bacteria surrounding the cytoplasmic membrane. The glycan strands are typically comprised of repeating N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) disaccharides. Each MurNAc is linked to a peptide of three to five amino acid residues. Disaccharide subunits are first assembled on the cytoplasmic side of the bacterial membrane on a polyisoprenoid anchor (lipid I and II). Polymerization of disaccharide subunits by transglycosylases and cross-linking of glycan strands by transpeptidases occur on the other side of the membrane. Bacterial cell wall biosynthesis inhibitors form a major class of antibiotics.","Metabolism; Glycan biosynthesis and metabolism"
"map00552",nothing,nothing,"Metabolism; Glycan biosynthesis and metabolism"
"map00561",nothing,nothing,"Metabolism; Lipid metabolism"
"map00562",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00563","Glycosylphosphatidylinositol (GPI)-anchor biosynthesis","Cell surface proteins can be attached to the cell membrane via the glycolipid structure called glycosylphosphatidylinositol (GPI) anchor. Hundreds of GPI-anchored proteins have been identified in many eukaryotes ranging from protozoa and fungi to mammals. All protein-linked GPI anchors share a common core structure, characterized by the substructure Man (a1-4) GlcN (a1-6) myo-inositol-1P-lipid. Biosynthesis of GPI anchors proceeds in three stages: (i) preassembly of a GPI precursor in the ER membrane, (ii) attachment of the GPI to the C-terminus of a newly synthesized protein in the lumen of the ER, and (iii) lipid remodeling and/or carbohydrate side-chain modifications in the ER and the Golgi. Defects of GPI anchor biosynthesis gene result in a genetic disorder, paroxysmal nocturnal hemoglobinuria.","Metabolism; Glycan biosynthesis and metabolism"
"map00564",nothing,nothing,"Metabolism; Lipid metabolism"
"map00565",nothing,nothing,"Metabolism; Lipid metabolism"
"map00571","Lipoarabinomannan (LAM) biosynthesis","Lipoarabinomannan (LAM), as well as structurally related lipomannan (LM) and phosphatidylinositol mannosides (PIMs), are major glycolipids found on the mycobacterial cell wall. LAM is synthesized from phosphatidylinositol (PI) and in a biochemical pathway of PI => PIMs => LM =>LAM. Structually, LAM and LM are an extension of PIMs containing an alpha1,6-linked mannan core with alpha1,2-monomannose side chains. The mannan core of LAM is in turn arabinosylated by a linear alpha1,5-linked Araf backbone, punctutated by alpha1,3-linked branching. LAM can be substituted by several capping motifs, which determine the ability of LAM to modulate the immune response through the interaction with different receptors containing C-type lectins (map04625). It has been shown that the immunomodulatory properties of LAM and related glycolipids contribute to the survival of Mycobacteriaum tuberculosis, the causative agent of tuberculosis (map05152).","Metabolism; Glycan biosynthesis and metabolism"
"map00572","Arabinogalactan biosynthesis - Mycobacterium","Just like lipoarabinomannan (map00571), arabinogalactan (AG) is a major heteropolysaccharide found on the mycobacterium cell wall. AG consists of a linear galactan chain of galactofuranosyl (Galf) residues covalently connected to peptidoglycan (PG), with branches of three similar arabinan chains comprising arabinofuranosyl (Araf) residues. The non-reducing ends of arabinans are often covalently attached to the long fatty acids of mycolic acids. Thus, the covalently linked network of PG and mycolylated AG, termed the mycolyl-arabinogalactan-peptidoglycan (mAGP) complex, forms an exceptionally robust cell wall and provides a permeability barrier to antibiotics.","Metabolism; Glycan biosynthesis and metabolism"
"map00590",nothing,nothing,"Metabolism; Lipid metabolism"
"map00591",nothing,nothing,"Metabolism; Lipid metabolism"
"map00592",nothing,nothing,"Metabolism; Lipid metabolism"
"map00600",nothing,nothing,"Metabolism; Lipid metabolism"
"map00601",nothing,nothing,"Metabolism; Glycan biosynthesis and metabolism"
"map00603",nothing,nothing,"Metabolism; Glycan biosynthesis and metabolism"
"map00604",nothing,nothing,"Metabolism; Glycan biosynthesis and metabolism"
"map00620",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00621","Dioxin degradation","Dioxins and dioxin-like compounds, including PCDDs, PCDFs and PCBs, are persistent organic pollutants (POPs) that are resistant to environmental degradation. However, POPs can be degraded by certain microorganisms with acquisition of a novel set of enzymes, such as biphenyl degradation by Paraburkholderia xenovorans LB400 involving four novel enzymes encoded in operon-like structures [MD:M00543]. DDT, another POP, and carbazol are also known to be degraded in similar pathways.","Metabolism; Xenobiotics biodegradation and metabolism"
"map00622",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00623",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00624",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00625",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00626",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00627",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00630",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00633",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00640",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00642",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00643",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00650",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00660",nothing,nothing,"Metabolism; Carbohydrate metabolism"
"map00670",nothing,nothing,"Metabolism; Metabolism of cofactors and vitamins"
"map00680","Methane metabolism","Methane is metabolized principally by methanotrophs and methanogens in the global carbon cycle. Methanotrophs consume methane as the only source of carbon, while methanogens produce methane as a metabolic byproduct. Methylotrophs, which are microorganisms that can obtain energy for growth by oxidizing one-carbon compounds, such as methanol and methane, are situated between methanotrophs and methanogens. Methanogens can obtain energy for growth by converting a limited number of substrates to methane under anaerobic conditions. Three types of methanogenic pathways are known: CO2 to methane [MD:M00567], methanol to methane [MD:M00356], and acetate to methane [MD:M00357]. Methanogens use 2-mercaptoethanesulfonate (CoM; coenzyme M) as the terminal methyl carrier in methanogenesis and have four enzymes for CoM biosynthesis [MD:M00358]. Coenzyme B-Coenzyme M heterodisulfide reductase (Hdr), requiring for the final reaction steps of methanogenic pathway, is divided into two types: cytoplasmic HdrABC in most methanogens and membrane-bound HdrED in Methanosarcina species. In methanotrophs and methyltrophs methane is oxidized to form formaldehyde, which is at the diverging point for further oxidation to CO2 for energy source and assimilation for biosynthesis. There are three pathways that convert formaldehyde to C2 or C3 compounds: serine pathway [MD:M00346], ribulose monophosphate pathway [MD:M00345], and xylulose monophosphate pathway [MD:M00344]. The first two pathways are found in prokaryotes and the third is found in yeast. As a special case of methylotrophs, various amines can be used as carbon sources in trimethylamine metabolism [MD:M00563].","Metabolism; Energy metabolism"
"map00710",nothing,nothing,"Metabolism; Energy metabolism"
"map00720","Carbon fixation pathways in prokaryotes","Carbon fixation is an important pathway for autotrophs living in various environments. Plants and cyanobacteria fix CO2 as organic compounds using solar energy mainly by the reductive pentose phosphate cycle (also called Calvin cycle, Calvin-Benson cycle, or Calvin-Benson-Bassham cycle) [MD:M00165]. There are, at least, five additional carbon fixation pathways known to exist in autotrophic bacteria and archaea, which differ in reducing compounds, energy source, and oxygen sensitivity of enzymes. (i) The reductive citric acid cycle (Arnon-Buchanan cycle) [MD:M00173] is found in microaerophiles and anaerobes, such as green sulfur bacteria. In one complete turn of this cycle, four molecules of CO2 are fixed by the enzymes that are sensitive to oxygen, resulting in the production of one molecule of oxaloacetate, which is itself an intermediate of the cycle. (ii) The reductive acetyl-CoA pathway (Wood-Ljungdahl pathway) [MD:M00377] is found in strictly anaerobic bacteria and archaea (Proteobacteria, Planctomycetes, Spirochaetes, and Euryarchaeota), some of which are methane-forming. A bifunctional enzyme, carbon monoxide dehydrogenase/acetyl-CoA synthase, catalyzes the reactions from CO2 to CO and from CO2 to a methyl group, and then to generate acetyl-CoA. (iii) The 3-hydroxypropionate bicycle [MD:M00376] is found in some green non-sulphur bacteria of the family Chloroflexaceae. In one complete turn of this bicycle, three molecules of bicarbonate are converted into one molecule of pyruvate. In addition, this bicycle provides the secondary benefit of useful intermediates for biosynthesis: acetyl-CoA, glyoxylate, and succinyl-CoA. (iv) The hydroxypropionate-hydroxybutyrate cycle [MD:M00375] is found in aerobic Crenarchaeota, Acidianus, Metallosphaera, and Sulfolobales. Some of the intermediates and the carboxylation reactions are the same as in the 3-hydroxypropionate bicycle. One complete turn of this cycle generates two molecules of acetyl-CoA, one of which is reutilized in the the cycle and the other is removed for cell material biosynthesis. (v) The dicarboxylate-hydroxybutyrate cycle [MD:M00374] was named after its intermediates: succinate (a kind of dicarboxylate) and hydroxybutyrate. This cycle has been found only in Ignicoccus hospitals, a strictly anaerobic hyperthermophilic archaea. Recent genome study suggests that this cycle may exist in Desulfurococcales (to which Ignicoccus belongs) and Thermoproteales (a taxon close to the origin of archaea). The first half of the cycle, from acetyl-CoA to succinate-CoA, corresponds to the reductive citric acid cycle and the latter half of the cycle, from succinate-CoA to two molecules of acetyl-CoA, corresponds to the hydroxypropionate-hydroxybutyrate cycle.","Metabolism; Energy metabolism"
"map00730",nothing,nothing,"Metabolism; Metabolism of cofactors and vitamins"
"map00740",nothing,nothing,"Metabolism; Metabolism of cofactors and vitamins"
"map00750",nothing,nothing,"Metabolism; Metabolism of cofactors and vitamins"
"map00760",nothing,nothing,"Metabolism; Metabolism of cofactors and vitamins"
"map00770",nothing,nothing,"Metabolism; Metabolism of cofactors and vitamins"
"map00780","Biotin metabolism","Biotin (vitamin H or vitamin B7) is the essential cofactor of biotin-dependent carboxylases, such as pyruvate carboxylase and acetyl-CoA carboxylase. Mammals cannot synthesize biotin, while in bacteria, fungi, and plants it is synthesized from pimelate thioester through different pathways. In E. coli and many organisms, pimelate thioester is derived from malonyl-ACP. The pathway starts with the methylation to malonyl-ACP methyl ester, followed by the fatty acid chain elongation cycle to form pimeloyl-ACP methyl ester, which is then demethylated to form pimeloyl-ACP [MD:M00572]. Pimeloyl-ACP is converted to biotin through the final four steps in the biotin bicyclic ring assembly, which are conserved among biotin-producing organisms [MD:M00123]. In B. subtilis, biotin is derived from pimeloyl-ACP formed by oxidative cleavage of long-chain acyl-ACPs [MD:M00573]. Some bacteria synthesize biotin from pimeloyl-CoA derived from pimelate [MD:M00577]. Biotin is covalently attached to biotin-dependent carboxylase by biotin protein ligase, also known as holocarboxylase synthase in mammals, to form an active holocarboxylase. After degradation of the biotinylated carboxylase into biocytin, it is further degraded by biotinidase to release free biotin, which is recycled in holocarboxylase synthesis. Biotin is catabolized by beta-oxidation of the valeric acid side chain or oxidation of sulfur in the heterocyclic ring.","Metabolism; Metabolism of cofactors and vitamins"
"map00785",nothing,nothing,"Metabolism; Metabolism of cofactors and vitamins"
"map00790",nothing,nothing,"Metabolism; Metabolism of cofactors and vitamins"
"map00791",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00830",nothing,nothing,"Metabolism; Metabolism of cofactors and vitamins"
"map00860","Porphyrin metabolism","Porphyrins are a group of chemical compounds with the backbone ring structure consisting of four linked pyrrole units. Metal complexes of porphyrins, as well as those of corrinoids with the one-carbon shorter ring structure, play important biological roles. They include iron-containing heme, magnesium-containing chlorophyll, nickel-containing coenzyme F430 and cobalt-containing cobamide (such as vitamin B12 coenzyme) as shown in this map.","Metabolism; Metabolism of cofactors and vitamins"
"map00900","Terpenoid backbone biosynthesis","Terpenoids, also known as isoprenoids, are a large class of natural products consisting of isoprene (C5) units. There are two biosynthetic pathways, the mevalonate pathway [MD:M00095] and the non-mevalonate pathway or the MEP/DOXP pathway [MD:M00096], for the terpenoid building blocks: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). The action of prenyltransferases then generates higher-order building blocks: geranyl diphosphate (GPP), farsenyl diphosphate (FPP), and geranylgeranyl diphosphate (GGPP), which are the precursors of monoterpenoids (C10), sesquiterpenoids (C15), and diterpenoids (C20), respectively. Condensation of these building blocks gives rise to the precursors of sterols (C30) and carotenoids (C40). The MEP/DOXP pathway is absent in higher animals and fungi, but in green plants the MEP/DOXP and mevalonate pathways co-exist in separate cellular compartments. The MEP/DOXP pathway, operating in the plastids, is responsible for the formation of essential oil monoterpenes and linalyl acetate, some sesquiterpenes, diterpenes, and carotenoids and phytol. The mevalonate pathway, operating in the cytosol, gives rise to triterpenes, sterols, and most sesquiterpenes.","Metabolism; Metabolism of terpenoids and polyketides"
"map00901",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00902","Monoterpenoid biosynthesis","Monoterpenoids (C10 terpenoids) are a group of terpenoids consisting of two isoprene units. They are derived from geranyl diphosphate (GPP). Most monoterpenoids are volatile oils with highly distinctive aromas and flavors, such as essential oils, turpentine, and oleoresins of coniferous plants. This map shows some examples. The monoterpene ketone l-menthone is specifically converted to l-menthol and d-neomenthol in mature peppermint leaves. The iridoids constitute a family of highly oxygenated monoterpenes, mixtures of which are present in many medicinal plants, such as valerian. They are derived from geraniol or nerol via oxidation of a terminal methyl group. The cyclopentane ring of loganin can itself be cleaved in a further P450-dependent step, leading to secologanin, which provides the carbon skeleton for many powerfully bioactive secondary metabolites of indole alkaloids.","Metabolism; Metabolism of terpenoids and polyketides"
"map00903",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map00904",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map00905","Brassinosteroid biosynthesis","Brassinosteroids are a group of plant steroid hormones that regulate growth and development. More than fifty naturally occurring brassinosteroids have been identified in a wide range of plant species. The most abundant and widely occurring brassinosteroids are C28 steroids, and among them brassinolide (BL) is the most biologically active. Plants have multiple pathways for biosynthesis of BL, which are derived from the steroid biosynthetic pathway. Two pathways from campestanol to castasterone (CS), C6 oxidation and the late-C6 oxidation pathways, operate in many plants. Another branching pathway, the early-C22 oxidation pathway, was demonstrated using a brassinosteroid-deficient mutant of Arabidopsis thaliana. Recently, a new shortcut pathway from campesterol to 6-deoxotyphasterol was demonstrated by a functional analysis of cytochrome P450 monooxygenases responsible for brassinosteroid biosynthesis. Thus, at least four pathways are involved in the biosynthesis of CS, and CS is further metabolized to BL by lactonization of the B ring.","Metabolism; Metabolism of terpenoids and polyketides"
"map00906",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map00908","Zeatin biosynthesis","Zeatin is a member of the cytokinin family, a class of phytohormones involved in various processes of growth and development in plants. Most abundant cytokinins are adenine-type, where the N6 position of adenine is substituted with an isoprenoid, such as in zeatin, or an aromatic side chain, such as in kinetin. Zeatin can be synthesized in two different pathways: the tRNA pathway and the AMP pathway. In the tRNA pathway zeatin is a recycled product of isopentenylated tRNAs. In the AMP pathway zeatin is synthesized from an isopentenyl donor, dimethylallyl diphosphate (DMAPP), and AMP, ADP, or ATP by isopentenyltransferases. After synthesis cytokinins can be glucosylated.","Metabolism; Metabolism of terpenoids and polyketides"
"map00909","Sesquiterpenoid and triterpenoid biosynthesis","Sesquiterpenoids (C15 terpenoids) are a group of terpenoids consisting of three isoprene units. They are derive from farnesyl diphosphate (FPP) and can be cyclized to produce various skeletal structures. Sesquiterpenoid biosynthesis begins with the loss of diphosphate from FPP under the action of sesquiterpene synthesis enzymes, generating an allylic cation that is highly susceptible to intramolecular attacks. Cyclization of the farnesyl cation may take place onto either of the remaining double bonds with the result that 6-, 10-, or 11-membered rings may be formed. Many sesquiterpenoids have been isolated from plants, fungi, marine organisms, and Streptomyces species. This map shows a few examples of acyclic and cyclic sesquiterpenoids.","Metabolism; Metabolism of terpenoids and polyketides"
"map00910","Nitrogen metabolism","The biological process of the nitrogen cycle is a complex interplay among many microorganisms catalyzing different reactions, where nitrogen is found in various oxidation states ranging from +5 in nitrate to -3 in ammonia. The core nitrogen cycle involves four reduction pathways and two oxidation pathways. Nitrogen fixation [MD:M00175] is the process of reducing atmospheric molecular nitrogen to ammonia, a biologically useful reduced form incorporated into amino acids and other vital compounds. The ability of fixing atmospheric nitrogen by the nitrogenase enzyme complex is present in restricted prokaryotes (diazotrophs). The other reduction pathways are assimilatory nitrate reduction [MD:M00531] and dissimilatory nitrate reduction [MD:M00530] both for conversion to ammonia, and denitrification [MD:M00529]. Denitrification is a respiration in which nitrate or nitrite is reduced as a terminal electron acceptor under low oxygen or anoxic conditions, producing gaseous nitrogen compounds (N2, NO and N2O) to the atmosphere. The two oxidation pathways are nitrification [MD:M00528] and anaerobic ammonium oxidation (anammox). Nitrification is the oxidation of ammonia (NH3) with oxygen into nitrite followed by the oxidation of nitrite into nitrate. The first step is performed by ammonia-oxidizing microorganisms (e.g., Nitrosomonas and Nitrosococcus) and the second step by nitrite-oxidizing microorganisms (e.g., Nitrobacter). Anammox is a biochemical process of oxidizing ammonium (NH4+) into dinitrogen gas (N2) using nitrite as an electron acceptor. It occurs in the anammoxosome, a membrane bound compartment inside the cytoplasm, of anammox bacteria (e.g., Planctomycetes).","Metabolism; Energy metabolism"
"map00920","Sulfur metabolism","Sulfur is an essential element for life and the metabolism of organic sulfur compounds plays an important role in the global sulfur cycle. Sulfur occurs in various oxidation states ranging from +6 in sulfate to -2 in sulfide (H2S). Sulfate reduction can occur in both an energy consuming assimilatory pathway and an energy producing dissimilatory pathway. The assimilatory pathway, which is found in a wide range of organisms, produces reduced sulfur compounds for the biosynthesis of S-containing amino acids and does not lead to direct excretion of sulfide. In the dissimilatory pathway, which is restricted to obligatory anaerobic bacterial and archaeal lineages, sulfate (or sulfur) is the terminal electron acceptor of the respiratory chain producing large quantities of inorganic sulfide. Both pathways start from the activation of sulfate by reaction with ATP to form adenylyl sulfate (APS). In the assimilatory pathway [MD:M00176] APS is converted to 3'-phosphoadenylyl sulfate (PAPS) and then reduced to sulfite, and sulfite is further reduced to sulfide by the assimilatory sulfite reductase. In the dissimilatory pathway [MD:M00596] APS is directly reduced to sulfite, and sulfite is further reduced to sulfide by the dissimilatory sulfite reductase. The capacity for oxidation of sulfur is quite widespread among bacteria and archaea, comprising phototrophs and chemolithoautotrophs. The SOX (sulfur-oxidation) system [MD:M00595] is a well-known sulfur oxidation pathway and is found in both photosynthetic and non-photosynthetic sulfur-oxidizing bacteria. Green sulfur bacteria and purple sulfur bacteria carry out anoxygenic photosynthesis with reduced sulfur compounds such as sulfide and elemental sulfur, as well as thiosulfate (in some species with the SOX system), as the electron donor for photoautotrophic growth. In some chemolithoautotrophic sulfur oxidizers (such as Thiobacillus denitrificans), it has been suggested that dissimilatory sulfur reduction enzymes operate in the reverse direction, forming a sulfur oxidation pathway from sulfite to APS and then to sulfate.","Metabolism; Energy metabolism"
"map00930",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00940","Phenylpropanoid biosynthesis","Phenylpropanoids are a group of plant secondary metabolites derived from phenylalanine and having a wide variety of functions both as structural and signaling molecules. Phenylalanine is first converted to cinnamic acid by deamination. It is followed by hydroxylation and frequent methylation to generate coumaric acid and other acids with a phenylpropane (C6-C3) unit. Reduction of the CoA-activated carboxyl groups of these acids results in the corresponding aldehydes and alcohols. The alcohols are called monolignols, the starting compounds for biosynthesis of lignin.","Metabolism; Biosynthesis of other secondary metabolites"
"map00941","Flavonoid biosynthesis","Flavonoids are a major class of plant secondary metabolites that serves a multitude of functions including pigments and antioxidant activity. Flavonoids are synthesized from phenylpropanoid derivatives by condensation with malonyl-CoA. For example, condensation of p-coumaroyl-CoA (C6-C3) with three malonyl-CoA (C3) molecules results in naringenin chalcone with a diphenylpropane (C6-C3-C6) unit, which is converted to naringenin with the flavone (2-phenylchromen-4-one) backbone by conjugate ring closure. These and further modifications yield a variety of structural forms including chalcones, flavanones, dihyroflavonols, and flavans, anthocyanins, flavones and flavonols, and isoflavonoids.","Metabolism; Biosynthesis of other secondary metabolites"
"map00942","Anthocyanin biosynthesis","Anthocyanidins (aglycones) and anthocyanins (glycosides) are common plant pigments and belong to a structural subclass of flavonoids characterized by a 2-phenylbenzopyrylium unit. They are derived along the flavonoid modification pathways and further separated into three types, pelargonidin, cyanidin, and delphinidin, due to the different number of hydroxyl groups in the phenyl group.","Metabolism; Biosynthesis of other secondary metabolites"
"map00943","Isoflavonoid biosynthesis","Isoflavonoids are biologically active compounds, such as phytoestrogens, produced by pea family plants. While flavonoids (in the narrow sense) have the 2-phenylchromen-4-one backbone, isoflavonoids have the 3-phenylchromen-4-one backbone with no hydroxyl group substitution at position 2. Isoflavonoids are derived from the flavonoid biosynthesis pathway via liquiritigenin or naringenin.","Metabolism; Biosynthesis of other secondary metabolites"
"map00944","Flavone and flavonol biosynthesis","Flavones and flavonols (3-hydroxyflavones) are common flavonoids in the plant kingdom. They are synthesized as part of the flavonoid modification pathways in aglycone and glucoside forms.","Metabolism; Biosynthesis of other secondary metabolites"
"map00945","Stilbenoid, diarylheptanoid and gingerol biosynthesis","Stilbenoids are a group of phenolic compounds, biosynthetically interrelated through their common origin from a C6-C2-C6 intermediate, such as resveratol found in grapes. Stilbenoids can also exist as glycosides (e.g., piceid). Combretastatins are potentially useful stilbenoid natural products with known antitumor activity. Diarylheptanoid is a compound group having phenyl rings at 1,7 positions of n-heptane (C6-C7-C6), such as curcumin found in the ginger family. [6]-Gingerol is a major active component of ginger and has diverse pharmacologic effects.","Metabolism; Biosynthesis of other secondary metabolites"
"map00950","Isoquinoline alkaloid biosynthesis","Isoquinoline alkaloids are tyrosine-derived plant alkaloids with an isoquinoline skeleton. Among them benzylisoquinoline alkaloids form an important group with potent pharmacological activity, including analgesic compounds of morphine and codeine, and anti-infective agents of berberine, palmatine, and magnoflorine. Biosynthesis of isoquinoline alkaloids proceeds via decarboxylation of tyrosine or DOPA to yield dopamine, which together with 4-hydroxyphenylacetaldehyde, an aldehyde derived from tyrosine, is converted to reticuline, an important precursor of various benzylisoquinoline alkaloids.","Metabolism; Biosynthesis of other secondary metabolites"
"map00960",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00965","Betalain biosynthesis","Betalains are water-soluble nitrogen-containing pigments that are present in plants belonging to the order Caryophyllales (such as cactus and amaranth families) and in higher fungi. They contain betalamic acid as the chromophore and are classified into two types: betacyanins and betaxanthins. Betacyanins contain a cyclo-DOPA residue and exhibit red/violet coloration, while betaxanthins contain different amino acids or amino side chains and exhibit a yellow/orange coloration. The condensation of betalamic acid with amino acids (including cyclo-DOPA or amines) in plants is a spontaneous reaction, not an enzyme-catalyzed reaction.","Metabolism; Biosynthesis of other secondary metabolites"
"map00966","Glucosinolate biosynthesis","Glucosinolates are biologically active secondary metabolites found in Brassicaceae (mustard family) and related families.These compounds are genetically variable within plant species and used as natural pesticides, such as against insect herbivores. All glucosinolates share a common structure consisting of a beta-thioglucose moiety, a sulfonated oxime moiety, and a variable aglycone side chain derived from an alpha-amino acid. Genes encoding glucosinolate biosynthetic enzymes have been identified in Arabidopsis thaliana by genetic polymorphisms and loss-of-function mutations. This map shows examples of side chain elongation in methionine-derived glucosinolates and the core pathway for biosynthesis of glucosinolates from amino acids.","Metabolism; Biosynthesis of other secondary metabolites"
"map00970",nothing,nothing,"Genetic Information Processing; Translation"
"map00980",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00981",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map00982",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00983",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00984",nothing,nothing,"Metabolism; Xenobiotics biodegradation and metabolism"
"map00996",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00997",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00998",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map00999",nothing,nothing,"Metabolism; Biosynthesis of other secondary metabolites"
"map01010",nothing,nothing,nothing
"map01040",nothing,nothing,"Metabolism; Lipid metabolism"
"map01051",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map01052",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map01053",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map01054",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map01055",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map01056",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map01057",nothing,nothing,"Metabolism; Metabolism of terpenoids and polyketides"
"map01059","Biosynthesis of enediyne antibiotics","Enediyne natural products are potent antitumor antibiotics produced by a variety of Actinomycetes. Enediyne has a unique structure consisting of three building blocks: aromatic, sugar and enediyne core. The enediyne core contains two acetylenic groups conjugated to a double bond in a 9- or 10-membered ring, and it is synthesized by an iterative type I polyketide synthase and other tailoring proteins [MD:M00824 M00825]. The 10-membered enediyne such as calicheamicin also contains an allylic trisulfide group, which acts as a trigger for diradical formation. This diagram shows the biosynthesis of C-1027, maduropeptin, neocarzinostatin, kedarcidin and calicheamicin. Some aromatic moieties are synthesized via iterative type I polyketide synthases, and others are derived from chorismate and aromatic amino acids such as tyrosine and azatyrosine [MD:M00829 M00830 M00831 M00834 M00826 M00827 M00828 M00832]. Finally, the aromatic and sugar building blocks are attached to the enediyne core by acyltransferases, condensation enzymes and glucosyltransferases [MD:M00833].","Metabolism; Metabolism of terpenoids and polyketides"
"map01060",nothing,nothing,nothing
"map01061",nothing,nothing,nothing
"map01062",nothing,nothing,nothing
"map01063",nothing,nothing,nothing
"map01064",nothing,nothing,nothing
"map01065",nothing,nothing,nothing
"map01066",nothing,nothing,nothing
"map01070",nothing,nothing,nothing
"map01100",nothing,nothing,nothing
"map01110",nothing,nothing,nothing
"map01120",nothing,nothing,nothing
"map01200","Carbon metabolism",nothing,nothing
"map01210","2-Oxocarboxylic acid metabolism",nothing,nothing
"map01212",nothing,nothing,nothing
"map01220","Degradation of aromatic compounds",nothing,nothing
"map01230","Biosynthesis of amino acids",nothing,nothing
"map01232",nothing,nothing,nothing
"map01240",nothing,nothing,nothing
"map01250",nothing,nothing,nothing
"map01501","beta-Lactam resistance","The beta-lactam antibiotics are the most widely used group of antibiotics, which exert their effect by interfering with the structural crosslinking of peptidoglycans in bacterial cell walls. Over the past decades, a rapid increase in the number of beta-lactam-resistant clinical isolates is observed. Bacterial resistance to beta-lactam antibiotics can be achieved by any of the following strategies: producing inactivating enzymes called beta-lactamases, altering the beta-lactam targets of penicillin-binding proteins (PBPs), reducing transport of beta-lactams into the periplasmic space via changes in porins, and using the mechanisms for exclusion of beta-lactams by way of efflux pumps. Resistance may result from intrinsic properties of organisms, through gene mutations, and through plasmid- and transposon-specified genes.","Human Diseases; Drug resistance: antimicrobial"
"map01502","Vancomycin resistance","Vancomycin (VCM) is a glycopeptide antibiotic agent that inhibits the synthesis of peptidolgycan in the production of bacterial cell walls. It is active in most Gram-positive bacteria and acts by binding to the D-Ala-D-Ala C-terminus of pentapeptide, thus blocking the addition of subunits to the peptidoglycan backbone. The resistance to VCM was first described among enterococci in the late 1980s in Europe. Subsequently, vancomycin-resistant enteococci (VRE) have been observed in many countries. The genes encoding resistance are carried on plasmids that can tranfer themselves from cell to cell and on tranponsons that can jump from plamids to the chromosome. Up to now, at least six resistance operon types are characterized, namely VanA, VanB, VanC, VanD, VanE and VanG. The VanA and VanB operons are detected on plasmids or in the chromosome, whereas the rest are found in the chromosome. In addition, Streptomyces, which is non-pathogenic, non-glycopeptide-producing actinomycete, also shows high-level resistance to VCM. In Streptomyces, novel genes (vanK and vanJ) are characterized with no counterparts found in the resistance clusters of pathogenic bacteria.
            The expression of vancomycin resistance pathway is induced by the VanS-VanR two component system, and D-Ala-D-Lac or D-Ala-D-Ser dipsipeptides are formed in place of D-Ala-D-Ala dipeptide. Thus, VCM cannot bind to pentadepsipeptide[D-Lac] or pentadepsipeptide[D-Ser]. The D-Ala-D-Lac variation shows high levels of resistance to VCM, especially in VanA type, wheras the D-Ala-D-Ser variation shows low levels of resistance. The modified pepidoglycan can interact with cross-linking enzymes (PBPs), thus cell wall is successfully formed.","Human Diseases; Drug resistance: antimicrobial"
"map01503","Cationic antimicrobial peptide (CAMP) resistance","Cationic antimicrobial peptides (CAMPs) play an important role in host defense against microbial infection and are key components of the innate immune response. These are found among all classes of life ranging from prokaryotes to humans. In addition to the natural peptides, thousands of synthetic variants have been produced. CAMPs weaken the integrity of the bacterial inner and outer membranes and subsequently kill bacterial cells. On the other hand, bacteria have developed a number of mechanisms against CAMPs. These resistance mechanisms include decreased affinity to CAMPs by substitution of anionic cell surface constituents with cationic molecules; biosynthesis and crosslinking of cell envelope components; external trapping mechanisms that bind or neutralize the CAMPs by direct secretion of proteins, or the release of CAMPs binding molecules from the host cell surface; membrane efflux pumps; and production of peptidases.","Human Diseases; Drug resistance: antimicrobial"
"map01521","EGFR tyrosine kinase inhibitor resistance","EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. EGFR also serves as a stimulus for cancer growth. EGFR gene mutations and protein overexpression, both of which activate down- stream pathways, are associated with cancers, especially lung cancer. Several tyrosine kinase inhibitor (TKI) therapies against EGFR are currently administered and are initially effective in cancer patients who have EGFR mutations or aberrant activation of EGFR. However, the development of TKI resistance is common and results in the recurrence of tumors. Studies over the last decade have identified mechanisms that drive resistance to EGFR TKI treatment. Most outstanding mechanisms are: the secondary EGFR mutation (T790M), activation of alternative pathways (c-Met, HGF, AXL), aberrance of the downstream pathways (K-RAS mutations, loss of PTEN), impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism), histologic transformation, etc.","Human Diseases; Drug resistance: antineoplastic"
"map01522","Endocrine resistance","Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. The most commonly used endocrine therapy agents are selective estrogen receptor modulators (SERMs, e.g. tamoxifen), estrogen synthesis inhibitors (e.g. aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane), and selective estrogen receptor down-regulators (SERDs, e.g. fulvestrant). However, resistance to these agents has become a major clinical obstacle. Mechanisms of endocrine resistance include loss of ER-alpha expression, altered expression of coactivators or coregulators that play a critical role in ER-mediated gene transcription, ligand-independent growth factor signaling cascades that activate kinases and ER-phosphorylation, altered availability of active tamoxifen metabolites regulated by drug-metabolizing enzymes, such as CYP2D6, and deregulation of the cell cycle and apoptotic machinery.","Human Diseases; Drug resistance: antineoplastic"
"map01523","Antifolate resistance","Since the 1940s, antifolates have played a pivotal role in drug treatment of malignant, microbial, parasitic and chronic inflammatory diseases. The molecular basis of the anti-proliferative activity of antifolates relies on inhibition of key enzymes in folate metabolism, which results in disruption of purine and thymidylate biosynthesis, inhibition of DNA replication and cell death. The anti-inflammatory properties of antifolate have been most strongly related to its ability to block the release of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-alpha or interleukin (IL)-1beta. Cells may develop resistance to an antifolate drug by virtue of impaired drug transport into cells, augmented drug export, impaired activation of antifolates through polyglutamylation, augmented hydrolysis of antifolate polyglutamates, increased expression and mutation of target enzymes, and the augmentation of cellular tetrahydrofolate-cofactor pools in cells.","Human Diseases; Drug resistance: antineoplastic"
"map01524","Platinum drug resistance","Platinum-based drugs cisplatin, carboplatin and oxaliplatin are widely used in the therapy of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. The mechanism of action of Platinum-based drugs involves covalent binding to purine DNA bases, which primarily leads to cellular apoptosis. Their clinical success is, however, limited due to severe side effects and intrinsic or acquired resistance to the treatment. Platinum resistance could arise from decreased drug influx, increased drug efflux, intracellular detoxification by glutathione, etc., decreased binding (e.g., due to high intracellular pH), increased DNA repair, decreased mismatch repair, defective apoptosis, and altered oncogene expression.","Human Diseases; Drug resistance: antineoplastic"
"map02010","ABC transporters","The ATP-binding cassette (ABC) transporters form one of the largest known protein families, and are widespread in bacteria, archaea, and eukaryotes. They couple ATP hydrolysis to active transport of a wide variety of substrates such as ions, sugars, lipids, sterols, peptides, proteins, and drugs. The structure of a prokaryotic ABC transporter usually consists of three components; typically two integral membrane proteins each having six transmembrane segments, two peripheral proteins that bind and hydrolyze ATP, and a periplasmic (or lipoprotein) substrate-binding protein. Many of the genes for the three components form operons as in fact observed in many bacterial and archaeal genomes. On the other hand, in a typical eukaryotic ABC transporter, the membrane spanning protein and the ATP-binding protein are fused, forming a multi-domain protein with the membrane-spanning domain (MSD) and the nucleotide-binding domain (NBD).","Environmental Information Processing; Membrane transport"
"map02020","Two-component system","Two-component signal transduction systems enable bacteria to sense, respond, and adapt to changes in their environment or in their intracellular state. Each two-component system consists of a sensor protein-histidine kinase (HK) and a response regulator (RR). In the prototypical two-component pathway, the sensor HK phosphorylates its own conserved His residue in response to a signal(s) in the environment. Subsequently, the phosphoryl group of HK is transferred onto a specific Asp residue on the RR. The activated RR can then effect changes in cellular physiology, often by regulating gene expression. Two-component pathways thus often enable cells to sense and respond to stimuli by inducing changes in transcription.","Environmental Information Processing; Signal transduction"
"map02024","Quorum sensing","Quorum sensing (QS) is a regulatory system that allows bacteria to share information about cell density and adjust gene expression accordingly. All QS bacteria produce and release chemical signal molecules called autoinducers (AIs) that increase in concentration as a function of cell density. The most commonly studied AIs belong to one of the following three categories: acylated homoserine lactones, also referred to as AI-1, used by Gram-negative bacteria; peptide signals, used by Gram-positive bacteria; and AI-2, used by both Gram-negative and Gram-positive bacteria. QS can be divided into at least 4 steps: production of AIs by the bacterial cell; release of AIs, either actively or passively, into the surrounding environment; recognition of AIs by specific receptors; and leading to changes in gene regulation once they exceed a threshold concentration. The processes controlled by QS include virulence, competence, conjugation, antibiotic production, motility, sporulation, and biofilm formation.","Cellular Processes; Cellular community - prokaryotes"
"map02025","Biofilm formation - Pseudomonas aeruginosa","Surface colonization and subsequent biofilm formation and development provide numerous advantages to microorganisms. The main key actors relevant in the regulation of biofilm formation by Pseudomonas aeruginosa include cAMP/Vfr signaling, quorum sensing (QS) systems, Gac/Rsm pathway, and c-di-GMP signaling. cAMP/Vfr signaling regulates the transcription of hundreds of genes encoding diverse virulence factors, including the type 2 secretion system and type 3 secretion system and their associated toxins, type IV pili, and flagella. It is demonstrated that the accumulation of cAMP inhibits the attachment phase of biofilm formation. The QS systems are arranged hierarchically with the las system positively regulating both the rhl and PQS systems. These three QS systems are involved in the regulation of virulence factor production, biofilm maturation, and motility phenotypes. GacS/GacA two-component system is promoting the expression of two small regulatory RNAs, RsmY and RsmZ, which sequester the translational repressor RsmA. Titration of RsmA induces the production of sessile and biofilm determinants, whereas free RsmA leads to a planktonic and more virulent lifestyle. c-di-GMP is a ubiquitous bacterial second messenger. Synthesis and degradation of c-di-GMP is facilitated by diguanylate cyclases (DGC) and phosphodiesterases (PDE). High intracellular levels of c-di-GMP evoke the processes leading to the production of biofilm matrix, while a decrease in its level causes an increase in cell motility and transition into the planktonic forms of growth.","Cellular Processes; Cellular community - prokaryotes"
"map02026","Biofilm formation - Escherichia coli","Bacteria inhabiting a biofilm are protected from physical stress, antimicrobials, and the host immune system, and thereby cause severe medical, environmental, and technical problems. Biofilm formation in Escherichia coli is regulated by two inversely controlled transcriptional feedforward cascades, the FlhDC/FliA cascade and the sigmaS/MlrA/CsgD cascade, which are active in post-exponentially growing and in stationary phase cells, respectively. Their final outputs, flagella production or the synthesis of the biofilm matrix components curli and cellulose, are mutually exclusive due to complementary sigma factor requirements, the abundant DNA-binding regulator FliZ, and opposite regulation by c-di-GMP. The RNA-binding protein CsrA, a central component of the global regulatory system, inhibits synthesis of the poly-N-acetyl-glucosamine (PGA) exopolysaccharide and glycogen and stimulates the expression of the flagellar master regulator FlhDC. CsrA activity is counteracted by two sRNAs, CsrB and CsrC. The lower figure shows that FlhDC, sigmaS, and CsgD, the transcription factors that control large regulons involved in flagellar and biofilm formation, serve as regulatory hubs for multiple environmental signal integration with a series of sRNAs providing distinct inputs.","Cellular Processes; Cellular community - prokaryotes"
"map02030","Bacterial chemotaxis","Chemotaxis is the process by which cells sense chemical gradients in their environment and then move towards more favorable conditions. In chemotaxis, events at the receptors control autophosphorylation of the CheA histidine kinase, and the phosphohistidine is the substrate for the response regulator CheY, which catalyzes the transfer of the phosphoryl group to a conserved aspartate. The resulting CheY-P can interact with the switch mechanism in the motor. This interaction causes a change in behavior, such as in direction or speed of rotation of flagella.","Cellular Processes; Cell motility"
"map02040",nothing,nothing,"Cellular Processes; Cell motility"
"map02060","Phosphotransferase system (PTS)","The phosphoenolpyruvate (PEP)-dependent phosphotransferase system (PTS) is a major mechanism used by bacteria for uptake of carbohydrates, particularly hexoses, hexitols, and disaccharides, where the source of energy is from PEP. The PTS consists of two general components, enzyme I (EI) and histidine phosphocarrier protein (HPr), and of membrane-bound sugar specific permeases (enzymes II). Each enzyme II (EII) complex consists of one or two hydrophobic integral membrane domains (domains C and D) and two hydrophilic domains (domains A and B). EII complexes may exist as distinct proteins or as a single multidomain protein. The PTS catalyzes the uptake of carbohydrates and their conversion into their respective phosphoesters during transport. There are four successive phosphoryl transfers in the PTS. Initial autophosphorylation of EI, using PEP as a substrate, is followed by transfer of the phosphoryl group from EI to HPr. EIIA catalyzes the self-phosphoryl transfer from HPr after which the phosphoryl group is transferred to histidine or cysteine residues of EIIB. The sugar is transported through the membrane-bound EIIC and is phosphorylated by the appropriate sugar-specific EIIB.","Environmental Information Processing; Membrane transport"
"map03008","Ribosome biogenesis in eukaryotes","Ribosomes are the cellular factories responsible for making proteins. In eukaryotes, ribosome biogenesis involves the production and correct assembly of four rRNAs and about 80 ribosomal proteins. It requires hundreds of factors not present in the mature particle. In the absence of these proteins, ribosome biogenesis is stalled and cell growth is terminated even under optimal growth conditions. The primary pre-rRNA transcript is assembled into the 90S pre-ribosome, which contains both 40S and 60S assembly factors. Within this complex, the pre-rRNA is cleaved. pre-60S ribosomes are subjected to several sequential processing steps in the nucleoplasm involving numerous assembly intermediates before it is exported to the cytoplasm and matured into the 60S ribosomal subunit. The pre-40S ribosome is matured to the small ribosomal subunit in the cytoplasm by cleavage.","Genetic Information Processing; Translation"
"map03010",nothing,nothing,"Genetic Information Processing; Translation"
"map03013","Nucleocytoplasmic transport","The exchange of molecules between the nucleus and cytoplasm is mediated through nuclear pore complexes (NPCs) embedded in the nuclear envelope. The NPC is composed of highly conserved, distinct structural modules: the inner pore ring, the cytoplasmic and nuclear rings as well as the cytoplasmic filaments and the nuclear basket. Nuclear transport receptors (e.g. importins and exportins) mediate translocation of cargos through the NPC. Cargo proteins harbouring a nuclear export signal (NES) bind to exportins and Ran-GTP to form an export complex in the nucleoplasm. Nuclear export of bulk mRNA is provided by the non-karyopherin transport proteins TAP-p15 in a Ran-GTP-independent manner. Several EJC factors are known to function in mRNA export.","Genetic Information Processing; Translation"
"map03015","mRNA surveillance pathway","The mRNA surveillance pathway is a quality control mechanism that detects and degrades abnormal mRNAs. These pathways include nonsense-mediated mRNA decay (NMD), nonstop mRNA decay (NSD), and no-go decay (NGD). NMD is a mechanism that eliminates mRNAs containing premature translation-termination codons (PTCs). In vertebrates, PTCs trigger efficient NMD when located upstream of an exon junction complex (EJC). Upf3, together with Upf1 and Upf2, may signal the presence of the PTC to the 5'end of the transcript, resulting in decapping and rapid exonucleolytic digestion of the mRNA. In the NSD pathway, which targets mRNAs lacking termination codons, the ribosome is believed to translate through the 3' untranslated region and stall at the end of the poly(A) tail. NSD involves an eRF3-like protein, Ski7p, which is hypothesized to bind the empty A site of the ribosome and recruit the exosome to degrade the mRNA from the 3' end. NGD targets mRNAs with stalls in translation elongation for endonucleolytic cleavage in a process involving the Dom34 and Hbs1 proteins.","Genetic Information Processing; Translation"
"map03018","RNA degradation","The correct processing, quality control and turnover of cellular RNA molecules are critical to many aspects in the expression of genetic information. In eukaryotes, two major pathways of mRNA decay exist and both pathways are initiated by poly(A) shortening of the mRNA. In the 5' to 3' pathway, this is followed by decapping which then permits the 5' to 3' exonucleolytic degradation of transcripts. In the 3' to 5' pathway, the exosome, a large multisubunit complex, plays a key role. The exosome exists in archaeal cells, too. In bacteria, endoribonuclease E, a key enzyme involved in RNA decay and processing, organizes a protein complex called degradosome. RNase E or R interacts with the phosphate-dependent exoribonuclease polynucleotide phosphorylase, DEAD-box helicases, and additional factors in the RNA-degrading complex.","Genetic Information Processing; Folding, sorting and degradation"
"map03020",nothing,nothing,"Genetic Information Processing; Transcription"
"map03022",nothing,nothing,"Genetic Information Processing; Transcription"
"map03030","DNA replication","A complex network of interacting proteins and enzymes is required for DNA replication. Generally, DNA replication follows a multistep enzymatic pathway. At the DNA replication fork, a DNA helicase (DnaB or MCM complex) precedes the DNA synthetic machinery and unwinds the duplex parental DNA in cooperation with the SSB or RPA. On the leading strand, replication occurs continuously in a 5 to 3 direction, whereas on the lagging strand, DNA replication occurs discontinuously by synthesis and joining of short Okazaki fragments. In prokaryotes, the leading strand replication apparatus consists of a DNA polymerase (pol III core), a sliding clamp (beta), and a clamp loader (gamma delta complex). The DNA primase (DnaG) is needed to form RNA primers. Normally, during replication of the lagging-strand DNA template, an RNA primer is removed either by an RNase H or by the 5 to 3 exonuclease activity of DNA pol I, and the DNA ligase joins the Okazaki fragments. In eukaryotes, three DNA polymerases (alpha, delta, and epsilon) have been identified. DNA primase forms a permanent complex with DNA polymerase alpha. PCNA and RFC function as a clamp and a clamp loader. FEN 1 and RNase H1 remove the RNA from the Okazaki fragments and DNA ligase I joins the DNA.","Genetic Information Processing; Replication and repair"
"map03040","Spliceosome","After transcription, eukaryotic mRNA precursors contain protein-coding exons and noncoding introns. In the following splicing, introns are excised and exons are joined by a macromolecular complex, the spliceosome. The standard spliceosome is made up of five small nuclear ribonucleoproteins (snRNPs), U1, U2, U4, U5, and U6 snRNPs, and several spliceosome-associated proteins (SAPs). Spliceosomes are not a simple stable complex, but a dynamic family of particles that assemble on the mRNA precursor and help fold it into a conformation that allows transesterification to proceed. Various spliceosome forms (e.g. A-, B- and C-complexes) have been identified.","Genetic Information Processing; Transcription"
"map03050","Proteasome","The proteasome is a protein-destroying apparatus involved in many essential cellular functions, such as regulation of cell cycle, cell differentiation, signal transduction pathways, antigen processing for appropriate immune responses, stress signaling, inflammatory responses, and apoptosis. It is capable of degrading a variety of cellular proteins in a rapid and timely fashion and most substrate proteins are modified by ubiquitin before their degradation by the proteasome. The proteasome is a large protein complex consisting of a proteolytic core called the 20S particle and ancillary factors that regulate its activity in various ways. The most common form is the 26S proteasome containing one 20S core particle and two 19S regulatory particles that enable the proteasome to degrade ubiquitinated proteins by an ATP-dependent mechanism. Another form is the immunoproteasome containing two 11S regulatory particles, PA28 alpha and PA28 beta, which are induced by interferon gamma under the conditions of intensified immune response. Other regulatory particles include PA28 gamma and PA200. Although PA28 gamma also belongs to a family of activators of the 20S proteasome, it is localized within the nucleus and forms a homoheptamer. PA28 gamma has been implicated in the regulation of cell cycle progression and apoptosis. PA200 has been identified as a large nuclear protein that stimulates proteasomal hydrolysis of peptides.","Genetic Information Processing; Folding, sorting and degradation"
"map03060","Protein export","The protein export is the active transport of proteins from the cytoplasm to the exterior of the cell, or to the periplasmic compartment in Gram-negative bacteria. The sec dependent pathway is the general protein export system that transports newly synthesized proteins into or across the cell membrane. The translocation channel is formed from a conserved trimeric membrane protein complex, called the Sec61/SecY complex. The twin-arginine translocation (Tat) pathway is another protein transport system that transports folded proteins in bacteria, archaea, and chloroplasts. Many Tat systems comprise three functionally different membrane proteins, TatA, TatB, and TatC, but TatA and TatE seem to have overlapping functions, with TatA having by far the more important role.","Genetic Information Processing; Folding, sorting and degradation"
"map03070","Bacterial secretion system","Gram-negative bacteria secrete a wide range of proteins whose functions include biogenesis of organelles, such as pilli and flagella, nutrient acquisition, virulence, and efflux of drugs and other toxins. Six distinct secretion systems have been shown to mediate protein export through the inner and outer membranes of Gram-negative bacteria. These pathways are highly conserved throughout the Gram-negative bacterial species. In Gram-positive bacteria, secreted proteins are commonly translocated across the single membrane by the Sec pathway or the two-arginine (Tat) pathway.","Environmental Information Processing; Membrane transport"
"map03230",nothing,nothing,"Genetic Information Processing; Information processing in viruses"
"map03240",nothing,nothing,"Genetic Information Processing; Information processing in viruses"
"map03250",nothing,nothing,"Genetic Information Processing; Information processing in viruses"
"map03320","PPAR signaling pathway","Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are activated by fatty acids and their derivatives. PPAR has three subtypes (PPARalpha, beta/delta, and gamma) showing different expression patterns in vertebrates. Each of them is encoded in a separate gene and binds fatty acids and eicosanoids. PPARalpha plays a role in the clearance of circulating or cellular lipids via the regulation of gene expression involved in lipid metabolism in liver and skeletal muscle. PPARbeta/delta is involved in lipid oxidation and cell proliferation. PPARgamma promotes adipocyte differentiation to enhance blood glucose uptake.","Organismal Systems; Endocrine system"
"map03410","Base excision repair","Base excision repair (BER) is the predominant DNA damage repair pathway for the processing of small base lesions, derived from oxidation and alkylation damages. BER is normally defined as DNA repair initiated by lesion-specific DNA glycosylases and completed by either of the two sub-pathways: short-patch BER where only one nucleotide is replaced and long-patch BER where 2-13 nucleotides are replaced. Each sub-pathway of BER relies on the formation of protein complexes that assemble at the site of the DNA lesion and facilitate repair in a coordinated fashion. This process of complex formation appears to provide an increase in specificity and efficiency to the BER pathway, thereby facilitating the maintenance of genome integrity by preventing the accumulation of highly toxic repair intermediates.","Genetic Information Processing; Replication and repair"
"map03420","Nucleotide excision repair","Nucleotide excision repair (NER) is a mechanism to recognize and repair bulky DNA damage caused by compounds, environmental carcinogens, and exposure to UV-light. In humans hereditary defects in the NER pathway are linked to at least three diseases: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). The repair of damaged DNA involves at least 30 polypeptides within two different sub-pathways of NER known as transcription-coupled repair (TCR-NER) and global genome repair (GGR-NER). TCR refers to the expedited repair of lesions located in the actively transcribed strand of genes by RNA polymerase II (RNAP II). In GGR-NER the first step of damage recognition involves XPC-hHR23B complex together with XPE complex (in prokaryotes, uvrAB complex). The following steps of GGR-NER and TCR-NER are similar.","Genetic Information Processing; Replication and repair"
"map03430","Mismatch repair","DNA mismatch repair (MMR) is a highly conserved biological pathway that plays a key role in maintaining genomic stability. MMR corrects DNA mismatches generated during DNA replication, thereby preventing mutations from becoming permanent in dividing cells. MMR also suppresses homologous recombination and was recently shown to play a role in DNA damage signaling. Defects in MMR are associated with genome-wide instability, predisposition to certain types of cancer including HNPCC, resistance to certain chemotherapeutic agents, and abnormalities in meiosis and sterility in mammalian systems.
            The Escherichia coli MMR pathway has been extensively studied and is well characterized. In E. coli, the mismatch-activated MutS-MutL-ATP complex licenses MutH to incise the nearest unmethylated GATC sequence. UvrD and an exonuclease generate a gap. This gap is filled by pol III and DNA ligase. The GATC sites are then methylated by Dam. Several human MMR proteins have been identified based on their homology to E. coli MMR proteins. These include human homologs of MutS and MutL. Although E. coli MutS and MutL proteins are homodimers, human MutS and MutL homologs are heterodimers. The role of hemimethylated dGATC sites as a signal for strand discrimination is not conserved from E. coli to human. Human MMR is presumed to be nick-directed in vivo, and is thought to discriminate daughter and template strands using a strand-specific nick.","Genetic Information Processing; Replication and repair"
"map03440","Homologous recombination","Homologous recombination (HR) is essential for the accurate repair of DNA double-strand breaks (DSBs), potentially lethal lesions. HR takes place in the late S-G2 phase of the cell cycle and involves the generation of a single-stranded region of DNA, followed by strand invasion, formation of a Holliday junction, DNA synthesis using the intact strand as a template, branch migration and resolution. It is investigated that RecA/Rad51 family proteins play a central role. The breast cancer susceptibility protein Brca2 and the RecQ helicase BLM (Bloom syndrome mutated) are tumor suppressors that maintain genome integrity, at least in part, through HR.","Genetic Information Processing; Replication and repair"
"map03450","Non-homologous end-joining","Nonhomologous end joining (NHEJ) eliminates DNA double-strand breaks (DSBs) by direct ligation. NHEJ involves binding of the KU heterodimer to double-stranded DNA ends, recruitment of DNA-PKcs (MRX complex in yeast), processing of ends, and recruitment of the DNA ligase IV (LIG4)-XRCC4 complex, which brings about ligation. A recent study shows that bacteria accomplish NHEJ using just two proteins (Ku and DNA ligase), whereas eukaryotes require many factors. NHEJ repairs DSBs at all stages of the cell cycle, bringing about the ligation of two DNA DSBs without the need for sequence homology, and so is error-prone.","Genetic Information Processing; Replication and repair"
"map03460","Fanconi anemia pathway","The Fanconi anemia pathway is required for the efficient repair of damaged DNA, especially interstrand cross-links (ICLs). DNA ICL is directly recognized by FANCM and associated proteins, that recruit the FA core complex. The FA core complex monoubiquitinates FANCD2 and FANCI. The monoubiquitinated FANCD2/FANCI becomes an active form and interacts with a series of DNA repair proteins and facilitates downstream repair pathways. Fanconi anemia is caused by mutations in one of at least 13 FA genes and is characterized by congenital growth abnormalities, bone marrow failure and cancer predisposition.","Genetic Information Processing; Replication and repair"
"map04010","MAPK signaling pathway","The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli.","Environmental Information Processing; Signal transduction"
"map04011","MAPK signaling pathway - yeast","The S. cerevisiae genome encodes multiple MAP kinase orthologs. One (Fus3) mediates cellular response to peptide pheromones. Another (Kss1) permits adjustment to nutrient limiting conditions. A third (Hog1) is necessary for survival under hyperosmotic conditions. A fourth (Slt2/Mpk1) is required for repair of injuries to the cell wall. As in mammalian cells, these pathways consist of a conserved module in which three kinases phosphorylate each other in sequence. The MAPK is phosphorylated by the MAPK/ERK kinase (MAPKK/MEK), which is itself phosphorylated by a MEK kinase (MAPKKK/MEKK).","Environmental Information Processing; Signal transduction"
"map04012","ErbB signaling pathway","The ErbB family of receptor tyrosine kinases (RTKs) couples binding of extracellular growth factor ligands to intracellular signaling pathways regulating diverse biologic responses, including proliferation, differentiation, cell motility, and survival. Ligand binding to the four closely related members of this RTK family -epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4)-induces the formation of receptor homo- and heterodimers and the activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues (pY) within the cytoplasmic tail. Signaling effectors containing binding pockets for pY-containing peptides are recruited to activated receptors and induce the various signaling pathways. The Shc- and/or Grb2-activated mitogen-activated protein kinase (MAPK) pathway is a common target downstream of all ErbB receptors. Similarly, the phosphatidylinositol-3-kinase (PI-3K) pathway is directly or indirectly activated by most ErbBs. Several cytoplasmic docking proteins appear to be recruited by specific ErbB receptors and less exploited by others. These include the adaptors Crk, Nck, the phospholipase C gamma (PLCgamma), the intracellular tyrosine kinase Src, or the Cbl E3 ubiquitin protein ligase.","Environmental Information Processing; Signal transduction"
"map04013","MAPK signaling pathway - fly","The mitogen-activated protein kinase (MAPK) signaling cascades that are highly conserved from yeast to mammals use protein phosphorylation to convey signals intracellularly, and play a crucial role in mitosis, apoptosis, motility and metabolism. In fruit fly, three major classes of MAPK pathways have been distinguished with little or no redundancy, including extracellular signal-regulated kinase (ERK) / Rolled, c-Jun N-terminal kinase (JNK) / Bsk, and p38 kinase. Signals from growth factors or mitogens are dominantly transduced by the ERK pathway, whereas the JNK and p38 pathways are activated mostly by environmental stresses. The MAPK signaling cascades are typically linked to regulation of gene expression, because transcription factors are often the targets of regulatory phosphorylation events.","Environmental Information Processing; Signal transduction"
"map04014","Ras signaling pathway","The Ras proteins are GTPases that function as molecular switches for signaling pathways regulating cell proliferation, survival, growth, migration, differentiation or cytoskeletal dynamism. Ras proteins transduce signals from extracellular growth factors by cycling between inactive GDP-bound and active GTP-bound states. The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated RAS (RAS-GTP) regulates multiple cellular functions through effectors including Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide-dissociation stimulator (RALGDS).","Environmental Information Processing; Signal transduction"
"map04015","Rap1 signaling pathway","Rap1 is a small GTPase that controls diverse processes, such as cell adhesion, cell-cell junction formation and cell polarity. Like all G proteins, Rap1 cycles between an inactive GDP-bound and an active GTP-bound conformation. A variety of extracellular signals control this cycle through the regulation of several unique guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Rap1 plays a dominant role in the control of cell-cell and cell-matrix interactions by regulating the function of integrins and other adhesion molecules in various cell types. Rap1 also regulates MAP kinase (MAPK) activity in a manner highly dependent on the context of cell types.","Environmental Information Processing; Signal transduction"
"map04016","MAPK signaling pathway - plant","Mitogen-activated protein kinase (MAPK) cascades, the evolutionarily conserved signaling modules in all eukaryotes, serve in transducing extracellular signals to the nucleus or cytoplasm for appropriate cellular responses, including cell division, differentiation, programmed cell death, and adaption to various stresses. In plant, several cascades are triggered by different biotic and abiotic stress stimuli such as pathogen infection, wounding, low temperature, drought, osmotic shock, high salinity, and reactive oxygen species. MAPK pathways also play pivotal roles in processes such as hormonal and developmental signaling. Multiple functional pathways initiated from distinct receptors often share the same kinase components while maintaining their signaling specificity. In contrast to those of animals and fungi, all the plant MAPK genes that have been reported belong to extracellular signal-regulated kinase (ERK) subfamily.","Environmental Information Processing; Signal transduction"
"map04020","Calcium signaling pathway","Ca2+ that enters the cell from the outside is a principal source of signal Ca2+. Entry of Ca2+ is driven by the presence of a large electrochemical gradient across the plasma membrane. Cells use this external source of signal Ca2+ by activating various entry channels with widely different properties. The voltage-operated channels (VOCs) are found in excitable cells and generate the rapid Ca2+ fluxes that control fast cellular processes. There are many other Ca2+-entry channels, such as the receptor-operated channels (ROCs), for example the NMDA (N-methyl-D-aspartate) receptors (NMDARs) that respond to glutamate. There also are second-messenger-operated channels (SMOCs) and store-operated channels (SOCs).
            The other principal source of Ca2+ for signalling is the internal stores that are located primarily in the endoplasmic/sarcoplasmic reticulum (ER/SR), in which inositol-1,4,5-trisphosphate receptors (IP3Rs) or ryanodine receptors (RYRs) regulate the release of Ca2+. The principal activator of these channels is Ca2+ itself and this process of Ca2+-induced Ca2+ release is central to the mechanism of Ca2+ signalling. Various second messengers or modulators also control the release of Ca2+. IP3, which is generated by pathways using different isoforms of phospholipase C (PLCbeta, delta, epsilon, gamma and zeta), regulates the IP3Rs. Cyclic ADP-ribose (cADPR) releases Ca2+ via RYRs. Nicotinic acid adenine dinucleotide phosphate (NAADP) may activate a distinct Ca2+ release mechanism on separate acidic Ca2+ stores. Ca2+ release via the NAADP-sensitive mechanism may also feedback onto either RYRs or IP3Rs. cADPR and NAADP are generated by CD38. This enzyme might be sensitive to the cellular metabolism, as ATP and NADH inhibit it.
            The influx of Ca2+ from the environment or release from internal stores causes a very rapid and dramatic increase in cytoplasmic calcium concentration, which has been widely exploited for signal transduction. Some proteins, such as troponin C (TnC) involved in muscle contraction, directly bind to and sense Ca2+. However, in other cases Ca2+ is sensed through intermediate calcium sensors such as calmodulin (CALM).","Environmental Information Processing; Signal transduction"
"map04022","cGMP-PKG signaling pathway","Cyclic GMP (cGMP) is the intracellular second messenger that mediates the action of nitric oxide (NO) and natriuretic peptides (NPs), regulating a broad array of physiologic processes. The elevated intracellular cGMP level exerts its physiological action through two forms of cGMP-dependent protein kinase (PKG), cGMP-regulated phosphodiesterases (PDE2, PDE3) and cGMP-gated cation channels, among which PKGs might be the primary mediator. PKG1 isoform-specific activation of established substrates leads to reduction of cytosolic calcium concentration and/or decrease in the sensitivity of myofilaments to Ca2+ (Ca2+-desensitization), resulting in smooth muscle relaxation. In cardiac myocyte, PKG directly phosphorylates a member of the transient potential receptor canonical channel family, TRPC6, suppressing this nonselective ion channel's Ca2+ conductance, G-alpha-q agonist-induced NFAT activation, and myocyte hypertrophic responses. PKG also opens mitochondrial ATP-sensitive K+ (mitoKATP) channels and subsequent release of ROS triggers cardioprotection.","Environmental Information Processing; Signal transduction"
"map04024","cAMP signaling pathway","cAMP is one of the most common and universal second messengers, and its formation is promoted by adenylyl cyclase (AC) activation after ligation of G protein-coupled receptors (GPCRs) by ligands including hormones, neurotransmitters, and other signaling molecules. cAMP regulates pivotal physiologic processes including metabolism, secretion, calcium homeostasis, muscle contraction, cell fate, and gene transcription. cAMP acts directly on three main targets: protein kinase A (PKA), the exchange protein activated by cAMP (Epac), and cyclic nucleotide-gated ion channels (CNGCs). PKA modulates, via phosphorylation, a number of cellular substrates, including transcription factors, ion channels, transporters, exchangers, intracellular Ca2+ -handling proteins, and the contractile machinery. Epac proteins function as guanine nucleotide exchange factors (GEFs) for both Rap1 and Rap2. Various effector proteins, including adaptor proteins implicated in modulation of the actin cytoskeleton, regulators of G proteins of the Rho family, and phospholipases, relay signaling downstream from Rap.","Environmental Information Processing; Signal transduction"
"map04060","Cytokine-cytokine receptor interaction","Cytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell growth, differentiation, cell death, angiogenesis, and development and repair processes aimed at the restoration of homeostasis. Cytokines are released by various cells in the body, usually in response to an activating stimulus, and they induce responses through binding to specific receptors on the cell surface of target cells. Cytokines can be grouped by structure into different families and their receptors can likewise be grouped.","Environmental Information Processing; Signaling molecules and interaction"
"map04061","Viral protein interaction with cytokine and cytokine receptor","Viruses have evolved diverse mechanisms to evade detection and destruction by the immune system, including copying and repurposing host cytokine and cytokine receptor genes. Viral cytokines and cytokine receptors, together with a group of structurally unique, soluble, cytokine-binding or cytokine receptor-binding proteins, represent the three major molecular strategies for subversion and modulation of the host cytokine networks mainly in large DNA viruses. Viral cytokines and cytokine receptor homologs, including other binding proteins, may activate or inhibit cytokine signaling and possibly affect different aspects of immunity.","Environmental Information Processing; Signaling molecules and interaction"
"map04062","Chemokine signaling pathway","Inflammatory immune response requires the recruitment of leukocytes to the site of inflammation upon foreign insult. Chemokines are small chemoattractant peptides that provide directional cues for the cell trafficking and thus are vital for protective host response. In addition, chemokines regulate plethora of biological processes of hematopoietic cells to lead cellular activation, differentiation and survival.
            The chemokine signal is transduced by chemokine receptors (G-protein coupled receptors) expressed on the immune cells. After receptor activation, the alpha- and beta-gamma-subunits of G protein dissociate to activate diverse downstream pathways resulting in cellular polarization and actin reorganization. Various members of small GTPases are involved in this process. Induction of nitric oxide and production of reactive oxygen species are as well regulated by chemokine signal via calcium mobilization and diacylglycerol production.","Organismal Systems; Immune system"
"map04064","NF-kappa B signaling pathway","Nuclear factor-kappa B (NF-kappa B) is the generic name of a family of transcription factors that function as dimers and regulate genes involved in immunity, inflammation and cell survival. There are several pathways leading to NF-kappa B-activation. The canonical pathway is induced by tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) or byproducts of bacterial and viral infections. This pathway relies on IKK- mediated IkappaB-alpha phosphorylation on Ser32 and 36, leading to its degradation, which allows the p50/p65 NF-kappa B dimer to enter the nucleus and activate gene transcription. Atypical pathways are IKK-independent and rely on phosphorylation of IkappaB-alpha on Tyr42 or on Ser residues in IkappaB-alpha PEST domain. The non-canonical pathway is triggered by particular members of the TNFR superfamily, such as lymphotoxin-beta (LT-beta) or BAFF. It involves NIK and IKK-alpha-mediated p100 phosphorylation and processing to p52, resulting in nuclear translocation of p52/RelB heterodimers.","Environmental Information Processing; Signal transduction"
"map04066","HIF-1 signaling pathway","Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. It consists of two subunits: an inducibly-expressed HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Under normoxia, HIF-1 alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the subunit. In contrast, under hypoxia, HIF-1 alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, or various growth factors.","Environmental Information Processing; Signal transduction"
"map04068","FoxO signaling pathway","The forkhead box O (FOXO) family of transcription factors regulates the expression of genes in cellular physiological events including apoptosis, cell-cycle control, glucose metabolism, oxidative stress resistance, and longevity. A central regulatory mechanism of FOXO proteins is phosphorylation by the serine-threonine kinase Akt/protein kinase B (Akt/PKB), downstream of phosphatidylinositol 3-kinase (PI3K), in response to insulin or several growth factors. Phosphorylation at three conserved residues results in the export of FOXO proteins from the nucleus to the cytoplasm, thereby decreasing expression of FOXO target genes. In contrast, the stress-activated c-Jun N-terminal kinase (JNK) and the energy sensing AMP-activated protein kinase (AMPK), upon oxidative and nutrient stress stimuli phosphorylate and activate FoxOs. Aside from PKB, JNK and AMPK, FOXOs are regulated by multiple players through several post-translational modifications, including phosphorylation, but also acetylation, methylation and ubiquitylation.","Environmental Information Processing; Signal transduction"
"map04070",nothing,nothing,"Environmental Information Processing; Signal transduction"
"map04071","Sphingolipid signaling pathway","Sphingomyelin (SM) and its metabolic products are now known to have second messenger functions in a variety of cellular signaling pathways. Particularly, the sphingolipid metabolites, ceramide (Cer) and sphingosine-1-phosphate (S1P), have emerged as a new class of potent bioactive molecules. Ceramide can be generated de novo or by hydrolysis of membrane sphingomyelin by sphingomyelinase (SMase). Ceramide is subsequently metabolized by ceramidase to generate sphingosine (Sph) which in turn produces S1P through phosphorylation by sphingosine kinases 1 and 2 (SphK1, 2). Both ceramide and S1P regulate cellular responses to stress, with generally opposing effects. S1P functions as a growth and survival factor, acting as a ligand for a family of G protein-coupled receptors, whereas ceramide activates intrinsic and extrinsic apoptotic pathways through receptor-independent mechanisms.","Environmental Information Processing; Signal transduction"
"map04072","Phospholipase D signaling pathway","Phospholipase D (PLD) is an essential enzyme responsible for the production of the lipid second messenger phosphatidic acid (PA), which is involved in fundamental cellular processes, including membrane trafficking, actin cytoskeleton remodeling, cell proliferation and cell survival. PLD activity can be stimulated by a large number of cell surface receptors and is elaborately regulated by intracellular factors, including protein kinase C isoforms, small GTPases of the ARF, Rho and Ras families and the phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP2). The PLD-produced PA activates signaling proteins and acts as a node within the membrane to which signaling proteins translocate. Several signaling proteins, including Raf-1 and mTOR, directly bind PA to mediate translocation or activation, respectively.","Environmental Information Processing; Signal transduction"
"map04075",nothing,nothing,"Environmental Information Processing; Signal transduction"
"map04080",nothing,nothing,"Environmental Information Processing; Signaling molecules and interaction"
"map04110","Cell cycle","Mitotic cell cycle progression is accomplished through a reproducible sequence of events, DNA replication (S phase) and mitosis (M phase) separated temporally by gaps known as G1 and G2 phases. Cyclin-dependent kinases (CDKs) are key regulatory enzymes, each consisting of a catalytic CDK subunit and an activating cyclin subunit. CDKs regulate the cell's progression through the phases of the cell cycle by modulating the activity of key substrates. Downstream targets of CDKs include transcription factor E2F and its regulator Rb. Precise activation and inactivation of CDKs at specific points in the cell cycle are required for orderly cell division. Cyclin-CDK inhibitors (CKIs), such as p16Ink4a, p15Ink4b, p27Kip1, and p21Cip1, are involved in the negative regulation of CDK activities, thus providing a pathway through which the cell cycle is negatively regulated.
             Eukaryotic cells respond to DNA damage by activating signaling pathways that promote cell cycle arrest and DNA repair. In response to DNA damage, the checkpoint kinase ATM phosphorylates and activates Chk2, which in turn directly phosphorylates and activates p53 tumor suppressor protein. p53 and its transcriptional targets play an important role in both G1 and G2 checkpoints. ATR-Chk1-mediated protein degradation of Cdc25A protein phosphatase is also a mechanism conferring intra-S-phase checkpoint activation.","Cellular Processes; Cell growth and death"
"map04111","Cell cycle - yeast","Mitotic cell cycle progression is accomplished through a reproducible sequence of events, DNA replication (S phase) and mitosis (M phase) separated temporally by gaps (G1 and G2 phases). G1, S, and G2 phases are collectively known as interphase. In yeast Cdc28 is the catalytic subunit of the cyclin-dependent kinase (CDK). At G1 phase Cdc28 associates with G1-cyclins Cln1 to Cln3, while B-type cyclins Clb1 to Clb6 regulate Cdc28 during S, G2, and M phases. Cln3/Cdc28 activity is required for cells to pass through 'start', the commitment point in G1. When Cln3/Cdc28 accumulates more than a certain threshold, SBF (Swi4/Swi6) and MBF (Mbp1/Swi6) are activated, promoting transcription of Cln1, Cln2, and other genes required for S-phase progression. Cln1 and Cln2 interacting with Cdc28 promote activation of B-type cyclin associated CDK, which drives DNA replication and entry into mitosis. Specifically, Cdc28 association with Clb2 and Clb1 promotes entry into mitosis. Cells suffering from DNA damage, spindle misorientation, or spindle assembly defect do not undergo the metaphase-anaphase transition for chromosome segregation and fail to exit from mitosis. The spindle assembly checkpoint activates Mad2, which in turn prevents chromosome segregation by inhibiting degradation of the securin Pds1. Moreover, Pds1 is phosphorylated and stabilized in response to DNA damage in a Chk1-dependent manner. The spindle checkpoint is also involved in the Cdc14 release from the nucleolus. Cdc14 dephosphorylates Swi5, Sic1, and Cdh1, leading to inhibition of Cdc28 and degradation of cyclin required for mitotic exit.","Cellular Processes; Cell growth and death"
"map04112","Cell cycle - Caulobacter","Cell cycle progression of Caulobacter crescentus is implemented by an elaborate transcriptional regulatory network. During the life cycle, Caulobacter divides asymmetrically producing two distinct cell types with specialized development programs. The sessile stalked cell immediately initiates a new round of division cycle, whereas the motile swarmer cell remains in the G1 phase for a defined interval before differentiating into the stalked cell and entering into the S phase. The division process is centered around three master regulator proteins, DnaA, GcrA, and CtrA. DnaA and GcrA together drive the synthesis of proteins needed to complete DNA replication. CtrA controls the transcription of a diverse group of genes, which are required for essential morphological, metabolic, and cell cycle events.","Cellular Processes; Cell growth and death"
"map04113","Meiosis - yeast","During meiosis, a single round of DNA replication is followed by two rounds of chromosome segregation, called meiosis I and meiosis II. At meiosis I, one pair of sister chromatids recombines with, then segregates from, its homologous pair, while the sister chromatids segregate from each other at meoisis II. In yeast, the switch to enter growth phase or meiosis phase is controlled by nutritional signals. At the onset of meiosis, nutritional signaling pathways converge on transcriptional regulation of Ime1. Ime1 is a transcriptional activator to promote expression of early meiosis-specific genes required for pre-meiotic DNA replication and meiotic recombination. Two of the early meiosis-specific genes, a transcriptional activator, Ndt80, and a CDK2 homolog, Ime2, are required for the transcription of middle meiosis-specific genes, which includes B-type cyclin genes and genes involved in spore wall formation. Polo-like kinase Cdc5, whose expression is activated by Ndt80, is required for the critical step in meiotic progression. Cdc5 regulates sister-kinetochore co-orientation by promoting the localization of Mam1 and Lrs4, components of the co-orientation complex, to kinetochores. Cdc5 also phosphorylates the meiotic cohesin subunit Rec8, which is essential for its cleavage and removal by separase. Moreover, Cdc5 promotes the release of protein phosphatase Cdc14 from the nuclezus, which is required for anaphase I spindle disassembly and exit from meiosis I. The centromeric protein Sgo1 is a key regulator of meiotic chromosome segregation. Sgo1 with PP2A may protect pericentromeric but not arm cohesion of sister chromatids during meiosis I. Sgo1 then disappears at meiosis II to allow sister chromatids to separate.","Cellular Processes; Cell growth and death"
"map04114","Oocyte meiosis","During meiosis, a single round of DNA replication is followed by two rounds of chromosome segregation, called meiosis I and meiosis II. At meiosis I, homologous chromosomes recombine and then segregate to opposite poles, while the sister chromatids segregate from each other at meoisis II. In vertebrates, immature oocytes are arrested at the PI (prophase of meiosis I). The resumption of meiosis is stimulated by progesterone, which carries the oocyte through two consecutive M-phases (MI and MII) to a second arrest at MII. The key activity driving meiotic progression is the MPF (maturation-promoting factor), a heterodimer of CDC2 (cell division cycle 2 kinase) and cyclin B. In PI-arrested oocytes, MPF is initially inactive and is activated by the dual-specificity CDC25C phosphatase as the result of new synthesis of Mos induced by progesterone. MPF activation mediates the transition from the PI arrest to MI. The subsequent decrease in MPF levels, required to exit from MI into interkinesis, is induced by a negative feedback loop, where CDC2 brings about the activation of the APC (anaphase-promoting complex), which mediates destruction of cyclin B. Re-activation of MPF for MII requires re-accumulation of high levels of cyclin B as well as the inactivation of the APC by newly synthesized Emi2 and other components of the CSF (cytostatic factor), such as cyclin E or high levels of Mos. CSF antagonizes the ubiquitin ligase activity of the APC, preventing cyclin B destruction and meiotic exit until fertilization occurs. Fertilization triggers a transient increase in cytosolic free Ca2+, which leads to CSF inactivation and cyclin B destruction through the APC. Then eggs are released from MII into the first embryonic cell cycle.","Cellular Processes; Cell growth and death"
"map04115","p53 signaling pathway","p53 activation is induced by a number of stress signals, including DNA damage, oxidative stress and activated oncogenes. The p53 protein is employed as a transcriptional activator of p53-regulated genes. This results in three major outputs; cell cycle arrest, cellular senescence or apoptosis. Other p53-regulated gene functions communicate with adjacent cells, repair the damaged DNA or set up positive and negative feedback loops that enhance or attenuate the functions of the p53 protein and integrate these stress responses with other signal transduction pathways.","Cellular Processes; Cell growth and death"
"map04120","Ubiquitin mediated proteolysis","Protein ubiquitination plays an important role in eukaryotic cellular processes. It mainly functions as a signal for 26S proteasome dependent protein degradation. The addition of ubiquitin to proteins being degraded is performed by a reaction cascade consisting of three enzymes, named E1 (ubiquitin activating enzyme), E2 (ubiquitin conjugating enzyme), and E3 (ubiquitin ligase). Each E3 has specificity to its substrate, or proteins to be targeted by ubiquitination. Many E3s are discovered in eukaryotes and they are classified into four types: HECT type, U-box type, single RING-finger type, and multi-subunit RING-finger type. Multi-subunit RING-finger E3s are exemplified by cullin-Rbx E3s and APC/C. They consist of a RING-finger-containing subunit (RBX1 or RBX2) that functions to bind E2s, a scaffold-like cullin molecule, adaptor proteins, and a target recognizing subunit that binds substrates.","Genetic Information Processing; Folding, sorting and degradation"
"map04122","Sulfur relay system","Ubiquitin and ubiquitin-like proteins (Ubls) are signalling messengers that control many cellular functions, such as cell proliferation, apoptosis, and DNA repair. It is suggested that Ub-protein modification evolved from prokaryotic sulfurtransfer systems. Molybdenum cofactor (Moco) and thiamin are sulfur-containing cofactors whose biosynthesis includes a key sulfur transfer step that uses unique sulfur carrier proteins, MoaD and ThiS. Ubiquitin, MoaD, and ThiS are all structurally related proteins whose C-termini are activated through adenylation by homologous E1-like enzymes. s2T biosynthesis may share similar chemistry with Moco and thiamin synthesis. In Saccharomyces cerevisiae, Urm1 and Uba4 function as part of a ubl protein conjugation system, though they have sequence homology to bacterial sulfur-transfer enzymes and the ability to function in sulfur transfer.","Genetic Information Processing; Folding, sorting and degradation"
"map04130",nothing,nothing,"Genetic Information Processing; Folding, sorting and degradation"
"map04136","Autophagy - other","Autophagy is a degradative pathway for the removal of cytoplasmic materials in eukaryotic cells, and is characterized by the formation of a double-membrane structure called the autophagosome, either in a housekeeping capacity or during stress and senescence. The process of autophagy could be divided into several stages: induction, vesicle nucleation, elongation and closure, and fusion and digestion. Most essential autophagic machineries are conserved throughout eukaryotes (see map04140 for animals and map04138 for fungi). This map is for other eukaryotes including plants and protists, where autophagy related genes (ATGs) play similar roles in the life cycle. However, autophagy has been relatively less studied in lower eukaryotes.","Cellular Processes; Transport and catabolism"
"map04137","Mitophagy - animal","Mitochondria act as the energy powerhouse of the cell, and are essential for eukaryotic cells to grow and function normally. However, deleterious byproducts of oxidative phosphorylation process called reactive oxidative species (ROS) lead to mitochondrial dysfunction. If the damage is too excessive to be repaired, such mitochondria are selectively recognized and targeted for degradation by a specific mode of autophagy, termed mitophagy. The loss of the mitochondrial membrane potential can induce mitophagy, involving the kinase PINK1 and the E3 ligase Parkin. PINK1 serves as the sensor for the mitochondrial depolarization and recruits Parkin, followed by ubiquitin-dependent recruitment of mitophagy receptors. There are also several PINK1/Parkin-independent mitophagy pathways, in which a group of LIR-containing receptors are required in response to different stimuli. Mitophagy contributes to the maintenance of a healthy mitochondrial network and the prevention of programmed cell death.","Cellular Processes; Transport and catabolism"
"map04138","Autophagy - yeast","Autophagy is a non-selective and bulk intracellular degradation system of eukaryotic cells and is highly conserved from yeast to human. In this process, the double-membrane vesicle, known as autophagosome, is formed and sequesters organelles or portions of cytosol. The autophagosome is subsequently fused with the vacuole for breakdown by resident hydrolases, and the resulting metabolites are delivered for reuse. In yeast, nutrient withdrawal is the primary stimulus that induces autophagy. Autophagy plays a central role in normal development and cell homeostasis of yeast.","Cellular Processes; Transport and catabolism"
"map04139","Mitophagy - yeast","Mitophagy, which refers to the selective elimination of impaired or excessive mitochondria, is considered to be the main mechanism for mitochondria quality and quantity control. In yeast, oxidative stress or inhibition of TOR induces expression of Agt32, the indispensable mitochondrial outer membrane receptor. Direct phosphorylation of Atg32 by CK2 triggers mitophagy, and two mitogen-activated protein kinase (MAPK) signal transduction pathways are also important in this process. Atg11 is an adaptor protein for selective autophagy, and recruits the cargo to the phagophore assembly site (PAS), where the autophagosome is generated. Then Atg32-Atg8 interaction enhances the formation of the autophagosome surrounding the mitochondria, which finally fuses with vacuoles for degradation. Atg32-Atg11 interaction may also be regulated by Yme1-mediated processing of Atg32, as well as by mitochondrial fission machinery. Some factors have been suggested to positively or negatively regulate the mitophagy via different mechanisms, including Atg1, Atg33, Mss4, Fmc1, Mdm38, Mip1, and Ubp3-Bre5 deubiquitination complex.","Cellular Processes; Transport and catabolism"
"map04140","Autophagy - animal","Autophagy (or macroautophagy) is a cellular catabolic pathway involving in protein degradation, organelle turnover, and non-selective breakdown of cytoplasmic components, which is evolutionarily conserved among eukaryotes and exquisitely regulated. This progress initiates with production of the autophagosome, a double-membrane intracellular structure of reticular origin that engulfs cytoplasmic contents and ultimately fuses with lysosomes for cargo degradation. Autophagy is regulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation and ER stress. Constitutive level of autophagy plays an important role in cellular homeostasis and maintains quality control of essential cellular components.","Cellular Processes; Transport and catabolism"
"map04141","Protein processing in endoplasmic reticulum","The endoplasmic reticulum (ER) is a subcellular organelle where proteins are folded with the help of lumenal chaperones. Newly synthesized peptides enter the ER via the sec61 pore and are glycosylated. Correctly folded proteins are packaged into transport vesicles that shuttle them to the Golgi complex. Misfolded proteins are retained within the ER lumen in complex with molecular chaperones. Proteins that are terminally misfolded bind to BiP and are directed toward degradation through the proteasome in a process called ER-associated degradation (ERAD). Accumulation of misfolded proteins in the ER causes ER stress and activates a signaling pathway called the unfolded protein response (UPR). In certain severe situations, however, the protective mechanisms activated by the UPR are not sufficient to restore normal ER function and cells die by apoptosis.","Genetic Information Processing; Folding, sorting and degradation"
"map04142","Lysosome","Lysosomes are membrane-delimited organelles in animal cells serving as the cell's main digestive compartment to which all sorts of macromolecules are delivered for degradation. They contain more than 40 hydrolases in an acidic environment (pH of about 5). After synthesis in the ER, lysosomal enzymes are decorated with mannose-6-phosphate residues, which are recognized by mannose-6-phosphate receptors in the trans-Golgi network. They are packaged into clathrin-coated vesicles and are transported to late endosomes. Substances for digestion are acquired by the lysosomes via a series of processes including endocytosis, phagocytosis, and autophagy.","Cellular Processes; Transport and catabolism"
"map04144","Endocytosis","Endocytosis is a mechanism for cells to remove ligands, nutrients, and plasma membrane (PM) proteins, and lipids from the cell surface, bringing them into the cell interior. Transmembrane proteins entering through clathrin-dependent endocytosis (CDE) have sequences in their cytoplasmic domains that bind to the APs (adaptor-related protein complexes) and enable their rapid removal from the PM. In addition to APs and clathrin, there are numerous accessory proteins including dynamin. Depending on the various proteins that enter the endosome membrane, these cargoes are sorted to distinct destinations. Some cargoes, such as nutrient receptors, are recycled back to the PM. Ubiquitylated membrane proteins, such as activated growth-factor receptors, are sorted into intraluminal vesicles and eventually end up in the lysosome lumen via multivesicular endosomes (MVEs). There are distinct mechanisms of clathrin-independent endocytosis (CIE) depending upon the cargo and the cell type.","Cellular Processes; Transport and catabolism"
"map04145","Phagosome","Phagocytosis is the process of taking in relatively large particles by a cell, and is a central mechanism in the tissue remodeling, inflammation, and defense against infectious agents. A phagosome is formed when the specific receptors on the phagocyte surface recognize ligands on the particle surface. After formation, nascent phagosomes progressively acquire digestive characteristics. This maturation of phagosomes involves regulated interaction with the other membrane organelles, including recycling endosomes, late endosomes and lysosomes. The fusion of phagosomes and lysosomes releases toxic products that kill most bacteria and degrade them into fragments. However, some bacteria have strategies to escape the bactericidal mechanisms associated with phagocytosis and survive within host phagocytes.","Cellular Processes; Transport and catabolism"
"map04146","Peroxisome","Peroxisomes are essential organelles that play a key role in redox signalling and lipid homeostasis. They contribute to many crucial metabolic processes such as fatty acid oxidation, biosynthesis of ether lipids and free radical detoxification. The biogenesis of peroxisomes starts with the early peroxins PEX3, PEX16 and PEX19 and proceeds via several steps. The import of membrane proteins into peroxisomes needs PEX19 for recognition, targeting and insertion via docking at PEX3. Matrix proteins in the cytosol are recognized by peroxisomal targeting signals (PTS) and transported to the docking complex at the peroxisomal membrane. Peroxisomes' deficiencies lead to severe and often fatal inherited peroxisomal disorders (PD). PDs are usually classified in two groups. The first group is disorders of peroxisome biogenesis which include Zellweger syndrome, and the second group is single peroxisomal enzyme deficiencies.","Cellular Processes; Transport and catabolism"
"map04150","mTOR signaling pathway","The mammalian (mechanistic) target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase, which exists in two complexes termed mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 contains mTOR, Raptor, PRAS40, Deptor, mLST8, Tel2 and Tti1. mTORC1 is activated by the presence of growth factors, amino acids, energy status, stress and oxygen levels to regulate several biological processes, including lipid metabolism, autophagy, protein synthesis and ribosome biogenesis. On the other hand, mTORC2, which consists of mTOR, mSin1, Rictor, Protor, Deptor, mLST8, Tel2 and Tti1, responds to growth factors and controls cytoskeletal organization, metabolism and survival.","Environmental Information Processing; Signal transduction"
"map04151","PI3K-Akt signaling pathway","The phosphatidylinositol 3' -kinase(PI3K)-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates fundamental cellular functions such as transcription, translation, proliferation, growth, and survival. The binding of growth factors to their receptor tyrosine kinase (RTK) or G protein-coupled receptors (GPCR) stimulates class Ia and Ib PI3K isoforms, respectively. PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. PIP3 in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle.","Environmental Information Processing; Signal transduction"
"map04152","AMPK signaling pathway","AMP-activated protein kinase (AMPK) is a serine threonine kinase that is highly conserved through evolution. AMPK system acts as a sensor of cellular energy status. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Several upstream kinases, including liver kinase B1 (LKB1), calcium/calmodulin kinase kinase-beta (CaMKK beta), and TGF-beta-activated kinase-1 (TAK-1), can activate AMPK by phosphorylating a threonine residue on its catalytic alpha-subunit. Once activated, AMPK leads to a concomitant inhibition of energy-consuming biosynthetic pathways, such as protein, fatty acid and glycogen synthesis, and activation of ATP-producing catabolic pathways, such as fatty acid oxidation and glycolysis.","Environmental Information Processing; Signal transduction"
"map04210","Apoptosis","Apoptosis is a genetically programmed process for the elimination of damaged or redundant cells by activation of caspases (aspartate-specific cysteine proteases). The onset of apoptosis is controlled by numerous interrelating processes. The 'extrinsic' pathway involves stimulation of members of the tumor necrosis factor (TNF) receptor subfamily, such as TNFRI, CD95/Fas or TRAILR (death receptors), located at the cell surface, by their specific ligands, such as TNF-alpha, FasL or TRAIL, respectively. The 'intrinsic' pathway is activated mainly by non-receptor stimuli, such as DNA damage, ER stress, metabolic stress, UV radiation or growth-factor deprivation. The central event in the 'intrinsic' pathway is the mitochondrial outer membrane permeabilization (MOMP), which leads to the release of cytochrome c. These two pathways converge at the level of effector caspases, such as caspase-3 and caspase-7. The third major pathway is initiated by the constituents of cytotoxic granules (e.g. Perforin and Granzyme B) that are released by CTLs (cytotoxic T-cells) and NK (natural killer) cells. Granzyme B, similarly to the caspases, cleaves its substrates after aspartic acid residues, suggesting that this protease has the ability to activate members of the caspase family directly. It is the balance between the pro-apoptotic and anti-apoptotic signals that eventually determines whether cells will undergo apoptosis, survive or proliferate. TNF family of ligands activates anti-apoptotic or cell-survival signals as well as apoptotic signals. NGF and Interleukin-3 promotes the survival, proliferation and differentiation of neurons or hematopoietic cells, respectively. Withdrawal of these growth factors leads to cell death, as described above.","Cellular Processes; Cell growth and death"
"map04211","Longevity regulating pathway","Regulation of longevity depends on genetic and environmental factors. Caloric restriction (CR), that is limiting food intake, is recognized in mammals as the best characterized and most reproducible strategy for extending lifespan. Four pathways have been implicated in mediating the CR effect. These are the insulin like growth factor (IGF-1)/insulin signaling pathway, the sirtuin pathway, the adenosine monophosphate (AMP) activated protein kinase (AMPK) pathway and the target of rapamycin (TOR) pathway. The collective response of these pathways to CR is believed to promote cellular fitness and ultimately longevity via activation of autophagy, stress defense mechanisms, and survival pathways while attenuating proinflammatory mediators and cellular growth. Furthermore, there is evidence supporting that life span extension can be achieved with pharmacologic agents that mimic the effects of caloric restriction, such as rapamycin, via mTOR signaling blockade, resveratrol, by activating SIRT1 activity, and metformin, which seems to be a robust stimulator of AMPK activity. As an aging suppressor, Klotho is an important molecule in aging processes and its overexpression results in longevity.","Organismal Systems; Aging"
"map04212","Longevity regulating pathway - worm","The nematode Caenorhabditis elegans has proven to be a very useful tool for studying the genetics of longevity due to its simple biology. Over 70 genes have been found to influence lifespan in this worm. The majority of the genes could be placed into canonical longevity pathways including insulin/IGF, germline, TOR signaling, and mitochondrial respiration. The insulin/IGF-1 signaling (IIS) pathway is a central regulator of life span. Transcription factors regulated by the IIS and the TOR-S6K pathways are implicated in the anti-aging effects of Dietary restriction (DR). Lifespan extension via germline removal depends on at least four signaling mechanisms: reduced TOR signaling, DAF-16/FOXO regulation, increased steroid signaling via the DAF-36/DAF-9/DAF-12 pathway, and increased NHR-80/HNF-4 signaling. The mitochondrial unfolded protein response (UPRmt), a mitochondrial stress response, can be regarded as a hormetic mechanism that extends lifespan in spite of mitochondrial dysfunction. Longevity- promoting compounds such as rapamycin and resveratrol also induce mitonuclear imbalance that activates the UPRmt.","Organismal Systems; Aging"
"map04213","Longevity regulating pathway - multiple species","Aging is a complex process of accumulation of molecular, cellular, and organ damage, leading to loss of function and increased vulnerability to disease and death. Despite the complexity of aging, recent work has shown that dietary restriction (DR) and genetic down-regulation of nutrient-sensing pathways, namely IIS (insulin/insulin-like growth factor signalling) and TOR (target-of- rapamycin) can substantially increase healthy life span of laboratory model organisms. These nutrient signaling pathways are conserved in various organisms. In worms, flies, and mammals, DR reduces signalling through IIS/TOR pathways, deactivating the PI3K/Akt/TOR intracellular signalling cascade and consequently activating the antiaging FOXO family transcription factor(s). In yeast, the effects of DR on life- span extension are associated with reduced activities of the TOR/Sch9 and Ras/PKA pathways and require the serine-threonine kinase Rim15 and transcription factors Gis1 and Msn2/4. These transcription factors (FOXO, DAF-16, Gis1, and Msn2/4) transactivate genes involved in resistance to oxidative stress, energy metabolism, DNA damage repair, glucose metabolism, autophagy and protection of proteins by chaperones.","Organismal Systems; Aging"
"map04214","Apoptosis - fly","Apoptosis, or programmed cell death, is a critical factor in homeostasis in all multicellular organisms, playing a crucial role in removing excess unwanted cells without stimulation of an immune response. Caspases are the central components of the apoptotic response. In Drosophila, Dark promotes activation of the initiator caspase Dronc. Drosophila inhibitor of apoptosis protein 1 (DIAP1) inhibits Dronc and the effector caspases Drice and Dcp-1. RHG family proteins such as Rpr, Hid, Grim, Sickle, and Jafrac-2 promote cell death, in part by disrupting DIAP1's ability to inhibit caspase activity. Proapoptotic proteins such as caspases and RHG proteins are regulated through multiple pathways. The Drosophila steroid hormone ecdysone mediates cell death by controling the up-regulation of a number of proapoptotic genes. Cytotoxic stress such as DNA damage can activate P53, which in turn induces the expression of RHG genes. Eiger can initiate cell death through an IAP-sensitive cell death pathway via JNK signaling. Hid, a member of the RHG family, is negatively regulated by the epidermal growth factor (EGF) receptor-dependent survival signaling and positively regulated by the tumor suppressors Hippo, Salvador, and Warts.","Cellular Processes; Cell growth and death"
"map04215","Apoptosis - multiple species","Apoptosis is an evolutionarily conserved process used by multicellular organisms to developmentally regulate cell number or to eliminate cells that are potentially detrimental to the organism. The major players are caspases, caspase inhibitors, members of the Bcl-2 family of pro- and anti-apoptotic proteins and adaptors of the Ced-4/APAF-1 type. Mammals, by comparison with Caenorhabditis and Drosophila, exhibit highly complex extrinsic and intrinsic pathways for apoptosis induction. However, recent analyses of whole genome sequences from cnidarians (e.g. Hydra) suggest that the caspase and Bcl-2 families were already highly complex in cnidarians and that Caenorhabditis and Drosophila lost many of the genes involved in apoptosis.","Cellular Processes; Cell growth and death"
"map04216","Ferroptosis","Ferroptosis is a regulated form of cell death and characterized by a production of reactive oxygen species (ROS) from accumulated iron and lipid peroxidation. It can be induced by experimental compounds (e.g.,erastin, RSL3) or clinical drugs(e.g., sulfasalazine, sorafenib) in cancer cell and certain normal cells. It is involved in multiple physiological and pathological processes, such as cancer cell death, neurodegenerative disease, tissue damage and acute renal failure.","Cellular Processes; Cell growth and death"
"map04217","Necroptosis","Necroptosis is a programmed form of necrosis. It can be initiated by different stimuli, such as tumor necrosis factor (TNF), TNF-related apoptosis-inducing ligand (TRAIL), Fas ligand (FasL), interferon (IFN), LPS, viral DNA or RNA, DNA-damage agent and requires the kinase activity of receptor-interacting protein 1 (RIPK1) and RIPK3. Its execution involves ROS generation, calcium overload, the opening of the mitochondrial permeability transition pore, mitochondrial fission, inflammatory response and chromatinolysis. Necroptosis participates in many pathogenesis of diseases, including neurological diseases, retinal disorders, acute kidney injury, inflammatory diseases and microbial infections.","Cellular Processes; Cell growth and death"
"map04218","Cellular senescence","Cellular senescence is a state of irreversible cellular arrest and can be triggered by a number of factors, such as telomere shortening, oncogene activation, irradiation, DNA damage and oxidative stress. It is characterized by enlarged flattened morphology, senescence-associated beta-galactosidase (SA-b-gal) activity, secretion of inflammatory cytokines, growth factors and matrix metalloproteinases, as part of the senescence-associated secretory phenotype (SASP). Cellular senescence is functionally associated with many biological processes including aging, tumor suppression, placental biology, embryonic development, and wound healing.","Cellular Processes; Cell growth and death"
"map04260","Cardiac muscle contraction","Contraction of the heart is a complex process initiated by the electrical excitation of cardiac myocytes (excitation-contraction coupling, ECC). In cardiac myocytes, Ca2+ influx induced by activation of voltage-dependent L-type Ca channels (DHP receptors) upon membrane depolarization triggers the release of Ca2+ via Ca2+ release channels (ryanodine receptors) of sarcoplasmic reticulum (SR) through a Ca2+ -induced Ca release (CICR) mechanism. Ca2+ ions released via the CICR mechanism diffuse through the cytosolic space to contractile proteins to bind to troponinC resulting in the release of inhibition induced by troponinI. The Ca2+ binding to troponinC thereby triggers the sliding of thin and thick filaments, that is, the activation of a crossbridge and subsequent cardiac force development and/or cell shortening. Recovery occurs as Ca2+ is pumped out of the cell by the Na+/Ca2+ exchanger (NCX) or is returned to the sarcoplasmic reticulum (SR) by sarco(endo)plasmic Ca2+ -ATPase (SERCA) pumps on the non-junctional region of the SR.","Organismal Systems; Circulatory system"
"map04261","Adrenergic signaling in cardiomyocytes","Cardiac myocytes express at least six subtypes of adrenergic receptor (AR) which include three subtypes of beta-AR (beta-1, beta-2, beta-3) and three subtypes of the alpha-1-AR (alpha-1A, alpha-1B, and alpha-1C). In the human heart the beta-1-AR is the pre- dominate receptor. Acute sympathetic stimulation of cardiac beta-1-ARs induces positive inotropic and chronotropic effects, the most effective mechanism to acutely increase output of the heart, by coupling to Gs, formation of cAMP by adenylyl cyclase (AC), and PKA- dependent phosphorylation of various target proteins (e.g., ryanodine receptor [RyR]; phospholamban [PLB], troponin I [TnI], and the L-type Ca2+ channel [LTCC]). Chronic beta-1-AR stimulation is detrimental and induces cardiomyocyte hypertrophy and apoptosis. beta-2-AR coupled to Gs exerts a proapoptotic action as well as beta-1-AR, while beta-2-AR coupled to Gi exerts an antiapoptotic action.","Organismal Systems; Circulatory system"
"map04270","Vascular smooth muscle contraction","The vascular smooth muscle cell (VSMC) is a highly specialized cell whose principal function is contraction. On contraction, VSMCs shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure. 
            The principal mechanisms that regulate the contractile state of VSMCs are changes in cytosolic Ca2+ concentration ([Ca2+]c). In response to vasoconstrictor stimuli, Ca2+ is mobilized from intracellular stores and/or the extracellular space to increase [Ca2+]c in VSMCs. The increase in [Ca2+]c, in turn, activates the Ca2+-CaM-MLCK pathway and stimulates MLC20 phosphorylation, leading to myosin-actin interactions and, hence, the development of contractile force. The sensitivity of contractile myofilaments or MLC20 phosphorylation to Ca2+ can be secondarily modulated by other signaling pathways. During receptor stimulation, the contractile force is greatly enhanced by the inhibition of myosin phosphatase. Rho/Rho kinase, PKC, and arachidonic acid have been proposed to play a pivotal role in this enhancement. 
            The signaling events that mediate relaxation include the removal of a contractile agonist (passive relaxation) and activation of cyclic nucleotide-dependent signaling pathways in the continued presence of a contractile agonist (active relaxation). Active relaxation occurs through the inhibition of both Ca2+ mobilization and myofilament Ca2+ sensitivity in VSMCs.","Organismal Systems; Circulatory system"
"map04310","Wnt signaling pathway","Wnt proteins are secreted morphogens that are required for basic developmental processes, such as cell-fate specification, progenitor-cell proliferation and the control of asymmetric cell division, in many different species and organs. There are at least three different Wnt pathways: the canonical pathway, the planar cell polarity (PCP) pathway and the Wnt/Ca2+ pathway. In the canonical Wnt pathway, the major effect of Wnt ligand binding to its receptor is the stabilization of cytoplasmic beta-catenin through inhibition of the bea-catenin degradation complex. Beta-catenin is then free to enter the nucleus and activate Wnt-regulated genes through its interaction with TCF (T-cell factor) family transcription factors and concomitant recruitment of coactivators. Planar cell polarity (PCP) signaling leads to the activation of the small GTPases RHOA (RAS homologue gene-family member A) and RAC1, which activate the stress kinase JNK (Jun N-terminal kinase) and ROCK (RHO-associated coiled-coil-containing protein kinase 1) and leads to remodelling of the cytoskeleton and changes in cell adhesion and motility. WNT-Ca2+ signalling is mediated through G proteins and phospholipases and leads to transient increases in cytoplasmic free calcium that subsequently activate the kinase PKC (protein kinase C) and CAMKII (calcium calmodulin mediated kinase II) and the phosphatase calcineurin.","Environmental Information Processing; Signal transduction"
"map04320",nothing,nothing,"Organismal Systems; Development and regeneration"
"map04330","Notch signaling pathway","The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in all metazoan organisms in the Animal kingdom. The Notch proteins (Notch1-Notch4 in vertebrates) are single-pass receptors that are activated by the Delta (or Delta-like) and Jagged/Serrate families of membrane-bound ligands. They are transported to the plasma membrane as cleaved, but otherwise intact polypeptides. Interaction with ligand leads to two additional proteolytic cleavages that liberate the Notch intracellular domain (NICD) from the plasma membrane. The NICD translocates to the nucleus, where it forms a complex with the DNA binding protein CSL, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from CSL. Components of an activation complex, such as MAML1 and histone acetyltransferases (HATs), are recruited to the NICD-CSL complex, leading to the transcriptional activation of Notch target genes.","Environmental Information Processing; Signal transduction"
"map04340","Hedgehog signaling pathway","The Hedgehog (Hh) signaling pathway has numerous roles in the control of cell proliferation, tissue patterning, stem cell maintenance and development. The primary cilium is an important center for transduction of the Hedgehog signal in vertebrates. In Hh's absence, the Ptch receptor localizes to the cilium, where it inhibits Smo activation. Gli proteins are phosphorylated by PKA, CKI and GSK3B and partially degraded into truncated Gli repressor form (GliR) that suppresses Hh target gene transcription in the nucleus. In Hh's presence, Ptch disappears from the cilium, and activated Smo contributes to the translocation of the protein complex Gli, Sufu, Kif7 to ciliary tip, where Gli dissociates from the negative regulator Sufu. The production of Gli activator form (GliA) occurs and the increased nuclear accumulation of GliA results in activation transcription of Hh target genes.","Environmental Information Processing; Signal transduction"
"map04341","Hedgehog signaling pathway - fly","Hedgehog (Hh) signaling plays essential roles in embryonic development and adult tissue homeostasis. It is first elucidated by genetic studies in Drosophila and the core of the Hh signaling pathway is conserved in evolution. The Hh signaling components include an important complex composed of Cos2, Fu, SuFu and Ci. In the absence of Hh, Ptc inhibits Smo and the complex promotes the formation of the Ci's repressor form CiR. In the presentation of Hh, binding Hh to Ptc relieves Smo repression, which results in Ci's activation and then the increased transcription of Hh target genes in the nucleus.","Environmental Information Processing; Signal transduction"
"map04350","TGF-beta signaling pathway","The transforming growth factor-beta (TGF-beta) family members, which include TGF-betas, activins and bone morphogenetic proteins (BMPs), are structurally related secreted cytokines found in species ranging from worms and insects to mammals. A wide spectrum of cellular functions such as proliferation, apoptosis, differentiation and migration are regulated by TGF-beta family members. TGF-beta family member binds to the Type II receptor and recruits Type I, whereby Type II receptor phosphorylates and activates Type I. The Type I receptor, in turn, phosphorylates receptor-activated Smads ( R-Smads: Smad1, Smad2, Smad3, Smad5, and Smad8). Once phosphorylated, R-Smads associate with the co-mediator Smad, Smad4, and the heteromeric complex then translocates into the nucleus. In the nucleus, Smad complexes activate specific genes through cooperative interactions with other DNA-binding and coactivator (or co-repressor) proteins.","Environmental Information Processing; Signal transduction"
"map04360","Axon guidance","Axon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as netrins, ephrins, Slits, and semaphorins. These guidance cues are read by growth cone receptors, and signal transduction pathways downstream of these receptors converge onto the Rho GTPases to elicit changes in cytoskeletal organization that determine which way the growth cone will turn.","Organismal Systems; Development and regeneration"
"map04361","Axon regeneration","Many mature central nervous system (CNS) neurons in non-mammals, such as C. elegans, Drosophila, and zebrafish, are able to regenerate after injuries. The MAPK cascade, DLK-1/MKK-4/PMK-3/MAK2, is identified as an essential signaling pathway involved in axon regeneration in C. elegans. Calcium influx, which is triggered by axotomy, is implicated in DLK-1 activation. Another MAP kinase pathway, MLK-1/MEK-1/KGB-1, acts in parallel with the DLK-1 pathway to control growth-cone formation after axotomy. SVH-1, a homolog of the mammalian hepatocyte growth factor and its receptor SVH-2 function upstream of the MLK-1 pathway to promote axon regeneration. There are also inhibitors of regeneration, such as lin-12/Notch and efa-6. It is possible that the C. elegans pathways that inhibit regeneration function to stabilize the mature, uninjured nervous system.","Organismal Systems; Development and regeneration"
"map04370","VEGF signaling pathway","There is now much evidence that VEGFR-2 is the major mediator of VEGF-driven responses in endothelial cells and it is considered to be a crucial signal transducer in both physiologic and pathologic angiogenesis. The binding of VEGF to VEGFR-2 leads to a cascade of different signaling pathways, resulting in the up-regulation of genes involved in mediating the proliferation and migration of endothelial cells and promoting their survival and vascular permeability. For example, the binding of VEGF to VEGFR-2 leads to dimerization of the receptor, followed by intracellular activation of the PLCgamma;PKC-Raf kinase-MEK-mitogen-activated protein kinase (MAPK) pathway and subsequent initiation of DNA synthesis and cell growth, whereas activation of the phosphatidylinositol 3' -kinase (PI3K)-Akt pathway leads to increased endothelial-cell survival. Activation of PI3K, FAK, and p38 MAPK is implicated in cell migration signaling.","Environmental Information Processing; Signal transduction"
"map04371","Apelin signaling pathway","Apelin is an endogenous peptide capable of binding the apelin receptor (APJ), which was originally described as an orphan G-protein-coupled receptor. Apelin and APJ are widely expressed in various tissues and organ systems. They are implicated in different key physiological processes such as angiogenesis, cardiovascular functions, cell proliferation and energy metabolism regulation. On the other hand, this ligand receptor couple is also involved in several pathologies including diabetes, obesity, cardiovascular disease and cancer.","Environmental Information Processing; Signal transduction"
"map04380","Osteoclast differentiation","The osteoclasts, multinucleared cells originating from the hematopoietic monocyte-macrophage lineage, are responsible for bone resorption. Osteoclastogenesis is mainly regulated by signaling pathways activated by RANK and immune receptors, whose ligands are expressed on the surface of osteoblasts. Signaling from RANK changes gene expression patterns through transcription factors like NFATc1 and characterizes the active osteoclast.","Organismal Systems; Development and regeneration"
"map04390","Hippo signaling pathway","Hippo signaling is an evolutionarily conserved signaling pathway that controls organ size from flies to humans. In humans and mice, the pathway consists of the MST1 and MST2 kinases, their cofactor Salvador and LATS1 and LATS2. In response to high cell densities, activated LATS1/2 phosphorylates the transcriptional coactivators YAP and TAZ, promoting its cytoplasmic localization, leading to cell apoptosis and restricting organ size overgrowth. When the Hippo pathway is inactivated at low cell density, YAP/TAZ translocates into the nucleus to bind to the transcription enhancer factor (TEAD/TEF) family of transcriptional factors to promote cell growth and proliferation. YAP/TAZ also interacts with other transcriptional factors or signaling molecules, by which Hippo pathway-mediated processes are interconnected with those of other key signaling cascades, such as those mediated by TGF-beta and Wnt growth factors.","Environmental Information Processing; Signal transduction"
"map04391","Hippo signaling pathway - fly","Hippo signaling is an evolutionarily conserved signaling pathway that controls organ size during development from flies to humans. The core of the drosophila pathway is a kinase cascade consisting of four proteins including Hippo, Salvador, Warts and Mats. Upon activation by stimuli such as high cell density in cell culture, the Hippo pathway kinase cascade phosphorylates and inhibits the transcriptional co-activator Yorkie, thereby promoting cell apoptosis and restricting organ size overgrowth. When the Hippo pathway is inactivated, Yorkie translocates into the nucleus to bind to transcriptional factors to promote cell growth and proliferation.","Environmental Information Processing; Signal transduction"
"map04392","Hippo signaling pathway - multiple species","Hippo signaling pathways control diverse aspects of cell proliferation, survival, and morphogenesis in eukaryotes. The core organization of these networks is conserved over a billion years of evolution, with related forms described in animals and fungi. In Drosophila and mammals, Hippo/MST co-operate with Mats/Mob1 and Salvador/WW45 to activate Warts/LATS, which negatively regulates Yorkie/YAP. Yorkie/YAP interact with Scalloped/TEAD to promote gene transcriptions and control organ size through the balance between cell proliferation and apoptosis. In C. elegans, WTS-1 YAP-1 EGL-44 axis is conserved and regulates thermotolerance and healthy lifespan. In S. cerevisiae, the LATS-related Dbf2 or Dbf20 kinase in complex with Mob1 controls mitotic exit and cytokinesis, and the Hippo/MST family of kinases, STE-20, modulates Tec1, the putative yeast TEAD ortholog.","Environmental Information Processing; Signal transduction"
"map04510","Focal adhesion","Cell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the cell-extracellular matrix contact points, specialized structures are formed and termed focal adhesions, where bundles of actin filaments are anchored to transmembrane receptors of the integrin family through a multi-molecular complex of junctional plaque proteins. Some of the constituents of focal adhesions participate in the structural link between membrane receptors and the actin cytoskeleton, while others are signalling molecules, including different protein kinases and phosphatases, their substrates, and various adapter proteins. Integrin signaling is dependent upon the non-receptor tyrosine kinase activities of the FAK and src proteins as well as the adaptor protein functions of FAK, src and Shc to initiate downstream signaling events. These signalling events culminate in reorganization of the actin cytoskeleton; a prerequisite for changes in cell shape and motility, and gene expression. Similar morphological alterations and modulation of gene expression are initiated by the binding of growth factors to their respective receptors, emphasizing the considerable crosstalk between adhesion- and growth factor-mediated signalling.","Cellular Processes; Cellular community - eukaryotes"
"map04512","ECM-receptor interaction","The extracellular matrix (ECM) consists of a complex mixture of structural and functional macromolecules and serves an important role in tissue and organ morphogenesis and in the maintenance of cell and tissue structure and function. Specific interactions between cells and the ECM are mediated by transmembrane molecules, mainly integrins and perhaps also proteoglycans, CD36, or other cell-surface-associated components. These interactions lead to a direct or indirect control of cellular activities such as adhesion, migration, differentiation, proliferation, and apoptosis. In addition, integrins function as mechanoreceptors and provide a force-transmitting physical link between the ECM and the cytoskeleton. Integrins are a family of glycosylated, heterodimeric transmembrane adhesion receptors that consist of noncovalently bound alpha- and beta-subunits.","Environmental Information Processing; Signaling molecules and interaction"
"map04514","Cell adhesion molecules","Cell adhesion molecules (CAMs) are (glyco)proteins expressed on the cell surface and play a critical role in a wide array of biologic processes that include hemostasis, the immune response, inflammation, embryogenesis, and development of neuronal tissue. There are four main groups: the integrin family, the immunoglobulin superfamily, selectins, and cadherins. Membrane proteins that mediate immune cell&#8211;cell interactions fall into different categories, namely those involved in antigen recognition, costimulation and cellular adhesion. Furthermore cell-cell adhesions are important for brain morphology and highly coordinated brain functions such as memory and learning. During early development of the nervous system, neurons elongate their axons towards their targets and establish and maintain synapses through formation of cell-cell adhesions. Cell-cell adhesions also underpin axon-axon contacts and link neurons with supporting schwann cells and oligodendrocytes.","Environmental Information Processing; Signaling molecules and interaction"
"map04520","Adherens junction","Cell-cell adherens junctions (AJs), the most common type of intercellular adhesions, are important for maintaining tissue architecture and cell polarity and can limit cell movement and proliferation. At AJs, E-cadherin serves as an essential cell adhesion molecules (CAMs). The cytoplasmic tail binds beta-catenin, which in turn binds alpha-catenin. Alpha-catenin is associated with F-actin bundles directly and indirectly. The integrity of the cadherin-catenin complex is negatively regulated by phosphorylation of beta-catenin by receptor tyrosine kinases (RTKs) and cytoplasmic tyrosine kinases (Fer, Fyn, Yes, and Src), which leads to dissociation of the cadherin-catenin complex. Integrity of this complex is positively regulated by beta -catenin phosphorylation by casein kinase II, and dephosphorylation by protein tyrosine phosphatases. Changes in the phosphorylation state of beta-catenin affect cell-cell adhesion, cell migration and the level of signaling beta-catenin. Wnt signaling acts as a positive regulator of beta-catenin by inhibiting beta-catenin degradation, which stabilizes beta-catenin, and causes its accumulation. Cadherin may acts as a negative regulator of signaling beta-catenin as it binds beta-catenin at the cell surface and thereby sequesters it from the nucleus. Nectins also function as CAMs at AJs, but are more highly concentrated at AJs than E-cadherin. Nectins transduce signals through Cdc42 and Rac, which reorganize the actin cytoskeleton, regulate the formation of AJs, and strengthen cell-cell adhesion.","Cellular Processes; Cellular community - eukaryotes"
"map04530","Tight junction","Tight junctions (TJs) are essential for establishing a selectively permeable barrier to diffusion through the paracellular space between neighboring cells. TJs are composed of at least three types of transmembrane protein -occludin, claudin and junctional adhesion molecules (JAMs)- and a cytoplasmic 'plaque' consisting of many different proteins that form large complexes. These are proposed to be involved in junction assembly, barrier regulation, cell polarity, gene transcription, and other pathways.","Cellular Processes; Cellular community - eukaryotes"
"map04540","Gap junction","Gap junctions contain intercellular channels that allow direct communication between the cytosolic compartments of adjacent cells. Each gap junction channel is formed by docking of two 'hemichannels', each containing six connexins, contributed by each neighboring cell. These channels permit the direct transfer of small molecules including ions, amino acids, nucleotides, second messengers and other metabolites between adjacent cells. Gap junctional communication is essential for many physiological events, including embryonic development, electrical coupling, metabolic transport, apoptosis, and tissue homeostasis. Communication through Gap Junction is sensitive to a variety of stimuli, including changes in the level of intracellular Ca2+, pH, transjunctional applied voltage and phosphorylation/dephosphorylation processes. This figure represents the possible activation routes of different protein kinases involved in Cx43 and Cx36 phosphorylation.","Cellular Processes; Cellular community - eukaryotes"
"map04550","Signaling pathways regulating pluripotency of stem cells","Pluripotent stem cells (PSCs) are basic cells with an indefinite self-renewal capacity and the potential to generate all the cell types of the three germinal layers. The types of PSCs known to date include embryonic stem (ES) and induced pluripotent stem (iPS) cells. ES cells are derived from the inner cell mass (ICM) of blastocyst-stage embryos. iPS cells are generated by reprogramming somatic cells back to pluripotent state with defined reprogramming factors, Oct4, Sox2, Klf4 and c-Myc (also known as Yamanaka factors). PSCs including ES cells and iPS cells are categorized into two groups by their morphology, gene expression profile and external signal dependence. Conventional mouse-type ES/iPS cells are called 'naive state' cells. They are mainly maintained under the control of LIF and BMP signaling. On the other hand, human-type ES/iPS cells, which are in need of Activin and FGF signaling, are termed 'primed state'. However, these signaling pathways converge towards the activation of a core transcriptional network that is similar in both groups and involves OCt4, Nanog and Sox2. The three transcription factors and their downstream target genes coordinately promote self-renewal and pluripotency.","Cellular Processes; Cellular community - eukaryotes"
"map04610","Complement and coagulation cascades","The complement system is a proteolytic cascade in blood plasma and a mediator of innate immunity, a nonspecific defense mechanism against pathogens. There are three pathways of complement activation: the classical pathway, the lectin pathway, and the alternative pathway. All of these pathways generate a crucial enzymatic activity that, in turn, generates the effector molecules of complement. The main consequences of complement activation are the opsonization of pathogens, the recruitment of inflammatory and immunocompetent cells, and the direct killing of pathogens. Blood coagulation is another series of proenzyme-to-serine protease conversions, culminating the formation of thrombin, the enzyme responsible for the conversion of soluble fibrinogen to the insoluble fibrin clot. Protease-activated receptors, such as those activated by thrombin, are members of G protein-coupled receptors and function as a mediator of innate immunity. The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). Kinin peptides are implicated in many physiological and pathological processes including the regulation of blood pressure and sodium homeostasis, inflammatory processes, and the cardioprotective effects of preconditioning.","Organismal Systems; Immune system"
"map04611","Platelet activation","Platelets play a key and beneficial role for primary hemostasis on the disruption of the integrity of vessel wall. Platelet adhesion and activation at sites of vascular wall injury is initiated by adhesion to adhesive macromolecules, such as collagen and von Willebrand factor (vWF), or by soluble platelet agonists, such as ADP, thrombin, and thromboxane A2. Different receptors are stimulated by various agonists, almost converging in increasing intracellular Ca2+ concentration that stimulate platelet shape change and granule secretion and ultimately induce the inside-out signaling process leading to activation of the ligand-binding function of integrin alpha IIb beta 3. Binding of alpha IIb beta 3 to its ligands, mainly fibrinogen, mediates platelet adhesion and aggregation and triggers outside-in signaling, resulting in platelet spreading, additional granule secretion, stabilization of platelet adhesion and aggregation, and clot retraction.","Organismal Systems; Immune system"
"map04612",nothing,nothing,"Organismal Systems; Immune system"
"map04613","Neutrophil extracellular trap formation","Neutrophils play a central role in innate immune defense. One of the mechanisms of neutrophil action is the formation of neutrophil extracellular traps (NETs), the extracellular structures composed of chromatin coated with histones, proteases and granular and cytosolic proteins that help catch and kill microorganisms. NETs are formed by a process known as NETosis that can be triggered by microorganisms and endogenous stimuli, such as damage-associated molecular patterns and immune complexes, and involves activation in most cases of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, which produces reactive oxygen species (ROS). Recent study has reported that there are two different mechanisms of NETosis, including a lytic NETosis and a vital NETosis. Lytic NETosis begins with nuclear delobulation and the disassembly of the nuclear envelope and continues with loss of cellular polarization, chromatin decondensation and plasma membrane rupture. Vital NETosis can occur independently of cell death and involves the secreted expulsion of nuclear chromatin that is accompanied by the release of granule proteins through degranulation.","Organismal Systems; Immune system"
"map04614","Renin-angiotensin system","The renin-angiotensin system (RAS) is a peptidergic system with endocrine characteristics regarding to the regulation of the blood pressure and hydro-electrolytic balance. In the classical RAS, the enzyme renin cleaves its substrate angiotensinogen (Agt) forming the decapeptide angiotensin I that is in turn cleaved by angiotensin-converting enzyme (ACE) to produce the angiotensin II (Ang II), a key player of this system. Ang II activates its AT1 receptor (AT1R), the principal receptor that mediates the majority of the known actions of Ang II in the kidney, including vasoconstriction, renal sodium (Na+) reabsorption, and aldosterone secretion, increasing blood pressure and contributing to the development of hypertension. In addition to (ACE)/Ang II/AT1R and AT2R axis, other signaling pathways in the RAS, such as ACE2/angiotensin-(1-7)/Mas and Ang IV/IRAP, and other active peptide of the RAS, with physiological relevance as Ang III, Ang A and alamandine, are now widely recognized.","Organismal Systems; Endocrine system"
"map04620","Toll-like receptor signaling pathway","Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-{kappa}B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-{kappa}B and MAPK.","Organismal Systems; Immune system"
"map04621","NOD-like receptor signaling pathway","Specific families of pattern recognition receptors are responsible for detecting various pathogens and generating innate immune responses. The intracellular NOD-like receptor (NLR) family contains more than 20 members in mammals and plays a pivotal role in the recognition of intracellular ligands. NOD1 and NOD2, two prototypic NLRs, sense the cytosolic presence of the bacterial peptidoglycan fragments that escaped from endosomal compartments, driving the activation of NF-{kappa}B and MAPK, cytokine production and apoptosis. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of multiprotein complexes called inflammasomes. The activated of caspase-1 regulates maturation of the pro-inflammatory cytokines IL-1B, IL-18 and drives pyroptosis.","Organismal Systems; Immune system"
"map04622","RIG-I-like receptor signaling pathway","Specific families of pattern recognition receptors are responsible for detecting viral pathogens and generating innate immune responses. Non-self RNA appearing in a cell as a result of intracellular viral replication is recognized by a family of cytosolic RNA helicases termed RIG-I-like receptors (RLRs). The RLR proteins include RIG-I, MDA5, and LGP2 and are expressed in both immune and nonimmune cells. Upon recognition of viral nucleic acids, RLRs recruit specific intracellular adaptor proteins to initiate signaling pathways that lead to the synthesis of type I interferon and other inflammatory cytokines, which are important for eliminating viruses.","Organismal Systems; Immune system"
"map04623","Cytosolic DNA-sensing pathway","Specific families of pattern recognition receptors are responsible for detecting foreign DNA from invading microbes or host cells and generating innate immune responses. DAI is the first identified sensor of cytosolic DNA which activates the IRF and NF-{kappa}B transcription factors, leading to production of type I interferon and other cytokines. The second type of cytoplasmic DNA sensor is AIM2. Upon sensing DNA, AIM2 triggers the assembly of the inflammasome, culminating in interleukin maturation. In addition to these receptors, there is a mechanism to sense foreign DNA, with the host RNA polymerase III converting the DNA into RNA for recognition by the RNA sensor RIG-I. These pathways provide various means to alert the cell.","Organismal Systems; Immune system"
"map04624","Toll and Imd signaling pathway","Insects, such as Drosophila, have evolved complex mechanisms to combat microbial infection. TOLL and IMD pathways are responsible for the immune response that functions through the production of antimicrobial peptides (AMPs). The TOLL pathway mainly detects fungi, Gram-positive bacteria and virulence factors (proteases et al.). Activation of the TOLL pathway results in degradation of Cactus and localization of Dorsal and Dif to the nucleus. On the other hand, the IMD pathway responses to Gram-negative bacteria and leads to the activation of Relish. Dorsal, Dif and Relish induce the transcriptional up-regulation of AMPs in the nucleus.","Organismal Systems; Immune system"
"map04625","C-type lectin receptor signaling pathway","C-type lectin receptors (CLRs) are a large superfamily of proteins characterized by the presence of one or more C-type lectin-like domains (CTLDs). CLRs function as pattern-recognition receptors (PRRs) for pathogen-derived ligands in dendric cells, macrophages, neutrophils, etc., such as Dectin-1 and Dectin-2 for recognition of fungi-derived B-glucan and high mannose-type carbohydrates. Upon ligand binding, CLRs stimulate intracellular signaling cascades that induce the production of inflammatory cytokines and chemokines, consequently triggering innate and adaptive immunity to pathogens.","Organismal Systems; Immune system"
"map04626","Plant-pathogen interaction","Plants lack animal-like adaptive immunity mechanisms, and therefore have evolved a specific system with multiple layers against invading pathogens. The primary response includes the perception of pathogens by cell-surface pattern-recognition receptors (PRRs) and is referred to as PAMP-triggered immunity (PTI). Activation of FLS2 and EFR triggers MAPK signaling pathway that activates defense genes for antimictobial compounds. The increase in the cytosolic Ca2+ concentration is also a regulator for production of reactive oxygen species and localized programmed cell death/hypersensitive response. The secondary response is called effector-triggered immunity (ETI). Pathogens can acquire the ability to suppress PTI by directly injecting effector proteins into the plant cell through secretion systems. In addition, pathogens can manipulate plant hormone signaling pathways to evade host immune responses using coronatine toxin. Some plants possess specific intracellular surveillance proteins (R proteins) to monitor the presence of pathogen virulence proteins. This ETI occurs with localized programmed cell death to arrest pathogen growth, resulting in cultivar-specific disease resistance.","Organismal Systems; Environmental adaptation"
"map04630","JAK-STAT signaling pathway","The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies. In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of cytokines and growth factors. Following the binding of cytokines to their cognate receptor, STATs are activated by members of the JAK family of tyrosine kinases. Once activated, they dimerize and translocate to the nucleus and modulate the expression of target genes. In addition to the activation of STATs, JAKs mediate the recruitment of other molecules such as the MAP kinases, PI3 kinase etc. These molecules process downstream signals via the Ras-Raf-MAP kinase and PI3 kinase pathways which results in the activation of additional transcription factors.","Environmental Information Processing; Signal transduction"
"map04640","Hematopoietic cell lineage","Blood-cell development progresses from a hematopoietic stem cell (HSC), which can undergo either self-renewal or differentiation into a multilineage committed progenitor cell: a common lymphoid progenitor (CLP) or a common myeloid progenitor (CMP). A CLP gives rise to the lymphoid lineage of white blood cells or leukocytes-the natural killer (NK) cells and the T and B lymphocytes. A CMP gives rise to the myeloid lineage, which comprises the rest of the leukocytes, the erythrocytes (red blood cells), and the megakaryocytes that produce platelets important in blood clotting. Cells undergoing these differentiation process express a stage- and lineage-specific set of surface markers. Therefore cellular stages are identified by the specific expression patterns of these genes.","Organismal Systems; Immune system"
"map04650","Natural killer cell mediated cytotoxicity","Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit MHC class I exprssion or alter its conformation. The mechanism of NK cell killing is the same as that used by the cytotoxic T cells generated in an adaptive immune response; cytotoxic granules are released onto the surface of the bound target cell, and the effector proteins they contain penetrate the cell membrane and induce programmed cell death.","Organismal Systems; Immune system"
"map04657","IL-17 signaling pathway","The interleukin 17 (IL-17) family, a subset of cytokines consisting of IL-17A-F, plays crucial roles in both acute and chronic inflammatory responses. IL-17A, the hallmark cytokine of the newly defined T helper 17 (TH17) cell subset, has important roles in protecting the host against extracellular pathogens, but also promotes inflammatory pathology in autoimmune disease, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses. IL-17C has biological functions similar to those of IL-17A. The functions of IL-17B and IL-17D remain largely elusive. The IL-17 family signals via their correspondent receptors and activates downstream pathways that include NF-kappaB, MAPKs and C/EBPs to induce the expression of antimicrobial peptides, cytokines and chemokines. The receptor proximal adaptor Act1 (an NF-kappaB activator 1) is considered as the master mediator in IL-17A signaling. It is likely that Act1 is a common signal adaptor also shared by other members mediated signalings in this family.","Organismal Systems; Immune system"
"map04658","Th1 and Th2 cell differentiation","Immunity to different classes of microorganisms is orchestrated by separate lineages of effector T helper (TH)-cells, which differentiate from naive CD4+ precursor cells in response to cues provided by antigen presenting cells (APC) and include T helper type 1 (Th1) and Th2. Th1 cells are characterized by the transcription factor T-bet and signal transducer and activator of transcription (STAT) 4, and the production of IFN-gamma. These cells stimulate strong cell-mediated immune responses, particularly against intracellular pathogens. On the other hand, transcription factors like GATA-3 and STAT6 drive the generation of Th2 cells that produce IL-4, IL-5 and IL-13 and are necessary for inducing the humoral response to combat parasitic helminths (type 2 immunity) and isotype switching to IgG1 and IgE. The balance between Th1/Th2 subsets determines the susceptibility to disease states, where the improper development of Th2 cells can lead to allergy, while an overactive Th1 response can lead to autoimmunity.","Organismal Systems; Immune system"
"map04659","Th17 cell differentiation","Interleukin (IL)-17-producing helper T (Th17) cells serve as a subset of CD4+ T cells involved in epithelial cell- and neutrophil mediated immune responses against extracellular microbes and in the pathogenesis of autoimmune diseases. In vivo, Th17 differentiation requires antigen presentation and co-stimulation, and activation of antigen presenting-cells (APCs) to produce TGF-beta, IL-6, IL-1, IL-23 and IL-21. This initial activation results in the activation and up-regulation of STAT3, ROR(gamma)t and other transcriptional factors in CD4+ T cells, which bind to the promoter regions of the IL-17, IL-21 and IL-22 genes and induce IL-17, IL-21 and IL-22. In contrast, the differentiation of Th17 cells and their IL-17 expression are negatively regulated by IL-2, Th2 cytokine IL-4, IL-27 and Th1 cytokine IFN-gamma through STAT5, STAT6 and STAT1 activation, respectively. Retinoid acid and the combination of IL-2 and TGF-beta upregulate Foxp3, which also downregulates cytokines like IL-17 and IL-21. The inhibition of Th17 differentiation may serve as a protective strategy to 'fine-tune' the expression IL-17 so it does not cause excessive inflammation. Thus, balanced differentiation of Th cells is crucial for immunity and host protection.","Organismal Systems; Immune system"
"map04660","T cell receptor signaling pathway","Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells.","Organismal Systems; Immune system"
"map04662","B cell receptor signaling pathway","B cells are an important component of adaptive immunity. They produce and secrete millions of different antibody molecules, each of which recognizes a different (foreign) antigen. The B cell receptor (BCR) is an integral membrane protein complex that is composed of two immunoglobulin (Ig) heavy chains, two Ig light chains and two heterodimers of Ig-alpha and Ig-beta. After BCR ligation by antigen, three main protein tyrosine kinases (PTKs) -the SRC-family kinase LYN, SYK and the TEC-family kinase BTK- are activated. Phosphatidylinositol 3-kinase (PI3K) and phospholipase C-gamma 2 (PLC-gamma 2) are important downstream effectors of BCR signalling. This signalling ultimately results in the expression of immediate early genes that further activate the expression of other genes involved in B cell proliferation, differentiation and Ig production as well as other processes.","Organismal Systems; Immune system"
"map04664","Fc epsilon RI signaling pathway","Fc epsilon RI-mediated signaling pathways in mast cells are initiated by the interaction of antigen (Ag) with IgE bound to the extracellular domain of the alpha chain of Fc epsilon RI. The activation pathways are regulated both positively and negatively by the interactions of numerous signaling molecules. Mast cells that are thus activated release preformed granules which contain biogenic amines (especially histamines) and proteoglycans (especially heparin). The activation of phospholipase A2 causes the release of membrane lipids followed by development of lipid mediators such as leukotrienes (LTC4, LTD4 and LTE4) and prostaglandins (especially PDG2). There is also secretion of cytokines, the most important of which are TNF-alpha, IL-4 and IL-5. These mediators and cytokines contribute to inflammatory responses.","Organismal Systems; Immune system"
"map04666","Fc gamma R-mediated phagocytosis","Phagocytosis plays an essential role in host-defense mechanisms through the uptake and destruction of infectious pathogens. Specialized cell types including macrophages, neutrophils, and monocytes take part in this process in higher organisms. After opsonization with antibodies (IgG), foreign extracellular materials are recognized by Fc gamma receptors. Cross-linking of Fc gamma receptors initiates a variety of signals mediated by tyrosine phosphorylation of multiple proteins, which lead through the actin cytoskeleton rearrangements and membrane remodeling to the formation of phagosomes. Nascent phagosomes undergo a process of maturation that involves fusion with lysosomes. The acquisition of lysosomal proteases and release of reactive oxygen species are crucial for digestion of engulfed materials in phagosomes.","Organismal Systems; Immune system"
"map04668","TNF signaling pathway","Tumor necrosis factor (TNF), as a critical cytokine, can induce a wide range of intracellular signal pathways including apoptosis and cell survival as well as inflammation and immunity. Activated TNF is assembled to a homotrimer and binds to its receptors (TNFR1, TNFR2) resulting in the trimerization of TNFR1 or TNFR2. TNFR1 is expressed by nearly all cells and is the major receptor for TNF (also called TNF-alpha). In contrast, TNFR2 is expressed in limited cells such as CD4 and CD8 T lymphocytes, endothelial cells, microglia, oligodendrocytes, neuron subtypes, cardiac myocytes, thymocytes and human mesenchymal stem cells. It is the receptor for both TNF and LTA (also called TNF-beta). Upon binding of the ligand, TNFR mediates the association of some adaptor proteins such as TRADD or TRAF2, which in turn initiate recruitment of signal transducers. TNFR1 signaling induces activation of many genes, primarily controlled by two distinct pathways, NF-kappa B pathway and the MAPK cascade, or apoptosis and necroptosis. TNFR2 signaling activates NF-kappa B pathway including PI3K-dependent NF-kappa B pathway and JNK pathway leading to survival.","Environmental Information Processing; Signal transduction"
"map04670","Leukocyte transendothelial migration","Leukocyte migaration from the blood into tissues is vital for immune surveillance and inflammation. During this diapedesis of leukocytes, the leukocytes bind to endothelial cell adhesion molecules (CAM) and then migrate across the vascular endothelium. A leukocyte adherent to CAMs on the endothelial cells moves forward by leading-edge protrusion and retraction of its tail. In this process, alphaL /beta2 integrin activates through Vav1, RhoA, which subsequently activates the kinase p160ROCK. ROCK activation leads to MLC phosphorylation, resulting in retraction of the actin cytoskeleton. Moreover, Leukocytes activate endothelial cell signals that stimulate endothelial cell retraction during localized dissociation of the endothelial cell junctions. ICAM-1-mediated signals activate an endothelial cell calcium flux and PKC, which are required for ICAM-1 dependent leukocyte migration. VCAM-1 is involved in the opening of the endothelial passage through which leukocytes can extravasate. In this regard, VCAM-1 ligation induces NADPH oxidase activation and the production of reactive oxygen species (ROS) in a Rac-mediated manner, with subsequent activation of matrix metallopoteinases and loss of VE-cadherin-mediated adhesion.","Organismal Systems; Immune system"
"map04672","Intestinal immune network for IgA production","The intestine is the largest lymphoid tissue in the body. One striking feature of intestinal immunity is its ability to generate great amounts of noninflammatory immunoglobulin A (IgA) antibodies that serve as the first line of defense against microorganisms. The basic map of IgA production includes induction of mucosal B cells in the Peyer's patches, circulation through the bloodstream and homing to intestinal mucosa of IgA-commited plasma cells, and local antibody production for export across the intestinal membranes. Multiple cytokines, including TGF-{beta}, IL-10, IL-4, IL-5, and IL-6, are required to promote IgA class switching and terminal differentiation process of the B cells. Secreted IgA promotes immune exclusion by entrapping dietary antigens and microorganisms in the mucus and functions for neutralization of toxins and pathogenic microbes.","Organismal Systems; Immune system"
"map04710","Circadian rhythm","Circadian rhythm is an internal biological clock, which enables to sustain an approximately 24-hour rhythm in the absence of environmental cues. In mammals, the circadian clock mechanism consists of cell-autonomous transcription-translation feedback loops that drive rhythmic, 24-hour expression patterns of core clock components. The first negative feedback loop is a rhythmic transcription of period genes (PER1, PER2, and PER3) and chryptochrome genes (CRY1 and CRY2). PER and CRY proteins form a heterodimer, which acts on the CLOCK/BMAL1 heterodimer to repress its own transcription. PER and CRY proteins are phosphorylated by casein kinase epsilon (CKIepsilon), which leads to degradation and restarting of the cycle. The second loop is a positive feedback loop driven by the CLOCK/BMAL1 heterodimer, which initiates transcription of target genes containing E-box cis-regulatory enhancer sequences.","Organismal Systems; Environmental adaptation"
"map04711","Circadian rhythm - fly","Circadian rhythm is an internal biological clock, which enables to sustain an approximately 24-hour rhythm in the absence of environmental cues. In the fruit fly Drosophila melanogaster, seven genes that contribute to the central clock function are known: period (per), timeless (tim), Clock (Clk), cycle (cyc), vrille (vri), double-time (dbt), and shaggy (sgg). The core of the circadian clock consists of molecular feedback loops where per and tim gene products (PER and TIM proteins) eventually turn off their own transcription. The CLK/CYC heterodimer activates transcription of per and tim genes, while the PER and TIM repressor proteins accumulate in the cytoplasm. After nuclear entry of PER and TIM, transcription is inhibited by direct binding of the PER/TIM heterodimer to the CLK/CYC heterodimer. This shutoff lasts until the PER and TIM proteins are degraded allowing a new round of transcription to occur.","Organismal Systems; Environmental adaptation"
"map04712","Circadian rhythm - plant","The circadian system is an endogenous rhythm with the period of about 24 hours to provide temporal organization of biological activity. In Arabidopsis the circadian oscillator at the core of this system is composed of the interlocked feedback loop formed by the major transcriptional factors CCA1 (circadian clock associated), LHY (late elongated hypocotyl) and TOC1 (timing of cab), a pseudo response regulator (PRR). The morning-expressed CCA1/LHY Myb transcription factors suppress TOC1 expression by binding to its promoter. Moreover, CCA1/LHY activates the expression of PRR7/9 in the morning and then PRR7/9 repress the transcription of CCA1/LHY during the rest of the day. By contrast, the evening-expressed TOC1 activates the expression of CCA1/LHY.","Organismal Systems; Environmental adaptation"
"map04713","Circadian entrainment","Circadian entrainment is a fundamental property by which the period of the internal biological clock is entrained by recurring exogenous signals, such that the organism's endocrine and behavioral rhythms are synchronized to environmental cues. In mammals, a master clock is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and may synchronize circadian oscillators in peripheral tissues. Light signal is the dominant synchronizer for master SCN clock. Downstream from the retina, glutamate and PACAP are released and trigger the activation of signal transduction cascades, including CamKII and nNOS activity, cAMP- and cGMP-dependent protein kinases, and mitogen-activated protein kinase (MAPK). Of non-photic entrainment, important phase shifting capabilities have been found for melatonin, which inhibits light-induced phase shifts through inhibition of adenylate cyclase (AC). Multiple entrainment pathways converge into CREB regulation. In turn, phosphorylated CREB activates clock gene expression.","Organismal Systems; Environmental adaptation"
"map04714","Thermogenesis","Thermogenesis is essential for warm-blooded animals, ensuring normal cellular and physiological function under conditions of environmental challenge. Thermogenesis in brown and beige adipose tissue is mainly controlled by norepinephrine, which is released from sympathetic nervous system in response to cold or dietary stimuli. The mitochondrial uncoupling protein 1 (UCP1) is responsible for the process whereby chemical energy is converted into heat in these adipocytes. Activation of these adipocytes leads to an increase in calorie consumption and is expected to improve overweight conditions, providing a potential strategy for treating obesity and its related metabolic disorders.","Organismal Systems; Environmental adaptation"
"map04720","Long-term potentiation","Hippocampal long-term potentiation (LTP), a long-lasting increase in synaptic efficacy, is the molecular basis for learning and memory. Tetanic stimulation of afferents in the CA1 region of the hippocampus induces glutamate release and activation of glutamate receptors in dendritic spines. A large increase in [Ca2+]i resulting from influx through NMDA receptors leads to constitutive activation of CaM kinase II (CaM KII) . Constitutively active CaM kinase II phosphorylates AMPA receptors, resulting in potentiation of the ionic conductance of AMPA receptors. Early-phase LTP (E-LTP) expression is due, in part, to this phosphorylation of the AMPA receptor. It is hypothesized that postsynaptic Ca2+ increases generated through NMDA receptors activate several signal transduction pathways including the Erk/MAP kinase and cAMP regulatory pathways. The convergence of these pathways at the level of the CREB/CRE transcriptional pathway may increase expression of a family of genes required for late-phase LTP (L-LTP).","Organismal Systems; Nervous system"
"map04721","Synaptic vesicle cycle","Communication between neurons is mediated by the release of neurotransmitter from synaptic vesicles (SVs). At the nerve terminal, SVs cycle through repetitive episodes of exocytosis and endocytosis. SVs are filled with neurotransmitters by active transport. The loaded SVs are then docked at a specialized region of the presynaptic plasma membrane known as the active zone, where they undergo a priming reaction. Upon arrival of an action potential, Ca2+ enters through voltage-gated channels and neurotransmitter is released by exocytosis, usually in less than a millisecond. After fusion, the vesicle is retrieved by endocytosis and reloaded for another round of exocytosis.","Organismal Systems; Nervous system"
"map04722","Neurotrophin signaling pathway","Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory.","Organismal Systems; Nervous system"
"map04723","Retrograde endocannabinoid signaling","Endogenous cannabinoids (endocannabinoids) serve as retrograde messengers at synapses in various regions of the brain. The family of endocannabinoids includes at least five derivatives of arachidonic acid; the two best characterized are arachydonoyl ethanolamide (anandamide, AEA) and 2-arachydonoil glycerol (2AG). They are released from postsynaptic neurons upon postsynaptic depolarization and/or receptor activation. The released endocannabinoids then activate the CB1 receptors (CB1R) at presynaptic terminals and suppress the release of inhibitory transmitter GABA (depolarization-induced suppression of inhibition, DSI) or excitatory transmitter glutamate (depolarization-induced suppression of excitation, DSE) by inhibiting Ca2+ channels. Besides the well-known expression of the CB1R in the plasma membrane, this receptor is also present in mitochondrial membranes, where it reduces the mitochondrial respiration and contributes to DSI. Whereas DSI and DSE result in short-term synaptic plasticity, endocannabinoids also mediate long-term synaptic changes (eCB-LTD). Persistent activation of CB1 receptors over a period of minutes triggers eCB-LTD by a RIM1alpha-dependent mechanism.","Organismal Systems; Nervous system"
"map04724","Glutamatergic synapse","Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system(CNS). Glutamate is packaged into synaptic vesicles in the presynaptic terminal. Once released into the synaptic cleft, glutamate acts on postsynaptic ionotropic glutamate receptors (iGluRs) to mediate fast excitatory synaptic transmission. Glutamate can also act on metabotropic glutamate receptors (mGluRs) and exert a variety of modulatory effects through their coupling to G proteins and the subsequent recruitment of second messenger systems. Presynaptically localized Group II and Group III mGluRs are thought to represent the classical inhibitory autoreceptor mechanism that suppresses excess glutamate release. After its action on these receptors, glutamate can be removed from the synaptic cleft by EAATs located either on the presynaptic terminal, neighboring glial cells, or the postsynaptic neuron. In glia, glutamate is converted to glutamine, which is then transported back to the presynaptic terminal and converted back to glutamate.","Organismal Systems; Nervous system"
"map04725","Cholinergic synapse","Acetylcholine (ACh) is a neurotransmitter widely distributed in the central (and also peripheral, autonomic and enteric) nervous system (CNS). In the CNS, ACh facilitates many functions, such as learning, memory, attention and motor control. When released in the synaptic cleft, ACh binds to two distinct types of receptors: Ionotropic nicotinic acetylcholine receptors (nAChR) and metabotropic muscarinic acetylcholine receptors (mAChRs). The activation of nAChR by ACh leads to the rapid influx of Na+ and Ca2+ and subsequent cellular depolarization. Activation of mAChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1-M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium. In the cleft, ACh may also be hydrolyzed by acetylcholinesterase (AChE) into choline and acetate. The choline derived from ACh hydrolysis is recovered by a presynaptic high-affinity choline transporter (CHT).","Organismal Systems; Nervous system"
"map04726","Serotonergic synapse","Serotonin (5-Hydroxytryptamine, 5-HT) is a monoamine neurotransmitter that plays important roles in physiological functions such as learning and memory, emotion, sleep, pain, motor function and endocrine secretion, as well as in pathological states including abnormal mood and cognition. Once released from presynaptic axonal terminals, 5-HT binds to receptors, which have been divided into 7 subfamilies on the basis of conserved structures and signaling mechanisms. These families include the ionotropic 5-HT3 receptors and G-protein-coupled 5-HT receptors, the 5-HT1 (Gi /Go -coupled), 5-HT2(Gq-coupled), 5-HT4/6/7 (Gs-coupled) and 5-HT5 receptors. Presynaptically localized 5-HT1B receptors are thought to be the autoreceptors that suppress excess 5-HT release. 5-HT's actions are terminated by transporter- mediated reuptake into neurons, leading to catabolism by monoamine oxidase.","Organismal Systems; Nervous system"
"map04727","GABAergic synapse","Gamma aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the mammalian central nervous system (CNS). When released in the synaptic cleft, GABA binds to three major classes of receptors: GABAA, GABAB, and GABAC receptors. GABAA and GABAC receptors are ionotropic and mediate fast GABA responses by triggering chloride channel openings, while GABAB receptors are metabotropic and mediate slower GABA responses by activating G-proteins and influencing second messenger systems. GABAA receptors, the major sites for fast inhibitory neurotransmission in the CNS, are regulated by phosphorylation mechanisms, affecting both their functional properties and their cell surface mobility and trafficking. GABA release by the presynaptic terminal is negatively regulated by GABAB autoreceptors, and is cleared from the extracellular space by GABA transporters (GATs) located either on the presynaptic terminal or neighboring glial cells.","Organismal Systems; Nervous system"
"map04728","Dopaminergic synapse","Dopamine (DA) is an important and prototypical slow neurotransmitter in the mammalian brain, where it controls a variety of functions including locomotor activity, motivation and reward, learning and memory, and endocrine regulation. Once released from presynaptic axonal terminals, DA interacts with at least five receptor subtypes in the central nervous system (CNS), which have been divided into two groups: the D1-like receptors (D1Rs), comprising D1 and D5 receptors, both positively coupled to adenylyl cyclase and cAMP production, and the D2-like receptors (D2Rs), comprising D2, D3, and D4 receptors, whose activation results in inhibition of adenylyl cyclase and suppression of cAMP production. In addition, D1Rs and D2Rs modulate intracellular Ca2+ levels and a number of Ca2+ -dependent intracellular signaling processes. Through diverse cAMP- and Ca2+-dependent and - independent mechanisms, DA influences neuronal activity, synaptic plasticity, and behavior. Presynaptically localized D2Rs regulate synthesis and release of DA as the main autoreceptor of the dopaminergic system.","Organismal Systems; Nervous system"
"map04730","Long-term depression","Cerebellar long-term depression (LTD), thought to be a molecular and cellular basis for cerebellar learning, is a process involving a decrease in the synaptic strength between parallel fiber (PF) and Purkinje cells (PCs) induced by the conjunctive activation of PFs and climbing fiber (CF). Multiple signal transduction pathways have been shown to be involved in this process. Activation of PFs terminating on spines in dendritic branchlets leads to glutamate release and activation of both AMPA and mGluRs. Activation of CFs, which make multiple synaptic contacts on proximal dendrites, also via AMPA receptors, opens voltage-gated calcium channels (VGCCs) and causes a generalized influx of calcium. These cellular signals, generated from two different synaptic origins, trigger a cascade of events culminating in a phosphorylation-dependent, long-term reduction in AMPA receptor sensitivity at the PF-PC synapse. This may take place either through receptor internalization and/or through receptor desensitization.","Organismal Systems; Nervous system"
"map04740","Olfactory transduction","Within the compact cilia of the olfactory receptor neurons (ORNs) a cascade of enzymatic activity transduces the binding of an odorant molecule to a receptor into an electrical signal that can be transmitted to the brain. Odorant molecules bind to a receptor protein (R) coupled to an olfactory specific Gs-protein (G) and activate a type III adenylyl cyclase (AC), increasing intracellular cAMP levels. cAMP targets an olfactory-specific cyclic-nucleotide gated ion channel (CNG), allowing cations, particularly Na and Ca, to flow down their electrochemical gradients into the cell, depolarizing the ORN. Furthermore, the Ca entering the cell is able to activate a Ca-activated Cl channel, which would allow Cl to flow out of the cell, thus further increasing the depolarization. Elevated intracellular Ca causes adaptation by at least two different molecular steps: inhibition of the activity of adenylyl cyclase via CAMKII-dependent phosphorylation and down-regulation of the affinity of the CNG channel to cAMP.","Organismal Systems; Sensory system"
"map04742","Taste transduction","Five basic tastes are recognized by humans and most other animals - bitter, sweet, sour, salty and umami. In vertebrates, taste stimuli are detected by taste receptor cells (TRCs). At least three distinct cell types are found in mammalian taste buds : type I cells, type II cells, and type III cells. Type I cells express epithelial sodium channel (ENaC) and are considered to be the major mediator of perception of low salt. In type II cells, transduction of bitter, sweet and umami is mediated by a canonical PLC-beta/IP3-signaling cascade, which culminates in the opening of the TRPM5 ion channel. This produces a depolarization that may allow CALMH1 channels to open and release ATP, which serves as a neurotransmitter to activate closely associated nerve afferents expressing P2X2, P2X3 receptors and adjacent type III cells expressing P2Y4 receptors. Type II taste cells also secrete acetylcholine (ACh) that appears to stimulate muscarinic receptors, specifically M3, on the same or neighboring Type II cells. This muscarinic feedback augments taste-evoked release of ATP. In type III cells, sour taste is initiated when protons enter through apically located proton-selective ion channels: polycystic kidney disease 2-like 1 protein (PKD2L1) and polycystic kidney disease 1-like 3 protein (PKD1L3) channels. Weak acids may also activate sour cells by penetrating the cell membrane and leading to closure of resting K+ channels and membrane depolarization. Further, voltage-gated Ca2+ channels are activated and release vesicular serotonin (5-HT), norepinephrine (NE) and gamma-aminobutyric acid (GABA). 5-HT and GABA provide negative paracrine feedback onto receptor cells by activating 5-HT1A and GABAA, GABAB receptors, respectively. 5-HT also functions as a transmitter between presynaptic cells and the sensory afferent.","Organismal Systems; Sensory system"
"map04744","Phototransduction","Phototransduction is a biochemical process by which the photoreceptor cells generate electrical signals in response to captured photons. The vertebrate cascade starts with the absorption of photons by the photoreceptive pigments, the rhodopsins, which consist of a membrane embedded chromophore, 11-cis-retinal, and a G-protein-coupled receptor, opsin. The photon isomerizes 11-cis-retinal to all-trans-retinal which induces a structural change that activates the opsin. This triggers hydrolysis of cGMP by activating a transducinphosphodiesterase 6 (PDE6) cascade, which results in closure of the cGMP-gated cation channels (CNG) in the plasma membrane and membrane hyperpolarization. The hyperpolarization of the membrane potential of the photoreceptor cell modulates the release of neurotransmitters to downstream cells. Recovery from light involves the deactivation of the light- activated intermediates: photolyzed rhodopsin is phosphorylated by rhodopsin kinase (RK) and subsequently capped off by arrestin; GTP-binding transducin alpha subunit deactivates through a process that is stimulated by RGS9.","Organismal Systems; Sensory system"
"map04745","Phototransduction - fly","Phototransduction is the process that converts the signal of light (photons) into a change of membrane potential in photoreceptor cells. Drosophila visual signaling is initiated with the activation of rhodopsin by light. Rhodopsin is composed of a protein, opsin, covalently linked to a chromophore, 3-hydroxy-11-cis-retinal. Upon absorption of a light photon the chromophore is isomerized from the 11-cis to the all-trans configuration which induces a structural change that activates the opsin. This photoconversion activates heterotrimeric Gq protein via GTP-GDP exchange, releasing the G(alpha)q subunit. G(alpha)q activates PLC, generating InsP3 and DAG from PIP2. DAG may further release polyunsaturated fatty acids (PUFAs) via action of DAG lipase. This reaction leads to the opening of cation-selective channels (trp and trpl genes) and causes the depolarization of the photoreceptor cells. The transduction proteins rhodopsin, G(alpha)q, PLC, PKC, TRP, and TRPL are coordinated by a polymer of INAD scaffold proteins.","Organismal Systems; Sensory system"
"map04750","Inflammatory mediator regulation of TRP channels","The TRP channels that exhibit a unique response to temperature have been given the name thermo-TRPs. Among all thermo- TRP channels, TRPV1-4, TRPM8, and TRPA1 are expressed in subsets of nociceptive dorsal root ganglion (DRG) neuron cell bodies including their peripheral and central projections. These channels can be modulated indirectly by inflammatory mediators such as PGE2, bradykinin, ATP, NGF, and proinflammatory cytokines that are generated during tissue injury. While the noxious heat receptor TRPV1 is sensitized (that is, their excitability can be increased) by post-translational modifications upon activation of G-protein coupled receptors (GPCRs) or tyrosine kinase receptors, the receptors for inflammatory mediators, the same action appears to mainly desensitize TRPM8, the main somatic innocuous cold sensor. This aforementioned sensitization could allow the receptor to become active at body temperature, so it not only contributes toward thermal hypersensitivity but also is possibly a substrate for ongoing persistent pain.","Organismal Systems; Sensory system"
"map04810",nothing,nothing,"Cellular Processes; Cell motility"
"map04910","Insulin signaling pathway","Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR.
            Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.","Organismal Systems; Endocrine system"
"map04911","Insulin secretion","Pancreatic beta cells are specialised endocrine cells that continuously sense the levels of blood sugar and other fuels and, in response, secrete insulin to maintain normal fuel homeostasis. Glucose-induced insulin secretion and its potentiation constitute the principal mechanism of insulin release. Glucose is transported by the glucose transporter (GLUT) into the pancreatic beta-cell. Metabolism of glucose generates ATP, which inhibits ATP-sensitive K+ channels and causes voltage-dependent Ca2+ influx. Elevation of [Ca2+]i triggers exocytotic release of insulin granules. Insulin secretion is further regulated by several hormones and neurotransmitters. Peptide hormones, such as glucagon-like peptide 1 (GLP-1), increase cAMP levels and thereby potentiate insulin secretion via the combined action of PKA and Epac2. Achetylcholine (ACh), a major parasympathetic neurotransmitter, binds to Gq-coupled receptors and activates phospholipase C- (PLC-), and the stimulatory effects involve activation of protein kinase C (PKC), which stimulates exocytosis. In addition, ACh mobilizes intracellular Ca2+ by activation of IP3 receptors.","Organismal Systems; Endocrine system"
"map04912","GnRH signaling pathway","Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnRHR is coupled to Gq/11 proteins to activate phospholipase C which transmits its signal to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates the intracellular protein kinase C (PKC) pathway and IP3 stimulates release of intracellular calcium. In addition to the classical Gq/11, coupling of Gs is occasionally observed in a cell-specific fashion. Signaling downstream of protein kinase C (PKC) leads to transactivation of the epidermal growth factor (EGF) receptor and activation of mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAPK. Active MAPKs translocate to the nucleus, resulting in activation of transcription factors and rapid induction of early genes.","Organismal Systems; Endocrine system"
"map04913","Ovarian steroidogenesis","The ovarian steroids, 17-beta estradiol (E2) and progesterone (P4), are critical for normal uterine function, establishment and maintenance of pregnancy, and mammary gland development. Furthermore, the local effects that are essential for normal ovarian physiology are dependent on the endocrine, paracrine, and autocrine actions of E2, P4, and androgens. In most mammals (including humans and mice), ovarian steroidogenesis occurs according to the two-cell/two-gonadotropin theory. This theory describes how granulosa and theca cells work together to make the ovarian steroids. Theca cells respond to LH signaling by increasing the expression of enzymes necessary for the conversion of cholesterol to androgens, such as androstenedione (A) and testosterone (T). Granulosa cells respond to FSH signaling by increasing the expression of enzymes necessary for the conversion of theca-derived androgens into estrogens (E2 and estrone).","Organismal Systems; Endocrine system"
"map04914","Progesterone-mediated oocyte maturation","Xenopus oocytes are naturally arrested at G2 of meiosis I. Exposure to either insulin/IGF-1 or the steroid hormone progesterone breaks this arrest and induces resumption of the two meiotic division cycles and maturation of the oocyte into a mature, fertilizable egg. This process is termed oocyte maturation. The transition is accompanied by an increase in maturation promoting factor (MPF or Cdc2/cyclin B) which precedes germinal vesicle breakdown (GVBD). Most reports point towards the Mos-MEK1-ERK2 pathway [where ERK is an extracellular signal-related protein kinase, MEK is a MAPK/ERK kinase and Mos is a p42(MAPK) activator] and the polo-like kinase/CDC25 pathway as responsible for the activation of MPF in meiosis, most likely triggered by a decrease in cAMP.","Organismal Systems; Endocrine system"
"map04915","Estrogen signaling pathway","Estrogens are steroid hormones that regulate a plethora of physiological processes in mammals, including reproduction, cardiovascular protection, bone integrity, cellular homeostasis, and behavior. Estrogen mediates its cellular actions through two signaling pathways classified as nuclear-initiated steroid signaling and membrane-initiated steroid signaling. In the nuclear pathway, estrogen binds either ERalpha or ERbeta, which in turn translocates to the nucleus, binds DNA at ERE elements and activates the expression of ERE-dependent genes. In membrane pathway, Estrogen can exert its actions through a subpopulation of ER at the plasma membrane (mER) or novel G-protein coupled E2 receptors (GPER). Upon activation of these receptors various signaling pathways (i.e. Ca2+, cAMP, protein kinase cascades) are rapidly activated and ultimately influence downstream transcription factors.","Organismal Systems; Endocrine system"
"map04916","Melanogenesis","Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortic peptides. MC1R activates the cyclic AMP (cAMP) response-element binding protein (CREB). Increased expression of MITF and its activation by phosphorylation (P) stimulate the transcription of tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT), which produce melanin. Melanin synthesis takes place within specialized intracellular organelles named melanosomes. Melanin-containing melanosomes then move from the perinuclear region to the dendrite tips and are transferred to keratinocytes by a still not well-characterized mechanism.","Organismal Systems; Endocrine system"
"map04917","Prolactin signaling pathway","Prolactin (PRL) is a polypeptide hormone known to be involved in a wide range of biological functions including osmoregulation, lactation, reproduction, growth and development, endocrinology and metabolism, brain and behavior, and immunomodulation. PRL mediates its action through PRLR, a transmembrane protein of the hematopoietin cytokine receptor superfamily. At the protein level, the long PRLR isoform (long-R) and several short PRLR isoforms (short-R) have been detected. Acting through the long-R, PRL activates many signaling cascades including Jak2/Stat, the major cascade, Src kinase, phosphatidylinositol-3-kinase (PI3K)/AKT, and mitogen-activated protein kinase (MAPK) pathways. PRL cannot activate Jak2/Stat5 through the short-R, but can activate pathways including MAPK and PI3K pathways.","Organismal Systems; Endocrine system"
"map04918","Thyroid hormone synthesis","Thyroid hormones triiodothyronine (T3) and thyroxine (T4) are essential for normal development, growth and metabolic homeostasis in all vertebrates, and synthesized in the thyroid gland. The functional unit of the thyroid gland is the follicle, delimited by a monolayer of thyrocytes. Polarized thyrocytes surround the follicular lumen; with their basal and apical surfaces facing the bloodstream and the lumen, respectively. To synthesize thyroid hormones, thyrocytes take up iodide at their basal side and concentrate it into the lumen. They also secrete in this lumen the specialized protein thyroglobulin (TG) which serves as a store for the hormones. In the follicular lumen oxidation of iodine, iodination of tyrosines (MIT, 3-monoiodotyrosine; DIT, 3,5-diiodotyrosine) and coupling of iodotyrosines takes place on tyrosine residues in TG, resulting in T3 and T4 synthesis. Iodinated TG is resorbed through the apical membrane and degraded to form T3/T4 in lysosomes; the T3/T4 is then secreted through the basal membrane.","Organismal Systems; Endocrine system"
"map04919","Thyroid hormone signaling pathway","The thyroid hormones (THs) are important regulators of growth, development and metabolism. The action of TH is mainly mediated by T3 (3,5,3'-triiodo-L-thyronine). Thyroid hormones, L-thyroxine (T4) and T3 enter the cell through transporter proteins. Although the major form of TH in the blood is T4, it is converted to the more active hormone T3 within cells. T3 binds to nuclear thyroid hormone receptors (TRs), which functions as a ligand-dependent transcription factor and controls the expression of target genes (genomic action). Nongenomic mechanisms of action is initiated at the integrin receptor. The plasma membrane alpha(v)beta(3)-integrin has distinct binding sites for T3 and T4. One binding site binds only T3 and activates the phosphatidylinositol 3-kinase (PI3K) pathway. The other binding site binds both T3 and T4 and activates the ERK1/2 MAP kinase pathway.","Organismal Systems; Endocrine system"
"map04920","Adipocytokine signaling pathway","Increased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin.
            Leptin is an important regulator of energy intake and metabolic rate primarily by acting at hypothalamic nuclei. Leptin exerts its anorectic effects by modulating the levels of neuropeptides such as NPY, AGRP, and alpha-MSH. This leptin action is through the JAK kinase, STAT3 phosphorylation, and nuclear transcriptional effect.
            Adiponectin lowers plasma glucose and FFAs. These effects are partly accounted for by adiponectin-induced AMPK activation, which in turn stimulates skeletal muscle fatty acid oxidation and glucose uptake. Furthermore, activation of AMPK by adiponectin suppresses endogenous glucose production, concomitantly with inhibition of PEPCK and G6Pase expression.
            The proinflammatory cytokine TNFalpha has been implicated as a link between obesity and insulin resistance. TNFalpha interferes with early steps of insulin signaling. Several data have shown that TNFalpha inhibits IRS1 tyrosine phosphorylation by promoting its serine phosphorylation. Among the serine/threonine kinases activated by TNFalpha, JNK, mTOR and IKK have been shown to be involved in this phosphorylation.","Organismal Systems; Endocrine system"
"map04921","Oxytocin signaling pathway","Oxytocin (OT) is a nonapeptide synthesized by the magno-cellular neurons located in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. It exerts a wide variety of central and peripheral effects. However, its best-known and most well-established roles are stimulation of uterine contractions during parturition and milk release during lactation. Oxytocin also influences cardiovascular regulation and various social behaviors. The actions of OT are all mediated by one type of OT receptor (OTR). This is a transmembrane receptor belonging to the G-protein-coupled receptor superfamily. The main signaling pathway is the Gq/PLC/Ins3 pathway, but the MAPK and the RhoA/Rho kinase pathways are also activated, contributing to increased prostaglandin production and direct contractile effect on myometrial cells. In the cardiovascular system, OTR is associated with the ANP-cGMP and NO-cGMP pathways, which reduce the force and rate of contraction and increase vasodilatation.","Organismal Systems; Endocrine system"
"map04922","Glucagon signaling pathway","Glucagon is conventionally regarded as a counterregulatory hormone for insulin and plays a critical anti-hypoglycemic role by maintaining glucose homeostasis in both animals and humans. To increase blood glucose, glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and glycolysis in a concerted fashion via multiple mechanisms. Glucagon also stimulates hepatic mitochondrial beta-oxidation to supply energy for glucose production. Glucagon performs its main effect via activation of adenylate cyclase. The adenylate-cyclase-derived cAMP activates protein kinase A (PKA), which then phosphorylates downstream targets, such as cAMP response element binding protein (CREB) and the bifunctional enzyme 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase (one of the isoforms being PFK/FBPase 1, encoded by PFKFB1).","Organismal Systems; Endocrine system"
"map04923","Regulation of lipolysis in adipocytes","Lipolysis in adipocytes, the hydrolysis of triacylglycerol (TAG) to release fatty acids (FAs) and glycerol for use by other organs as energy substrates, is a unique function of white adipose tissue. Lipolysis is under tight hormonal control. During fasting, catecholamines, by binding to Gs-coupled-adrenergic receptors (-AR), activate adenylate cyclase (AC) to increase cAMP and activate protein kinase A (PKA). PKA phosphorylates target protein such as hormone-sensitive lipase (HSL) and perilipin 1 (PLIN). PLIN phosphorylation is a key event in the sequential activation of TAG hydrolysis involving adipose triglyceride lipase (ATGL), HSL, and monoglyceride lipase (MGL). During the fed state, insulin, through activation of phosphodiesterase-3B (PDE-3B), inhibits catecholamine-induced lipolysis via the degradation of cAMP.","Organismal Systems; Endocrine system"
"map04924","Renin secretion","The aspartyl-protease renin is the key regulator of the renin-angiotensin-aldosterone system, which is critically involved in extracellular fluid volume and blood pressure homeostasis of the body. Renin is synthesized, stored in, and released into circulation by the juxtaglomerular (JG) cells of the kidney. Secretion of renin from JG cells at the organ level is controlled by the four main mechanisms: the sympathetic nervous system, the local JG apparatus baroreflex, the macula densa mechanism, and several hormones acting locally within the JG apparatus. Renin secretion at the level of renal JG cells appears to be controlled mainly by classic second messengers, namely cAMP, cGMP, and free cytosolic calcium concentration. While cAMP generally stimulates renin release and the intracellular calcium concentration suppresses the exocytosis of renin, the effects of cGMP in the regulation of the renin system are more complex as it both may stimulate or inhibit renin release.","Organismal Systems; Endocrine system"
"map04925","Aldosterone synthesis and secretion","Aldosterone is a steroid hormone synthesized in and secreted from the outer layer of the adrenal cortex, the zona glomerulosa. Aldosterone plays an important role in the regulation of systemic blood pressure through the absorption of sodium and water. Angiotensin II (Ang II), potassium (K+) and adrenocorticotropin (ACTH) are the main extracellular stimuli which regulate aldosterone secretion. These physiological agonists all converge on two major intracellular signaling pathways: calcium (Ca2+) mobilization and an increase in cAMP production. The increase in cytosolic calcium levels activates calcium/calmodulin- dependent protein kinases (CaMK), and the increased cAMP levels stimulate the activity of cAMP-dependent protein kinase, or protein kinase A (PKA). The activated CaMK, and possibly PKA, activates transcription factors (NURR1 and NGF1B, CREB) to induce StAR and CYP11B2 expression, the early and late rate- limiting steps in aldosterone biosynthesis, respectively, thereby stimulating aldosterone secretion.","Organismal Systems; Endocrine system"
"map04926","Relaxin signaling pathway","Human relaxin-2 (relaxin), originally identified as a peptidic hormone of pregnancy, is now known to exert a range of pleiotropic effects including vasodilatory, anti-fibrotic and angiogenic effects in both males and females. It belongs to the so-called relaxin peptide family which includes the insulin-like peptides INSL3 and INSL5, and relaxin-3 (H3) as well as relaxin. INSL3 has clearly defined specialist roles in male and female reproduction, relaxin-3 is primarily a neuropeptide involved in stress and metabolic control, and INSL5 is widely distributed particularly in the gastrointestinal tract. These members of relaxin peptide family exert such effects binding to different kinds of receptors, classified as relaxin family peptide (RXFP) receptors: RXFP1, RXFP2, RXFP3, and RXFP4. These G protein-coupled receptors predominantly bind relaxin, INSL3, relaxin-3, and INSL-5, respectively. RXFP1 activates a wide spectrum of signaling pathways to generate second messengers that include cAMP and nitric oxide, whereas RXFP2 activates a subset of these pathways. Both RXFP3 and RXFP4 inhibit cAMP production, and RXFP3 activate MAP kinases.","Organismal Systems; Endocrine system"
"map04927","Cortisol synthesis and secretion","Cortisol is the main endogenous glucocorticoid, which affects a plethora of physiological functions, e.g., lipid and glucose metabolism, metabolic homeostasis and adaptation to stress. Cortisol production is primarily regulated by corticotropin (ACTH) in zona fasciculata. The stimulatory effect of ACTH on cortisol synthesis depends on cAMP dependent signaling, but also involves membrane depolarization and increased cytosolic Ca2+. Each of cAMP and Ca2+ induces the expression of StAR, stimulating intramitochondrial cholesterol transfer, as well as the steroidogenic enzymes in the pathway from cholesterol to cortisol (e.g., CHE, CYP17A1, CYP11B1).","Organismal Systems; Endocrine system"
"map04928","Parathyroid hormone synthesis, secretion and action","Parathyroid hormone (PTH) is a key regulator of calcium and phosphorus homeostasis. The principal regulators of PTH secretion are extracellular ionized calcium (Ca2+) and 1,25-dihydroxyvitamin D (1,25(OH)2D3). Under conditions of dietary Ca restriction, a decrement in serum Ca concentration induces release of PTH from the parathyroid gland. PTH acts on bone and kidney to stimulate bone turnover, increase the circulating levels of 1,25(OH)2D3 and calcium and inhibit the reabsorption of phosphate from the glomerular filtrate. This hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R). PTH1R primarily activates two sub-types of heterotrimeric Gproteins: Gs and Gq , which in turn regulate the activity of adenylyl cyclases and phospholipase C (PLC) that control the flow of cAMP/PKA and IP/PKC signaling cascades, respectively.","Organismal Systems; Endocrine system"
"map04929","GnRH secretion","Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are key regulators of reproduction. They release GnRH into the portal circulation. In turn, GnRH stimulates the pituitary gland to secrete follicle-stimulating hormone and luteinizing hormone (LH) to regulate gonadal functions. Gonadal steroids provide feedback to regulate GnRH release. GnRH neurons express the kisspeptin receptor, GPR 54, and kisspeptins potently stimulate the release of GnRH by depolarising and inducing sustained action potential firing in GnRH neurons. It is also demonstrated that Kisspeptin-GPR54 system positively regulates the GnRH expression  with a time course consistent with activation of Akt and MAP kinase signaling pathways.","Organismal Systems; Endocrine system"
"map04930","Type II diabetes mellitus","Insulin resistance is strongly associated with type II diabetes. Diabetogenic factors including FFA, TNFalpha and cellular stress induce insulin resistance through inhibition of IRS1 functions. Serine/threonine phosphorylation, interaction with SOCS, regulation of the expression, modification of the cellular localization, and degradation represent the molecular mechanisms stimulated by them. Various kinases (ERK, JNK, IKKbeta, PKCzeta, PKCtheta and mTOR) are involved in this process.
            The development of type II diabetes requires impaired beta-cell function. Chronic hyperglycemia has been shown to induce multiple defects in beta-cells. Hyperglycemia has been proposed to lead to large amounts of reactive oxygen species (ROS) in beta-cells, with subsequent damage to cellular components including PDX-1. Loss of PDX-1, a critical regulator of insulin promoter activity, has also been proposed as an important mechanism leading to beta-cell dysfunction.
            Although there is little doubt as to the importance of genetic factors in type II diabetes, genetic analysis is difficult due to complex interaction among multiple susceptibility genes and between genetic and environmental factors. Genetic studies have therefore given very diverse results. Kir6.2 and IRS are two of the candidate genes. It is known that Kir6.2 and IRS play central roles in insulin secretion and insulin signal transmission, respectively.","Human Diseases; Endocrine and metabolic disease"
"map04931","Insulin resistance","Insulin resistance is a condition where cells become resistant to the effects of insulin. It is often found in people with health disorders, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular diseases. In this diagram multiple mechanisms underlying insulin resistance are shown: (a) increased phosphorylation of IRS (insulin receptor substrate) protein through serine/threonine kinases, such as JNK1 and IKKB, and protein kinase C, (b) increased IRS-1 proteasome degradation via mTOR signaling pathway, (c) decreased activation of signaling molecules including PI3K and AKT, (d) increase in activity of phosphatases including PTPs, PTEN, and PP2A. Regulatory actions such as oxidative stress, mitochondrial dysfunction, accumulation of intracellular lipid derivatives (diacylglycrol and ceramides), and inflammation (via IL-6 and TNFA) contribute to these mechanisms. Consequently, insulin resistance causes reduced GLUT4 translocation, resulting in glucose takeup and glycogen synthesis in skeletal muscle as well as increased hepatic gluconeogenesis and decreased glycogen synthesis in liver. At the bottom of the diagram, interplay between O-GlcNAcylation and serine/threonine phosphorylation is shown. Studies suggested that elevated O-GlcNAc level was correlated to high glucose-induced insulin resistance. Donor UDP-GlcNAc is induced through hexosamine biosynthesis pathway and added to proteins by O-GlcNAc transferase. Elevation of O-GlcNAc modification alters phosphorylation and function of key insulin signaling proteins including IRS-1, PI3K, PDK1, Akt and other transcription factor and cofactors, resulting in the attenuation of insulin signaling cascade.","Human Diseases; Endocrine and metabolic disease"
"map04932","Non-alcoholic fatty liver disease","Non-alcoholic fatty liver disease (NAFLD) represents a spectrum ranging from simple steatosis to more severe steatohepatitis with hepatic inflammation and fibrosis, known as nonalcoholic steatohepatitis (NASH). NASH may further lead to cirrhosis and hepatocellular carcinoma (HCC). This map shows a stage-dependent progression of NAFLD. In the first stage of NAFLD, excess lipid accumulation has been demonstrated. The main cause is the induction of insulin resistance, which leads to a defect in insulin suppression of free fatty acids (FAAs) disposal. In addition, two transcription factors, SREBP-1c and PPAR-alpha, activate key enzymes of lipogenesis and increase the synthesis of FAAs in liver. In the second stage, as a consequence of the progression to NASH, the production of reactive oxygen species (ROS) is enhanced due to oxidation stress through mitochondrial beta-oxidation of fatty acids and endoplamic reticulum (ER) stress, leading to lipid peroxidation. The lipid peroxidation can further cause the production of cytokines (Fas ligand, TNF-alpha, IL-8 and TGF), promoting cell death, inflammation and fibrosis. The activation of JNK, which is induced by ER stress, TNF-alpha and FAAs, is also associated with NAFLD progression. Increased JNK promotes cytokine production and initiation of HCC.","Human Diseases; Endocrine and metabolic disease"
"map04933","AGE-RAGE signaling pathway in diabetic complications","Advanced glycation end products (AGEs) are a complex group of compounds produced through the non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids, primarily due to aging and under certain pathologic condition such as huperglycemia. Some of the best chemically characterized AGEs include N-epsilon-carboxy-methyl-lysine (CML), N-epsilon-carboxy-ethyl-lysine (CEL), and Imidazolone. The major receptor for AGEs, known as receptor for advanced glycation end products (RAGE or AGER), belongs to the immunoglobulin superfamily and has been described as a pattern recognition receptor. AGE/RAGE signaling elicits activation of multiple intracellular signal pathways involving NADPH oxidase, protein kinase C, and MAPKs, then resulting in NF-kappaB activity. NF-kappa B promotes the expression of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha and a variety of atherosclerosis-related genes, including VCAM-1, tissue factor, VEGF, and RAGE. In addition, JAK-STAT-mediated and PI3K-Akt-dependent pathways are induced via RAGE, which in turn participate in cell proliferation and apoptosis respectively. Hypoxia-mediated induction of Egr-1 was also shown to require the AGE-RAGE interaction. The results of these signal transductions have been reported to be the possible mechanism that initates diabetic complications.","Human Diseases; Endocrine and metabolic disease"
"map04934","Cushing syndrome","Cushing syndrome (CS) is a rare disorder resulting from prolonged exposure to excess glucocorticoids via exogenous and endogenous sources. The typical clinical features of CS are related to hypercortisolism and include accumulation of central fat, moon facies, neuromuscular weakness, osteoporosis or bone fractures, metabolic complications, and mood changes. Traditionally, endogenous CS is classified as adrenocorticotropic hormone (ACTH)-dependent (about 80%) or ACTH- independent (about 20%). Among ACTH-dependent forms, pituitary corticotroph adenoma (Cushing's disease) is most common. Most pituitary tumors are sporadic, resulting from monoclonal expansion of a single mutated cell. Recently recurrent activating somatic driver mutations in the ubiquitin-specific protease 8 gene (USP8) were identified in almost half of corticotroph adenoma. Germline mutations in MEN1 (encoding menin), AIP (encoding aryl-hydrocarbon receptor-interacting protein), PRKAR1A (encoding cAMP-dependent protein kinase type I alpha regulatory subunit) and CDKN1B (encoding cyclin-dependent kinase inhibitor 1B; also known as p27 Kip1) have been identified in familial forms of pituitary adenomas. However, the frequency of familial pituitary adenomas is less than 5% in patients with pituitary adenomas. Among ACTH-independent CS, adrenal adenoma is most common. Rare adrenal causes of CS include primary bilateral macronodular adrenal hyperplasia (BMAH) or primary pigmented nodular adrenocortical disease (PPNAD).","Human Diseases; Endocrine and metabolic disease"
"map04935","Growth hormone synthesis, secretion and action","Growth hormone (GH) is a peptide hormone secreted from the anterior pituitary and plays a critical role in cell growth, development, and metabolism throughout the body. GH secretion occurs episodically and is primarily under the control of two hypothalamic neuroendocrine hormones: GH-releasing hormone (GHRH), which stimulates GH secretion, and somatostatin, which inhibits GH secretion. GHRH interacts with a G protein-coupled receptor (GHRHR) in somatotroph cells to activate the cAMP signaling pathway, which leads to increased GH mRNA transcription and release. Once released into the circulation, GH binds to cell-surface GHR in target tissues such as liver, muscle, bone, and adipose tissue. Binding leads to activation of JAK2 that in turn triggers an array of signaling cascade including Raf-MEK-ERK, PI3K-Akt, and STAT5. ERK, Akt, and STAT5 all promote growth via the synthesis and secretion of IGF-1.","Organismal Systems; Endocrine system"
"map04936","Alcoholic liver disease","Alcoholic liver disease (ALD) refers to the damages to the liver and its functions due to alcohol overconsumption. It ranges from simple steatosis to steatohepatitis, cirrhosis, and even hepatocellular carcinoma. Alcohol consumption promotes liver inflammation by increasing the translocation of gut-derived endotoxins to the portal circulation and activating Kupffer cells to produce TNF-alpha through the LPS/Toll like receptor (TLR) 4 pathways. TNF-alpha induces hepatocellular damage. When alcohol intake is chronic and heavy, steatosis is caused via generation of acetaldehyde, reactive oxygen species (ROS) and ER stress. ROS inhibits key hepatic transcriptional regulators such as AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor alpha (PPAR-alpha), which are responsible for fatty acid oxidation and export via ACC and CPT-1. The blockade of AMPK also leads to overexpression of SREBP-1, resulting in an increase of de novo lipogenesis. Moreover, excessive intracellular ROS production induced by ethanol and its metabolite have a critical role in ethanol-induced apoptosis, which may be the critical process in the exacerbation of ALD. It is inferred that the apoptotic signal derived from ROS that was produced by NOX, is mainly transduced through the JNK and p38 MAPK pathways.","Human Diseases; Endocrine and metabolic disease"
"map04940","Type I diabetes mellitus","Type I diabetes mellitus is a disease that results from autoimmune destruction of the insulin-producing beta-cells. Certain beta-cell proteins act as autoantigens after being processed by antigen-presenting cell (APC), such as macrophages and dendritic cells, and presented in a complex with MHC-II molecules on the surface of the APC. Then immunogenic signals from APC activate CD4+ T cells, predominantly of the Th1 subset. Antigen-activated Th1 cells produce IL-2 and IFNgamma. They activate macrophages and cytotoxic CD8+ T cells, and these effector cells may kill islet beta-cells by one or both of two types of mechanisms: (1) direct interactions of antigen-specific cytotoxic T cells with a beta-cell autoantigen-MHC-I complex on the beta-cell, and (2) non-specific inflammatory mediators, such as free radicals/oxidants and cytokines (IL-1, TNFalpha, TNFbeta, IFNgamma).
            Type I diabetes is a polygenic disease. One of the principle determining genetic factors in diabetes incidence is the inheritance of mutant MHC-II alleles. Another plausible candidate gene is the insulin gene.","Human Diseases; Endocrine and metabolic disease"
"map04950","Maturity onset diabetes of the young","About 2-5% of type II diabetic patients suffer from a monogenic disease with autosomal dominant inheritance. This monogenic form of type II diabetes is called maturity onset diabetes of the young (MODY).
            We now know that MODY is caused by heterozygous mutations in at least five genes encoding transcription factors: HNF4alpha (MODY1), HNF1alpha (MODY3), PDX1 (MODY4), HNF1beta (MODY5) and NEUROD1 (MODY6). MODY2, which is so far the only subtype not related to a transcription factor, is caused by mutations in the glucokinase gene. Mutations of MODY transcription factor genes lead to abnormal expression of genes involved in pancreatic islet development and metabolism.","Human Diseases; Endocrine and metabolic disease"
"map04960","Aldosterone-regulated sodium reabsorption","Sodium transport across the tight epithelia of Na+ reabsorbing tissues such as the distal part of the kidney nephron and colon is the major factor determining total-body Na+ levels, and thus, long-term blood pressure. Aldosterone plays a major role in sodium and potassium metabolism by binding to epithelial mineralocorticoid receptors (MR) in the renal collecting duct cells localized in the distal nephron, promoting sodium resorption and potassium excretion. Aldosterone enters a target cell and binds MR, which translocates into the nucleus and regulates gene transcription. Activation of MR leads to increased expression of Sgk-1, which phosphorylates Nedd4-2, an ubiquitin-ligase which targets ENAC to proteosomal degradation. Phosphorylated Nedd4-2 dissociates from ENAC, increasing its apical membrane abundance. Activation of MR also leads to increased expression of Na+/K+-ATPase, thus causing a net increase in sodium uptake from the renal filtrate. The specificity of MR for aldosterone is provided by 11beta-HSD2 by the rapid conversion of cortisol to cortisone in renal cortical collecting duct cells. Recently, besides genomic effects mediated by activated MR, rapid aldosterone actions that are independent of translation and transcription have been documented.","Organismal Systems; Excretory system"
"map04961","Endocrine and other factor-regulated calcium reabsorption","Calcium (Ca2+) is essential for numerous physiological functions including intracellular signalling processes, neuronal excitability, muscle contraction and bone formation. Therefore, its homeostasis is finely maintained through the coordination of intestinal absorption, renal reabsorption, and bone resorption. In kidney, the late part of the distal convoluted tubule (DCT) and the connecting tubule (CNT) are the site of active Ca2+ transport and precisely regulate Ca2+ reabsorption. Following Ca2+ entry through TRPV5, Ca2+ bound to calbindin-D28K diffuses to the basolateral side, where it is extruded into the blood compartment through NCX1 and to a lesser extent PMCA1b. In the urinary compartment, both klotho and tissue kallikrein (TK) increase the apical abundance of TRPV5. In the blood compartment, PTH, 1,25(OH)2D3 and estrogen increase the transcription and protein expression of the luminal Ca2+ channels, calbindins, and the extrusion systems.","Organismal Systems; Excretory system"
"map04962","Vasopressin-regulated water reabsorption","In the kidney, the antidiuretic hormone vasopressin (AVP) is a critical regulator of water homeostasis by controlling the water movement from lumen to the interstitium for water reabsorption and adjusting the urinary water excretion. In normal physiology, AVP is secreted into the circulation by the posterior pituitary gland, in response to an increase in serum osmolality or a decrease in effective circulating volume. When reaching the kidney, AVP binds to V2 receptors on the basolateral surface of the collecting duct epithelium, triggering a G-protein-linked signaling cascade, which leads to water channel aquaporin-2 (AQP2) vesicle insertion into the apical plasma membrane. This results in higher water permeability in the collecting duct and, driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels, which are constitutively expressed on the basolateral side of these cells. When isotonicity is restored, reduced blood AVP levels results in AQP2 internalization, leaving the apical membrane watertight again.","Organismal Systems; Excretory system"
"map04964","Proximal tubule bicarbonate reclamation","One of the major tasks of the renal proximal tubule (PT) is to secrete acid into the tubule lumen, thereby reabsorbing approximately 80% of the filtered bicarbonate (HCO3(-)), as well as generating new HCO3(-) for regulating blood pH. In the tubular lumen, filtered HCO3(-) combines with H(+) in a reaction catalyzed by CA IV. The CO2 thus produced rapidly diffuses into the tubular cells and is combined with water to produce intracellular H(+) and HCO3(-), catalyzed by soluble cytoplasmic CA II. HCO3(-) is then cotransported with Na(+) into blood via the NBC-1. The intracellular H(+) produced by CA II is secreted into the tubular lumen predominantly via the NHE-3. The PT creates the new HCO3(-) by taking glutamine and metabolizing it to two molecules each of NH4(+) and HCO3(-). The NH4(+) is excreted into the tubular lumen, and the HCO3(-) , which is new HCO3(-) , is returned to the blood, where it replaces the HCO3(-) lost earlier in the titration of nonvolatile acids.","Organismal Systems; Excretory system"
"map04966","Collecting duct acid secretion","One of the important roles of the collecting duct segment of the kidney nephron is acid secretion. As daily food intake loads acid into the body, urinary acid excretion is essential, and urine pH can drop as low as 4.5. The alpha-intercalated cell of collecting duct is the main responsible for hydrogen secretion into the urine. The carbon dioxide, which is generated in the cells and enters from the blood, is changed to carbonic acid. This carbonic acid is divided into hydrogen ion and bicarbonate ion. Intracellular CA II catalyses the formation of these ions. The hydrogen ion is secreted into the lumen by the luminal H(+)-ATPase. The bicarbonate ion is transported to the blood side by the anion exchanger type 1. Hydrogen ion in the lumen is trapped by urinary buffers. These include ammonium and phosphate.","Organismal Systems; Excretory system"
"map04970","Salivary secretion","Saliva has manifold functions in maintaining the integrity of the oral tissues, in protecting teeth from caries, in the tasting and ingestion of food, in speech and in the tolerance of tenures, for example. Salivary secretion occurs in response to stimulation by neurotransmitters released from autonomic nerve endings. There are two secretory pathways: protein exocytosis and fluid secretion. Sympathetic stimulation leads to the activation of adenylate cyclase and accumulation of intracellular cAMP. The elevation of cAMP causes the secretion of proteins such as amylase and mucin. In contrast, parasympathetic stimulation activates phospholipase C and causes the elevation of intracellular Ca2+, which leads to fluid secretion; that is, water and ion transport. Ca2+ also induces amylase secretion, but the amount is smaller than that induced by cAMP.","Organismal Systems; Digestive system"
"map04971","Gastric acid secretion","Gastric acid is a key factor in normal upper gastrointestinal functions, including protein digestion and calcium and iron absorption, as well as providing some protection against bacterial infections. The principal stimulants of acid secretion at the level of the parietal cell are histamine (paracrine), gastrin (hormonal), and acetycholine (ACh; neurocrine). Stimulation of acid secretion typically involves an initial elevation of intracellular calcium and cAMP, followed by activation of protein kinase cascades, which trigger the translocation of the proton pump, H+,K+-ATPase, from cytoplasmic tubulovesicles to the apical plasma membrane and thereby H+ secretion into the stomach lumen.","Organismal Systems; Digestive system"
"map04972","Pancreatic secretion","The pancreas performs both exocrine and endocrine functions. The exocrine pancreas consists of two parts, the acinar and duct cells. The primary functions of pancreatic acinar cells are to synthesize and secrete digestive enzymes. Stimulation of the cell by secretagogues such as acetylcholine (ACh) and cholecystokinin (CCK) causes the generation of an intracellular Ca2+ signal. This signal, in turn, triggers the fusion of the zymogen granules with the apical plasma membrane, leading to the polarised secretion of the enzymes. The major task of pancreatic duct cells is the secretion of fluid and bicarbonate ions (HCO3-), which neutralize the acidity of gastric contents that enter the duodenum. An increase in intracellular cAMP by secretin is one of the major signals of pancreatic HCO3- secretion. Activation of the CFTR Cl- channel and the CFTR-dependent Cl-/HCO3- exchange activities is responsible for cAMP-induced HCO3- secretion.","Organismal Systems; Digestive system"
"map04973","Carbohydrate digestion and absorption","Dietary carbohydrate in humans and omnivorous animals is a major nutrient. The carbohydrates that we ingest vary from the lactose in milk to complex carbohydrates. These carbohydrates are digested to monosaccharides, mostly glucose, galactose and fructose, prior to absorption in the small intestine. Glucose and galactose are initially transported into the enterocyte by SGLT1 located in the apical brush border membrane and then exit through the basolateral membrane by either GLUT2 or exocytosis. In a new model of intestinal glucose absorption, transport by SGLT1 induces rapid insertion and activation of GLUT2 in the brush border membrane by a PKC betaII-dependent mechanism. Moreover, trafficking of apical GLUT2 is rapidly up-regulated by glucose and artificial sweeteners, which act through T1R2 + T1R3/alpha-gustducin to activate PLC-beta2 and PKC-beta II. Fructose is transported separately by the brush border GLUT5 and then released out of the enterocyte into the blood by GLUT2.","Organismal Systems; Digestive system"
"map04974","Protein digestion and absorption","Protein is a dietary component essential for nutritional homeostasis in humans. Normally, ingested protein undergoes a complex series of degradative processes following the action of gastric, pancreatic and small intestinal enzymes. The result of this proteolytic activity is a mixture of amino acids and small peptides. Amino acids (AAs) are transported into the enterocyte (intestinal epithelial cell) by a variety of AA transporters that are specific for cationic (basic) AA, neutral AA, and anionic (acidic) AA. Small peptides are absorbed into enterocytes by the PEPT1 transporter. Inside enterocytes peptides are hydrolyzed, and the resulting amino acids are released together with those absorbed by AA transporters into blood via multiple, basolateral, AA transporters. Hydrolysis-resistant peptides, however, are transported out of the cells by a basolateral peptide transporter that has not been identified molecularly.","Organismal Systems; Digestive system"
"map04975","Fat digestion and absorption","Fat is an important energy source from food. More than 95% of dietary fat is long-chain triacylglycerols (TAG), the remaining being phospholipids (4.5%) and sterols. In the small intestine lumen, dietary TAG is hydrolyzed to fatty acids (FA) and monoacylglycerols (MAG) by pancreatic lipase. These products are then emulsified with the help of phospholipids (PL) and bile acids (BA) present in bile to form micelles. Free FAs and MAGs are taken up by the enterocyte where they are rapidly resynthesized in endoplasmic reticulum (ER) to form TAG. PLs from the diet as well as bile - mainly LPA - too are absorbed by the enterocyte and are acylated to form phosphatidic acid (PA), which is also converted into TAG. Absorbed cholesterol (CL) is acylated to cholesterol esters (CE). Within the ER, TAG joins CE and apolipoprotein B (ApoB) to form chylomicrons that enter circulation through the lymph.","Organismal Systems; Digestive system"
"map04976","Bile secretion","Bile is a vital secretion, essential for digestion and absorption of fats and fat-soluble vitamins in the small intestine. Moreover, bile is an important route of elimination for excess cholesterol and many waste product, bilirubin, drugs and toxic compounds. Bile secretion depends on the function of membrane transport systems in hepatocytes and cholangiocytes and on the structural and functional integrity of the biliary tree. The hepatocytes generate the so-called primary bile in their canaliculi. Cholangiocytes modify the canalicular bile by secretory and reabsorptive processes as bile passes through the bile ducts. The main solutes in bile are bile acids, which stimulate bile secretion osmotically, as well as facilitate the intestinal absorption of dietary lipids by their detergent properties. Bile acids are also important signalling molecules. Through the activation of nuclear receptors, they regulate their own synthesis and transport rates.","Organismal Systems; Digestive system"
"map04977","Vitamin digestion and absorption","Vitamins are a diverse and chemically unrelated group of organic substances that share a common feature of being essential for normal health and well-being. They catalyze numerous biochemical reactions. Because humans and other mammals cannot synthesize these compounds (except for some synthesis of niacin), they must obtain them from exogenous sources via intestinal absorption. Vitamins are classified based on their solubility in water or fat. Most of the water-soluble vitamins are transported across the small intestinal membrane by carrier-mediated mechanisms, but vitamin B12, cobalamin, is transported by a receptor-mediated mechanism. Intestinal absorption of fat-soluble vitamins requires all of the processes needed for fat absorption. After digestion, these vitamins and the products of pancreatic hydrolysis of triglycerides (TG) are emulsified by bile salts to form mixed micelles which are taken up by intestinal enterocytes and incorporated into chylomicrons (CM). CM are then secreted into the lymphatic system, and finally moves into the plasma.","Organismal Systems; Digestive system"
"map04978","Mineral absorption","Minerals are one of the five fundamental groups of nutrients needed to sustain life. Of the minerals, calcium plays innumerable roles in our bodies, serving as a main component of bone as well as an intracellular messenger in muscle contraction/relaxation, neural networks, the immune system, and endocrine/exocrine cells. Iron, copper, and other metals are required for redox reactions (as cofactors) and for oxygen transport and binding (in hemoglobin and myoglobin). Many enzymes require specific metal atoms to complete their catalytic functions. Animal tissues need moderate quantities of some elements (Ca, P, K, Na, Mg, S, and Cl) and trace amounts of others (Mn, Fe, I, Co, Cr, Cu, Zn, and Se). The minerals are absorbed by either passive or active transport systems through the intestinal mucosa, often using specialized transport proteins, such as ferritin for Fe3+ and vitamin D-induced protein for calcium.","Organismal Systems; Digestive system"
"map04979","Cholesterol metabolism","Cholesterol is an essential component of mammalian cell membranes as well as a precursor of bile acids, vitamin D and steroid hormones. Cholesterol homeostasis in humans is regulated by well-balanced mechanisms of intestinal uptake, endogenous synthesis, transport in lipoprotein particles, and biliary excretion. Its abnormal metabolism can lead to increased risk for various endocrine disorders and cardiovascular diseases.","Organismal Systems; Digestive system"
"map05010","Alzheimer disease","Alzheimer disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specfically the more amyloidogenic form, Abeta42. It was proposed that Abeta form Ca2+ permeable pores and bind to and modulate multiple synaptic proteins, including NMDAR, mGluR5 and VGCC, leading to the overfilling of neurons with calcium ions. Consequently, cellular Ca2+ disruptions will lead to neuronal apoptosis, autophagy deficits, mitochondrial abnormality, defective neurotransmission, impaired synaptic plasticity and neurodegeneration in AD. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress.","Human Diseases; Neurodegenerative disease"
"map05012","Parkinson disease","Parkinson disease (PD) is a progressive neurodegenerative movement disorder that results primarily from the death of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Both environmental factors and mutations in familial PD-linked genes such as SNCA, Parkin, DJ-1, PINK1 and LRRK2 are associated with PD pathogenesis. These pathogenic mutations and environmental factors are known to cause disease due to oxidative stress, intracellular Ca2+ homeostasis impairment, mitochondrial dysfunctions and altered protein handling compromising key roles of DA neuronal function and survival. The demise of DA neurons located in the SNc leads to a drop in the dopaminergic input to the striatum, which is hypothesized to impede movement by inducing hypo and hyper activity in striatal spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal ganglia, respectively.","Human Diseases; Neurodegenerative disease"
"map05014","Amyotrophic lateral sclerosis","Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive degeneration of motor neurons in the brain and spinal cord. In 90% of patients, ALS is sporadic, with no clear genetic linkage. On the other hand, the remaining 10% of cases show familial inheritance, with mutations in SOD1, TDP43(TARDBP), FUS, or C9orf72 genes being the most frequent causes. In spite of such difference, familial ALS and sporadic ALS have similarities in their pathological features. Proposed disease mechanisms contributing to motor neuron degeneration in ALS are: impaired proteostasis, aberrant RNA processing, mitochondrial disfunction and oxidative stress, microglia activation, and axonal dysfunction.","Human Diseases; Neurodegenerative disease"
"map05016","Huntington disease","Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). The symptoms are choreiform, involuntary movements, personality changes and dementia. HD is caused by a CAG repeat expansion in the IT15 gene, which results in a long stretch of polyglutamine (polyQ) close to the amino-terminus of the HD protein huntingtin (Htt). Mutant Htt (mHtt) has effects both in the cytoplasm and in the nucleus. Full-length huntingtin is cleaved by proteases in the cytoplasm, leading to the formation of cytoplasmic and neuritic aggregates. mHtt also alters vesicular transport and recycling, causes cytosolic and mitochondrial Ca2+  overload, triggers endoplasmic reticulum stress through proteasomal dysfunction, and impairs autophagy function, increasing neuronal death susceptibility. N-terminal fragments containing the polyQ strech translocate to the nucleus where they impair transcription and induce neuronal death.","Human Diseases; Neurodegenerative disease"
"map05017","Spinocerebellar ataxia","The autosomal dominant spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative diseases characterised by loss of balance and motor coordination due to the primary dysfunction of the cerebellum. Compelling evidence points to major aetiological roles for transcriptional dysregulation, protein aggregation and clearance, autophagy, the ubiquitin-proteasome system, alterations of calcium homeostasis, mitochondria defects, toxic RNA gain-of-function mechanisms and eventual cell death with apoptotic features of neurons during SCA disease progression.","Human Diseases; Neurodegenerative disease"
"map05020","Prion disease","Prion diseases, also termed transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases that affect humans and a number of other animal species. The etiology of these diseases is thought to be associated with the conversion of a normal protein, PrPC, into an infectious, pathogenic form, PrPSc. The conversion is induced by prion infections (for example, variant Creutzfeldt-Jakob disease (vCJD), iatrogenic CJD, Kuru), mutations (familial CJD, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia (FFI)) or unknown factors (sporadic CJD (sCJD)), and is thought to occur after PrPC has reached the plasma membrane or is re-internalized for degradation. The PrPSc form shows greater protease resistance than PrPC and accumulates in affected individuals, often in the form of extracellular plaques. Pathways that may lead to neuronal death comprise oxidative stress, regulated activation of complement, ubiquitin-proteasome and endosomal-lysosomal systems, synaptic alterations and dendritic atrophy, corticosteroid response, and endoplasmic reticulum stress. In addition, the conformational transition could lead to the lost of a beneficial activity of the natively folded protein, PrPC.","Human Diseases; Neurodegenerative disease"
"map05022","Pathways of neurodegeneration - multiple diseases","Neurodegeneration is generally defined as progressive, irreversible loss of neurons, which may affect either the peripheral or central nervous system (CNS). Neurodegenerative diseases (NDs) include highly debilitating illnesses, such as Alzheimer (AD), Parkinson disease (PD), amyotrophic lateral sclerosis, Huntington disease, spinocerebellar ataxias, and prion diseases (PrD). The hallmark event, which is thought to be at the root of these diseases, is the progressive accumulation of misfolded protein aggregates. Major basic processes include abnormal protein dynamics due to deficiency of the ubiquitin-proteosome-autophagy system, oxidative stress and free radical formation, endoplasmic reticulum stress, mitochondrial dysfunction and (secondary) disruptions of axonal transport.","Human Diseases; Neurodegenerative disease"
"map05030","Cocaine addiction","Drug addiction is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behavior persists despite serious negative consequences.There is strong evidence that the dopaminergic system that projects from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAc), and to other forebrain sites, is the major substrate of reward and reinforcement for both natural rewards and addictive drugs. Cocaine binds strongly to the dopamine-reuptake transporter, preventing the reuptake of dopamine into the nerve terminal. Because of this blocking effect, dopamine remains at high concentrations in the synapse and continues to affect adjacent neurons, producing the characteristic cocaine high. Activated D1 receptor activates the PKA signaling pathway, and this pathway plays a critical role in mediating the behavioral responses to cocaine administration. Cocaine-induced neuroadaptations, including dopamine depletion, may underlie craving and hedonic dysregulation.","Human Diseases; Substance dependence"
"map05031","Amphetamine addiction","Amphetamine is a psychostimulant drug that exerts persistent addictive effects. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the brain reward circuit. Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. Acute administration of amphetamine induces phosphorylation of cAMP response element-binding protein (CREB) and expression of a number of immediate early genes (IEGs), such as c-fos. The IEGs is likely to initiate downstream molecular events, which may have important roles in the induction and maintenance of addictive states. Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.","Human Diseases; Substance dependence"
"map05032","Morphine addiction","Morphine is an alkaloid from the plant extracts of opium poppy. Although morphine is highly effective for the treatment of pain, it is also known to be intensely addictive. We now know that the most important brain-reward circuit involves dopamine (DA) -containing neurons in the ventral tegmental area (VTA) of the midbrain and their target areas in the limbic forebrain, in particular, the nucleus accumbens (NAc) and frontal regions of cerebral cortex. Morphine can cause indirect excitation of VTA dopamine neurons by reducing inhibitory synaptic transmission mediated by GABAergic neurons. The chronic use of morphine is characterized by adaptive changes in neurons and neuronal communication; such adaptations (e.g., 'superactivation' of adenylyl cyclase) must underlie altered behaviour associated with morphine dependence and withdrawal syndrome, as well as drug-induced craving and relapse to drug use.","Human Diseases; Substance dependence"
"map05033","Nicotine addiction","Nicotine is one of the main psychoactive ingredients in tobacco that contributes to the harmful tobacco smoking habit. A common feature of addictive drugs, including nicotine, is that they increase dopamine (DA) release in the nucleus accumbens (NAc). The principal dopaminergic projections to NAc arise from neurons in the ventral tegmental area (VTA). In the VTA, alpha6- and alpha4beta2-containing nAChRs (alpha6*-AChRs and alpha4beta2*-AChRs, respectively) are located on GABAergic terminals and provide inhibitory inputs onto DAergic neuons, while alpha7*-nAChRs are located on glutamatergic terminals and activation of these receptors enhances glutamate release and increases excitability of DAergic neurons. Nicotine acts as an agonist to activate and desensitize these nicotinic acetylcholine receptors (nAChRs). After a short exposure to nicotine, alpha6*- and alpha4beta2*- nAChRs on GABAergic afferents are desensitized, decreasing GABA release and decreasing local inhibition of DA neurons. But the alpha7*-nAChRs on glutamatergic afferents remain active and enhance glutamate excitation of the DA neurons, leading to increased DA release in the NAc -and so facilitate the reinforcing effects of nicotine.","Human Diseases; Substance dependence"
"map05034","Alcoholism","Alcoholism, also called dependence on alcohol (ethanol), is a chronic relapsing disorder that is progressive and has serious detrimental health outcomes. As one of the primary mediators of the rewarding effects of alcohol, dopaminergic ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) have been identified. Acute exposure to alcohol stimulates dopamine release into the NAc, which activates D1 receptors, stimulating PKA signaling and subsequent CREB-mediated gene expression, whereas chronic alcohol exposure leads to an adaptive downregulation of this pathway, in particular of CREB function. The decreased CREB function in the NAc may promote the intake of drugs of abuse to achieve an increase in reward and thus may be involved in the regulation of positive affective states of addiction. PKA signaling also affects NMDA receptor activity and may play an important role in neuroadaptation in response to chronic alcohol exposure.","Human Diseases; Substance dependence"
"map05100","Bacterial invasion of epithelial cells","Many pathogenic bacteria can invade phagocytic and non-phagocytic cells and colonize them intracellularly, then become disseminated to other cells. Invasive bacteria induce their own uptake by non-phagocytic host cells (e.g. epithelial cells) using two mechanisms referred to as zipper model and trigger model. Listeria, Staphylococcus, Streptococcus, and Yersinia are examples of bacteria that enter using the zipper model. These bacteria express proteins on their surfaces that interact with cellular receptors, initiating signalling cascades that result in close apposition of the cellular membrane around the entering bacteria. Shigella and Salmonella are the examples of bacteria entering cells using the trigger model. These bacteria use type III secretion systems to inject protein effectors that interact with the actin cytoskeleton.","Human Diseases; Infectious disease: bacterial"
"map05110","Vibrio cholerae infection","Cholera toxin (CTX) is one of the main virulence factors of Vibrio cholerae. Once secreted, CTX B-chain (CTXB) binds to ganglioside GM1 on the surface of the host's cells. After binding takes place, the entire CTX complex is carried from plasma membrane (PM) to endoplasmic reticulum (ER). In the ER, the A-chain (CTXA) is recognized by protein disulfide isomerase (PDI), unfolded, and delivered to the membrane where the membrane-associated ER-oxidase, Ero1, oxidizes PDI to release the CTXA into the protein-conducting channel, Sec61. CTXA is then retro-translocated to the cytosol and induces water and electrolyte secretion by increasing cAMP levels via adenylate cyclase (AC) to exert toxicity.
            Other than CTX, Vibrio cholerae generates several toxins that are perilous to eukaryotic cells. Zonula occludens toxin (ZOT) causes tight junction disruption through protein kinase C-dependent actin polymerization. RTX toxin (RtxA) causes actin depolymerization by covalently cross-linking actin monomers into dimers, trimers, and higher multimers. Vibrio cholerae cytolysin (VCC) is an important pore-forming toxin. The assembly of VCC anion channels in cells cause vacuolization and lysis.","Human Diseases; Infectious disease: bacterial"
"map05111","Biofilm formation - Vibrio cholerae","Surface colonization and subsequent biofilm formation and development provide numerous advantages to microorganisms. On the other hand, biofilm formation is an energetically costly process and therefore must be tightly regulated and plastic, enabling biofilm bacteria to be responsive to the various environmental cues. The quorum sensing (QS) pathway of Vibrio cholerae activates the expression of VpsR, VpsT and AphA (the main activators of biofilm formation) at low cell density and HapR (the main repressor) at high cell density. At low cell density, biofilm genes, including Vibrio polysaccharide (VPS) biosynthesis genes and the major extracellular matrix genes RbmA, RbmC, and Bap1, are expressed. The QS pathway also leads to induction of virulence factors such as toxin coregulated pilus (TCP) and cholera toxin (CTX), essential for colonization of the host and enterotoxicity, respectively. The VarS/VarA signaling system responds to an unknown environmental cue and represses biofilm production by process which involves the regulatory sRNAs CsrB, CsrC and CsrD and the RNA-binding protein CsrA, interfering with LuxO of the QS pathway. The second messenger cAMP acts as a repressor of biofilm formation. cAMP is generated by adenylate cyclase CyaA, and in complex with cAMP receptor protein (CRP), this nucleotide has been shown to upregulate HapR production through the positive regulation of the CAI-I synthase CqsA and the negative regulation of Fis. The second messenger c-di-GMP is a key signalling molecule controlling motility and biofilm matrix production. High cellular levels of c-di-GMP promote enhanced transcription of genes involved in biofilm formation, possibly by promoting VpsT-mediated transcriptional activation of vps genes.","Cellular Processes; Cellular community - prokaryotes"
"map05120","Epithelial cell signaling in Helicobacter pylori infection","Two major virulence factors of H. pylori are the vacuolating cytotoxin (VacA) and the cag type-IV secretion system (T4SS) and its translocated effector protein, cytotoxin-associated antigen A (CagA).
            VacA binds to lipid rafts and glycosylphosphatidylinositol-anchored proteins (GPI-APs) of the target cell membrane. After insertion into the plasma membrane, VacA channels are endocytosed and eventually reach late endosomal compartments, increasing their permeability to anions with enhancement of the electrogenic vacuolar ATPase (v-ATPase) proton pump. In the presence of weak bases, osmotically active acidotropic ions will accumulate in the endosomes. This leads to water influx and vesicle swelling, an essential step in vacuole formation. In addition, it is reported that the VacA cleavage product binds to the tyrosine phosphatase receptor zeta (Ptprz) on epithelial cells and the induced signaling leads to the phosphorylation of the G protein-coupled receptor kinase-interactor 1 (Git1) and induces ulcerogenesis in mice.
            The other virulence factor cag T4SS mediates the translocation of the effector protein CagA, which is subsequently phosphorylated by a Src kinase. Phosphorylated CagA interacts with the protein tyrosine phosphatase SHP-2, thus stimulating its phosphatase activity. Activated SHP-2 is able to induce MAPK signalling through Ras/Raf-dependent and -independent mechanisms. Deregulation of this pathway by CagA may lead to abnormal proliferation and movement of gastric epithelial cells.","Human Diseases; Infectious disease: bacterial"
"map05130","Pathogenic Escherichia coli infection","Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) are closely related pathogenic strains of Escherichia coli. The hallmark of EPEC/EHEC infections [DS:H00278 H00277] is induction of attaching and effacing (A/E) lesions that damage intestinal epithelial cells. The capacity to form A/E lesions is encoded mainly by the locus of enterocyte effacement (LEE) pathogenicity island. Tir, Map, EspF, EspG are known LEE-encoded effector proteins secreted via the type III secretion system, which is also LEE-encoded, into the host cell. EPEC and EHEC Tir's link the extracellular bacterium to the cell cytoskeleton. Map and EspF are involved in mitochondrion membrane permeabilization. EspG interacts with tubulins and stimulates microtubule destabilization. LEE-encoded adhesin or intimin (Eae) is exported via the general secretory pathway to the periplasm, where it is inserted into the outer membrane. In addition to Tir, two potential host cell-carried intimin receptors, beta1 integrin (ITGB1) and nucleolin (NCL), have so far been identified. The distinguishing feature of EHEC is the elaboration of Shiga-like toxin (Stx). Stx cleaves ribosomal RNA, thereby disrupting protein synthesis and killing the intoxicated epithelial or endothelial cells.","Human Diseases; Infectious disease: bacterial"
"map05131","Shigellosis","Shigellosis, or bacillary dysentery, is an intestinal infection caused by Shigella, a genus of enterobacteria. Shigella are potential food-borne pathogens that are capable of colonizing the intestinal epithelium by exploiting epithelial-cell functions and circumventing the host innate immune response. During basolateral entry into the host-cell cytoplasm, Shigella deliver a subset of effectors into the host cells through the type III secretion system. The effectors induce membrane ruffling through the stimulation of the Rac1-WAVE-Arp2/3 pathway, enabling bacterial entry into the epithelial cells. During multiplication within the cells, Shigella secrete another subset of effectors. VirG induces actin polymerization at one pole of the bacteria, allowing the bacteria to spread intracellularly and to infect adjacent cells. OspF, OspG and IpaH(9.8) downregulate the production of proinflammatory cytokines such as IL-8, helping bacteria circumvent the innate immune response.","Human Diseases; Infectious disease: bacterial"
"map05132","Salmonella infection","Salmonella infection usually presents as a self-limiting gastroenteritis or the more severe typhoid fever and bacteremia. The common disease-causing Salmonella species in human is a single species, Salmonella enterica, which has numerous serovars.
            Following intestinal colonization Salmonella inject effector proteins into the host cells using a type III secretion system (T3SS), T3SS1. Then a small group of effector proteins induce rearrangement of the actin cytoskeleton resulting in membrane ruffles and rapid internalization of the bacteria.The T3SS2 is responsible for translocating effector proteins that direct Salmonella-containing vacuole (SCV) maturation. The majority of the bacteria are known to survive and replicate in SCV.","Human Diseases; Infectious disease: bacterial"
"map05133","Pertussis","Pertussis, also known as whooping cough, is an acute respiratory infectious disease caused by a bacteria called Bordetella Pertussis. The characteristic symptoms are paroxysmal cough, inspiratory wheezing and post-tussive vomiting.
            Following the inhalation of respiratory secretions from an infected individual, bacteria enter the upper respiratory tract and adhere to epithelial cells. Several adhesion factors have been implicated: the filamentous hemagglutinin (FHA), fimbriae, and pertactin (Prn).
            Pertussis toxin (Ptx) and adenylate cyclase toxin (ACT) have been identified so far as major protein toxins of B. pertussis. PTX is a hexameric AB5-type exotoxin. Catalytic A subunit catalyzes the ADP-ribosylation of the Gi subunits of the heterotrimeric G protein, then inhibits multiple downstream pathways. ACT is able to penetrate the cytoplasmic membrane of host cells and becomes activated through the cleavage and the binding of calmodulin (CaM). Activated ACT converts ATP to cyclic AMP and subverts cellular signaling pathways.","Human Diseases; Infectious disease: bacterial"
"map05134","Legionellosis","Legionellosis is a potentially fatal infectious disease caused by the bacterium Legionella pneumophila and other legionella species. Two distinct clinical and epidemiological syndromes are associated with Legionella species: Legionnaires' disease is the more severe form of the infection, which may involve pneumonia, and Pontiac fever is a milder respiratory illness.
            The pathogenesis of L. pneumophila is derived from its growth within lung macrophages. One of the L. pneumophila's type IV secretion systems, the Dot/Icm secretion system, is of critical importance for its ability to replicate and to cause disease. The Dot/Icm substrates modulate multiple host cell processes and in particular, redirect trafficking of the L. pneumophila phagosome and mediate its conversion into an ER-derived organelle competent for intracellular bacterial replication. L. pneumophila also manipulates host cell death and survival pathways in a way that allows continued intracellular replication.","Human Diseases; Infectious disease: bacterial"
"map05135","Yersinia infection","Pathogenic Yersinia injects virulent Yersinia outer proteins (Yops) into the host cell through a type three secretion system (T3SS) to express its pathogenicity. Through inactivation of small GTPases by YopT protease, YopE GTPase-activating protein, and YpkA/YopO sequestration of GDP-bound small GTPases, Yersinia prevents its uptake by phagocytic cells and disrupts the actin cytoskeleton. YopH phosphatase shuts down phagocytosis by dephosphorylating key host proteins as well as suppresses T cell activation. Yersinia induces macrophage pyroptosis via YopB/YopD activation of canonical and noncanonical inflammasomes and YopT/YopE-mediated activation of pyrin. These effects are counteracted by YopK and YopM. YopP/J is a member of an ubiquitin-like protein cysteine protease family and simultaneously targets signaling components of the MAPK and NF-kappaB signaling pathways following activation of Toll-like receptor4 to inhibit production of proinflammatory cytokines.","Human Diseases; Infectious disease: bacterial"
"map05140","Leishmaniasis","Leishmania is an intracellular protozoan parasite of macrophages that causes visceral, mucosal, and cutaneous diseases. The parasite is transmitted to humans by sandflies, where they survive and proliferate intracellularly by deactivating the macrophage. Successful infection of Leishmania is achieved by alteration of signaling events in the host cell, leading to enhanced production of the autoinhibitory molecules like TGF-beta and decreased induction of cytokines such as IL12 for protective immunity. Nitric oxide production is also inhibited. In addition, defective expression of major histocompatibility complex (MHC) genes silences subsequent T cell activation mediated by macrophages, resulting in abnormal immune responses.","Human Diseases; Infectious disease: parasitic"
"map05142","Chagas disease","Trypanosoma cruzi is an intracellular protozoan parasite that causes Chagas disease, also called American trypanosomiasis. The parasite life cycle involves hematophagous reduviid bugs as vectors. Once parasites enter the host body, they invade diverse host cells including cardiomyocytes. Establishment of infection depends on various parasite molecules such as cruzipain, oligopeptidase B, and trans-sialidase that activate Ca2+ signaling. Internalized parasites escape from the parasitophorous vacuole using secreted pore-forming TcTOX molecule and replicate in the cytosol. Multiplied parasites eventually lyse infected host cells and are released in the circulation. During these events, the parasites manipulate host innate immunity and elicit cardiomyocyte hypertrophy. T lymphocyte responses are also disturbed.","Human Diseases; Infectious disease: parasitic"
"map05143","African trypanosomiasis","Trypanosoma brucei, the parasite responsible for African trypanosomiasis (sleeping sickness), are spread by the tsetse fly in sub-Saharan Africa. The parasites are able to pass through the blood-brain barrier and cause neurological damage by inducing cytokines like TNF alpha, IFN gamma, and IL1. These cytokines and other metabolites such as nitric oxide and somnogenic prostaglandin D2 disturb circadian rhythms in patients with African trypanosomiasis.","Human Diseases; Infectious disease: parasitic"
"map05144","Malaria","Plasmodium protozoa are parasites that account for malaria infection. Sporozoite forms of the parasite are injected by mosquito bites under the skin and are carried to the liver where they develop into the merozoite form.
            Sporozoite invasion of hepatocytes is mediated by parasite surface protein like CSP. Subsequent infection into red blood cells (RBCs) by merozoites causes malaria disease via aberrant cytokine production and sequestration of parasite-infected red blood cells (pRBCs) to host endothelium. Microvasculature sequestration in the brain brings about cerebral malaria that can results in death or persisting neurological impairment. PfEMP1 has been suggested as the key adhesive molecule of pRBCs.","Human Diseases; Infectious disease: parasitic"
"map05145","Toxoplasmosis","Toxoplasma gondii is an obligate intracellular parasite that is prevalent worldwide. The tachyzoite form acquired by oral ingestion downmodulates proinflammatory signaling pathways via various mechanisms. During early infection, nuclear translocation of NFkB is temporally blocked and p38 MAPK phosphorylation is prevented, suppressing IL-12 production. Another pathway for IL-12 induction occurs through CCR5 dependent pathway, but parasitic induction of an eicosanoid LXA4 contributes to the downregulation of IL-12. Direct activation of STAT3 by the parasite enhance anti-inflammatory function of IL-10 and TGF beta. T. gondii can cause lifelong chronic infection by establishing an anti-apoptotic environment through induction of bcl-2 or IAPs and by redirecting LDL-mediated cholesterol transport to scavenge nutrients from the host.","Human Diseases; Infectious disease: parasitic"
"map05146","Amoebiasis","Entamoeba histolytica, an extracellular protozoan parasite is a human pathogen that invades the intestinal epithelium. Infection occurs on ingestion of contaminated water and food. The pathogenesis of amoebiasis begins with parasite attachment and disruption of the intestinal mucus layer, followed by apoptosis of host epithelial cells. Intestinal tissue destruction causes severe dysentery and ulcerations in amoebic colitis. Several amoebic proteins such as lectins, cysteine proteineases, and amoebapores are associated with the invasion process. The parasite can cause extraintestinal infection like amoebic liver abscess by evading immune response.","Human Diseases; Infectious disease: parasitic"
"map05150","Staphylococcus aureus infection","Staphylococcus aureus can cause multiple forms of infections ranging from superficial skin infections to food poisoning and life-threatening infections. The organism has several ways to divert the effectiveness of the immune system: secreting immune modulating proteins that inhibit complement activation and neutrophil chemotaxis or lysis, modulating the sensitivity to cationic antimicrobial peptides (such as defensin) by increasing the positive net charge of its cytoplasmic membrane, and expression of superantigens that prevent development of a normal immune response or cause an emetic response when ingested.","Human Diseases; Infectious disease: bacterial"
"map05152","Tuberculosis","Tuberculosis, or TB, is an infectious disease caused by Mycobacterium tuberculosis. One third of the world's population is thought to be infected with TB. About 90% of those infected result in latent infections, and about 10% of latent infections develop active diseases when their immune system is impaired due to the age, other diseases such as AIDS or exposure to immunosuppressive drugs. TB is transmitted through the air and primarily attacks the lungs, then it can spread by the circulatory system to other parts of body. Once TB bacilli have entered the host by the respiratory route and infected macrophages in the lungs, they interfere with phagosomal maturation, antigen presentation, apoptosis and host immune system to establish persistent or latent infection.","Human Diseases; Infectious disease: bacterial"
"map05160","Hepatitis C","Hepatitis C virus (HCV) is a major cause of chronic liver disease. The HCV employ several strategies to perturb host cell immunity. After invasion, HCV RNA genome functions directly as an mRNA in the cytoplasm of the host cell and forms membrane-associated replication complexes along with non-structural proteins. Viral RNA can trigger the RIG-I pathway and interferon production during this process. Translated HCV protein products regulate immune response to inhibit the action of interferon. HCV core and NS5A proteins appear to be the most important molecules with regulatory functions that modulate transcription, cellular proliferation, and apoptosis.","Human Diseases; Infectious disease: viral"
"map05161","Hepatitis B","Hepatitis B virus (HBV) is an enveloped virus and contains a partially double-stranded relaxed circular DNA (RC-DNA) genome. After entry into hepatocytes, HBV RC-DNA is transported to the nucleus and converted into a covalently closed circular molecule cccDNA. The cccDNA is the template for transcription of all viral RNAs including the pregenomic RNA (pgRNA), encoding for 7 viral proteins: large, middle, and small envelope proteins (LHBs, MHBs, and SHBs) that form the surface antigen (HBsAg), the core antigen (HBcAg), the e antigen (HBeAg), the HBV polymerase, and the regulatory protein X (HBx). The pgRNA interacts with the viral polymerase protein to initiate the encapsidation into the core particles. Through endoplasmic reticulum, the core particles finish assembling with the envelope proteins and are released. HBV infection leads to a wide spectrum of liver diseases raging from chronic hepatitis, cirrhosis to hepatocellular carcinoma. The mechanism of liver injury is still not clear. However, HBV proteins target host proteins, involved in a variety of functions, thus regulating transcription, cellular signaling cascades, proliferation, differentiation, and apoptosis.","Human Diseases; Infectious disease: viral"
"map05162","Measles","Measles virus (MV) is highly contagious virus that leads infant death worldwide. Humans are the unique natural reservoir for this virus. MV infection is characterized by virus-induced immune suppression that can lead to increased susceptibility to secondary bacterial and viral infections. The P, V and C proteins act as virulence factors to suppress innate immune response in host by inhibiting signaling for both type I IFN induction and JAK/STAT-mediated interferon-stimulated gene (ISG) induction. Moreover,  H protein expressed on viral particles and binding to SLAM or CD46,  as well as N protein liberated from infected cells and interacting with Fc-gamma R, causes an inhibition of IL-12 synthesis in dendritic cells. IL-12 is a key cytokine inducing cellular immune responses to protect host from the harm caused by pathogenic infections.","Human Diseases; Infectious disease: viral"
"map05163","Human cytomegalovirus infection","Human cytomegalovirus (HCMV) is an enveloped, double-stranded DNA virus that is a member of beta-herpesvirus family. HCMV is best known for causing significant morbidity and mortality in immunocompromised populations. As with other herpesviruses, HCMV gB and gH/gL envelope glycoproteins are essential for virus entry. HCMV gB could activate the PDGFRA, and induce activation of the oncogenic PI3-K/AKT pathway. Though it is unlikely that HCMV by itself can act as an oncogenic factor, HCMV may have an oncomodulatory role, to catalyze an oncogenic process that has already been initiated. US28, one of the four HCMV-encoded vGPCRs (US27, US28, UL33 and UL78), also has a specific role in the oncomodulatory properties. In addition, HCMV has developed numerous mechanisms for manipulating the host immune system. The virally encoded US2, US3, US6 and US11 gene products all interfere with major histocompatibility complex (MHC) class I antigen presentation. HCMV encodes several immediate early (IE) antiapoptotic proteins (IE1, IE2, vMIA and vICA). These proteins might avoid immune clearance of infected tumor cells by cytotoxic lymphocytes and NK cells.","Human Diseases; Infectious disease: viral"
"map05164","Influenza A","Influenza is a contagious respiratory disease caused by influenza virus infection. Influenza A virus is responsible for both annual seasonal epidemics and periodic worldwide pandemics. Novel strains that cause pandemics arise from avian influenza virus by genetic reassortment among influenza viruses and two surface glycoproteins HA and NA form the basis of serologically distinct virus types. The innate immune system recognizes invaded virus through multiple mechanisms. Viral non-structural NS1 protein is a multifunctional virulence factor that interfere IFN-mediated antiviral response. It inhibits IFN production by blocking activation of transcription factors such as NF-kappa B and IRF3. NS1 further inhibits the activation of IFN-induced antiviral genes. PB1-F2 protein is another virulence factor that induce apoptosis of infected cells, which results in life-threatening bronchiolitis.","Human Diseases; Infectious disease: viral"
"map05165","Human papillomavirus infection","Human papillomavirus (HPV) is a non-enveloped, double-stranded DNA virus. HPV infect mucoal and cutaneous epithelium resulting in several types of pathologies, most notably, cervical cancer. All types of HPV share a common genomic structure and encode eight proteins: E1, E2, E4, E5, E6, and E7 (early) and L1 and L2 (late). It has been demonstrated that E1 and E2 are involved in viral transcription and replication. The functions of the E4 protein is not yet fully understood. E5, E6, and E7 act as oncoproteins. E5 inhibits the V-ATPase, prolonging EGFR signaling and thereby promoting cell proliferation. The expression of E6 and E7 not only inhibits the tumor suppressors p53 and Rb, but also alters additional signalling pathways. Among these pathways, PI3K/Akt signalling cascade plays a very important role in HPV-induced carcinogenesis. The L1 and L2 proteins form icosahedral capsids for progeny virion generation.","Human Diseases; Infectious disease: viral"
"map05166","Human T-cell leukemia virus 1 infection","Human T-cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Expression of Tax, a viral regulatory protein is critical to the pathogenesis. Tax is a transcriptional co-factor that interfere several signaling pathways related to anti-apoptosis or cell proliferation. The modulation of the signaling by Tax involve its binding to transcription factors like CREB/ATF, NF-kappa B, and SRF.","Human Diseases; Infectious disease: viral"
"map05167","Kaposi sarcoma-associated herpesvirus infection","Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the most recently identified human tumor virus, and is associated with the pathogenesis of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and Multicentric Castleman's disease (MCD). Like all other herpesviruses, KSHV displays two modes of life cycle, latency and lytic replication, which are characterized by the patterns of viral gene expression. Genes expressed in latency (LANA, v-cyclin, v-FLIP, Kaposins A, B and C and viral miRNAs) are mainly thought to facilitate the establishment of life long latency in its host and survival against the host innate, and adaptive immune surveillance mechanisms. Among the viral proteins shown to be expressed during lytic replication are potent signaling molecules such as vGPCR, vIL6, vIRFs, vCCLs, K1 and K15, which have been implicated experimentally in the angiogenic and inflammatory phenotype observed in KS lesions. Several of these latent viral and lytic proteins are known to transform host cells, linking KSHV with the development of severe human malignancies.","Human Diseases; Infectious disease: viral"
"map05168","Herpes simplex virus 1 infection","Herpes simplex virus 1(HSV-1) is a common human pathogen, which initially infects orofacial mucosal surfaces. The virus replicates in epithelial cells at these sites, causing clinically overt disease characterized by vesicular lesions. HSV-1 then penetrates to the nervous system and establishes latency in sensory neurons. Throughout the lifetime of the host, HSV-1 may reactivate from its latent state and reinitiate a lytic infection cycle. HSV-1 has developed various mechanisms to escape its host innate immune responses and increased its capacity to replicate and to persist. ICP34.5, ICP0, ICP27, Us11 and Vhs (UL41) are the proteins involved in viral interference.","Human Diseases; Infectious disease: viral"
"map05169","Epstein-Barr virus infection","Epstein-Barr virus (EBV) is a gamma-herpes virus that widely infects human populations predominantly at an early age but remains mostly asymptomatic. EBV has been linked to a wide spectrum of human malignancies, including nasopharyngeal carcinoma and other hematologic cancers, like Hodgkin's lymphoma, Burkitt's lymphoma (BL), B-cell immunoblastic lymphoma in HIV patients, and posttransplant-associated lymphoproliferative diseases.  EBV has the unique ability to establish life-long latent infection in primary human B lymphocytes. During latent infection, EBV expresses a small subset of genes, including 6 nuclear antigens (EBNA-1, -2, -3A, -3B, -3C, and -LP), 3 latent membrane proteins (LMP-1, -2A, and -2B), 2 small noncoding RNAs (EBER-1 and 2). On the basis of these latent gene expression, three different latency patterns associated with the types of cancers are recognized.","Human Diseases; Infectious disease: viral"
"map05170","Human immunodeficiency virus 1 infection","Human immunodeficiency virus type 1 (HIV-1) , the causative agent of AIDS (acquired immunodeficiency syndrome), is a lentivirus belonging to the Retroviridae family. The primary cell surface receptor for HIV-1, the CD4 protein, and the co-receptor for HIV-1, either CCR5 or CXCR4, are found on macrophages and T lymphocytes. At the earliest step, sequential binding of virus envelope (Env) glycoprotein gp120 to CD4 and the co-receptor CCR5 or CXCR4 facilitates HIV-1 entry and has the potential to trigger critical signaling that may favor viral replication. At advanced stages of the disease, HIV-1 infection results in dramatic induction of T-cell (CD4+ T and CD8+ T cell) apoptosis both in infected and uninfected bystander T cells, a hallmark of HIV-1 pathogenesis. On the contrary, macrophages are resistant to the cytopathic effect of HIV-1 and produce virus for longer periods of time.","Human Diseases; Infectious disease: viral"
"map05171","Coronavirus disease - COVID-19","Coronavirus disease of 2019 (COVID-19) is a highly contagious respiratory infection that is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infects alveolar epithelial cells [mainly alveolar epithelial type 2 (AEC2) cells] through the angiotensin-converting enzyme 2 (ACE2) receptor. Upon the occupancy of ACE2 by SARS-CoV-2, the increased serum level of free Angiotensin II (Ang II) due to a reduction of ACE2-mediated degradation promotes activation of the NF-kappa B pathway via Ang II type 1 receptor (AT1R), followed by  interleukin-6 (IL-6) production. SARS-CoV-2 also activates the innate immune system; macrophage stimulation triggers the overproduction of pro-inflammatory cytokines, including IL-6, and the cytokine storm, which results in systemic inflammatory response syndrome and multiple organ failure. The combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability appear to be intertwined to drive the severe features of COVID-19.","Human Diseases; Infectious disease: viral"
"map05200",nothing,nothing,"Human Diseases; Cancer: overview"
"map05202","Transcriptional misregulation in cancer","In tumor cells, genes encoding transcription factors (TFs) are often amplified, deleted, rearranged via chromosomal translocation and inversion, or subjected to point mutations that result in a gain- or loss-of- function. In hematopoietic cancers and solid tumors, the translocations and inversions increase or deregulate transcription of the oncogene. Recurrent chromosome translocations generate novel fusion oncoproteins, which are common in myeloid cancers and soft-tissue sarcomas. The fusion proteins have aberrant transcriptional function compared to their wild-type counterparts. These fusion transcription factors alter expression of target genes, and thereby result in a variety of altered cellular properties that contribute to the tumourigenic process.","Human Diseases; Cancer: overview"
"map05203","Viral carcinogenesis","There is a strong association between viruses and the development of human malignancies. We now know that at least six human viruses, Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), human T-cell lymphotropic virus (HTLV-1) and Kaposi's associated sarcoma virus (KSHV) contribute to 10-15% of the cancers worldwide. Via expression of many potent oncoproteins, these tumor viruses promote an aberrant cell-proliferation via modulating cellular cell-signaling pathways and escape from cellular defense system such as blocking apoptosis. Human tumor virus oncoproteins can also disrupt pathways that are necessary for the maintenance of the integrity of host cellular genome. Viruses that encode such activities can contribute to initiation as well as progression of human cancers.","Human Diseases; Cancer: overview"
"map05204","Chemical carcinogenesis - DNA adducts","It has been estimated that exposure to environmental chemical carcinogens may contribute significantly to the causation of a sizable fraction, perhaps a majority, of human cancers. Human carcinogens act through a variety of genotoxic and non-genotoxic mechanisms. Genotoxic carcinogens can attack biological macromolecules such as DNA and RNA either directly or indirectly through metabolism, resulting in the formation of adducts with these macromolecules. If DNA adducts escape cellular repair mechanisms and persist, they may lead to miscoding, resulting in permanent mutations. Mutations cause an undefined number of cell changes, translated into aberrant protein expression and in changes in cell cycle control.","Human Diseases; Cancer: overview"
"map05205","Proteoglycans in cancer","Many proteoglycans (PGs) in the tumor microenvironment have been shown to be key macromolecules that contribute to biology of various types of cancer including proliferation, adhesion, angiogenesis and metastasis, affecting tumor progress. The four main types of proteoglycans include hyaluronan (HA), which does not occur as a PG but in free form, heparan sulfate proteoglycans (HSPGs), chondroitin sulfate proteoglycans (CSPGs), dematan sulfate proteoglycans (DSPG) and keratan sulfate proteoglycans (KSPGs) [BR:00535]. Among these proteoglycans such as HA, acting with CD44, promotes tumor cell growth and migration, whereas other proteoglycans such as syndecans (-1~-4), glypican (-1, -3) and perlecan may interact with growth factors, cytokines, morphogens and enzymes through HS chains [BR: 00536], also leading to tumor growth and invasion. In contrast, some of the small leucine-rich proteolgycans, such as decorin and lumican, can function as tumor repressors, and modulate the signaling pathways by the interaction of their core proteins and multiple receptors.","Human Diseases; Cancer: overview"
"map05206","MicroRNAs in cancer","MicroRNA (miRNA) is a cluster of small non-encoding RNA molecules of 21 - 23 nucleotides in length, which controls gene expression post-transcriptionally either via the degradation of target mRNAs or the inhibition of protein translation. Using high-throughput profiling, dysregulation of miRNAs has been widely observed in different stages of cancer. The upregulation (overexpression) of specific miRNAs could lead to the repression of tumor suppressor gene expression, and conversely the downregulation of specific miRNAs could result in an increase of oncogene expression; both these situations induce subsequent malignant effects on cell proliferation, differentiation, and apoptosis that lead to tumor growth and progress. The miRNA signatures of cancer observed in various studies differ significantly. These inconsistencies occur due to the differences in the study populations and methodologies used. This pathway map shows the summarized results from various studies in 9 cancers, each of which is presented in a review article.","Human Diseases; Cancer: overview"
"map05207","Chemical carcinogenesis - receptor activation","Carcinogenesis is a multistage process that consists of initiation, promotion, and progression stages. Chemicals or environmental factors may act at any of these stages to induce and/or enhance the carcinogenic process. Based on their mode-of-action, carcinogens can be classified as genotoxic or non-genotoxic. Genotoxic agent begins their action at the deoxyribonucleic acid (DNA) level, causing DNA damage through several mechanisms. Non-genotoxic carcinogens are chemicals that cause the development of tumors through multiple non-genotoxic events and epigenetic alterations without direct interaction with DNA. One non-genotoxic mechanism involves receptor activation. Biological mechanisms involving receptor activation fall into two broad categories: (i) those that involve cell surface receptors and some intracellular receptors that activate signal transduction pathways, resulting in biological responses, including gene transcription, and (ii) those that involve intracellular receptors that translocate into the nucleus and act as transcription factors regulating gene expression. Both classes of receptors can be involved in mechanisms of carcinogenesis.","Human Diseases; Cancer: overview"
"map05208","Chemical carcinogenesis - reactive oxygen species","It is well established that cancer is a multi-step process which involves initiation, promotion and progression. Chemical carcinogens can alter any of these processes to induce their carcinogenic effects. In the majority of instances, chemical carcinogens, directly or after xenobiotic metabolism, induce DNA damage and act in a 'genotoxic' manner. There is, however, a group of carcinogens that induce cancer via nongenotoxic mechanisms. The biochemical modes of action for nongenotoxic carcinogens are diverse, one example of which is induction of oxidative stress. Trace metals and organic xenobiotics are typical classes of environmental pollutants with prooxidant effects. Trace metals generate reactive oxygen species (ROS) depending on their ability to lose electrons and catalyze Haber Weiss and Fenton reactions. ROS are also generated due to induction of various cytochrome P450 isoenzymes during detoxification of chemical carcinogens. Increased ROS generation often has been linked to DNA damage that can lead to mutations and may, therefore, play an important role in the initiation and progression of multistage carcinogenesis. Besides causing DNA damage, ROS further induce multiple intracellular signaling pathways, notably NF-kappa B, JNK/SAPK/p38, as well as Erk/MAPK. These signaling routes can lead to transcriptional induction of target genes that could promote proliferation or confer apoptosis resistance to exposed cells.","Human Diseases; Cancer: overview"
"map05210","Colorectal cancer","Colorectal cancer (CRC) is the second largest cause of cancer-related deaths in Western countries. CRC arises from the colorectal epithelium as a result of the accumulation of genetic alterations in defined oncogenes and tumour suppressor genes (TSG). Two major mechanisms of genomic instability have been identified in sporadic CRC progression. The first, known as chromosomal instability (CIN), results from a series of genetic changes that involve the activation of oncogenes such as K-ras and inactivation of TSG such as p53, DCC/Smad4, and APC. The second, known as microsatellite instability (MSI), results from inactivation of the DNA mismatch repair genes MLH1 and/or MSH2 by hypermethylation of their promoter, and secondary mutation of genes with coding microsatellites, such as transforming growth factor receptor II (TGF-RII) and BAX. Hereditary syndromes have germline mutations in specific genes (mutation in the tumour suppressor gene APC on chromosome 5q in FAP, mutated DNA mismatch repair genes in HNPCC).","Human Diseases; Cancer: specific types"
"map05211","Renal cell carcinoma","Renal cell cancer (RCC) accounts for ~3% of human malignancies and its incidence appears to be rising. Although most cases of RCC seem to occur sporadically, an inherited predisposition to renal cancer accounts for 1-4% of cases. RCC is not a single disease, it has several morphological subtypes. Conventional RCC (clear cell RCC) accounts for ~80% of cases, followed by papillary RCC (10-15%), chromophobe RCC (5%), and collecting duct RCC (<1%). Genes potentially involved in sporadic neoplasms of each particular type are VHL, MET, BHD, and FH respectively. In the absence of VHL, hypoxia-inducible factor alpha (HIF-alpha) accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. Activated MET mediates a number of biological effects including motility, invasion of extracellular matrix, cellular transformation, prevention of apoptosis and metastasis formation. Loss of functional FH leads to accumulation of fumarate in the cell, triggering inhibition of HPH and preventing targeted pVHL-mediated degradation of HIF-alpha. BHD mutations cause the Birt-Hogg-Dube syndrome and its associated chromophobe, hybrid oncocytic, and conventional (clear cell) RCC.","Human Diseases; Cancer: specific types"
"map05212","Pancreatic cancer","Infiltrating ductal adenocarcinoma is the most common malignancy of the pancreas. When most investigators use the term 'pancreatic cancer' they are referring to pancreatic ductal adenocarcinoma (PDA). Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway.","Human Diseases; Cancer: specific types"
"map05213","Endometrial cancer","Endometrial cancer (EC) is the most common gynaecological malignancy and the fourth most common malignancy in women in the developed world after breast, colorectal and lung cancer. Two types of endometrial carcinoma are distinguished with respect to biology and clinical course. Type-I carcinoma is related to hyperestrogenism by association with endometrial hyperplasia, frequent expression of estrogen and progesterone receptors and younger age, whereas type-II carcinoma is unrelated to estrogen, associated with atrophic endometrium, frequent lack of estrogen and progesterone receptors and older age. The morphologic differences in these cancers are mirrored in their molecular genetic profile with type I showing defects in DNA-mismatch repair and mutations in PTEN, K-ras, and beta-catenin, and type II showing aneuploidy, p53 mutations, and her2/neu amplification.","Human Diseases; Cancer: specific types"
"map05214","Glioma","Gliomas are the most common of the primary brain tumors and account for more than 40% of all central nervous system neoplasms. Gliomas include tumours that are composed predominantly of astrocytes (astrocytomas), oligodendrocytes (oligodendrogliomas), mixtures of various glial cells (for example,oligoastrocytomas) and ependymal cells (ependymomas). The most malignant form of infiltrating astrocytoma - glioblastoma multiforme (GBM) - is one of the most aggressive human cancers. GBM may develop de novo (primary glioblastoma) or by progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). Primary glioblastomas develop in older patients and typically show genetic alterations (EGFR amplification, p16/INK4a deletion, and PTEN mutations) at frequencies of 24-34%. Secondary glioblastomas develop in younger patients and frequently show overexpression of PDGF and CDK4 as well as p53 mutations (65%) and loss of Rb playing major roles in such transformations. Loss of PTEN has been implicated in both pathways, although it is much more common in the pathogenesis of primary GBM.","Human Diseases; Cancer: specific types"
"map05215","Prostate cancer","Prostate cancer constitutes a major health problem in Western countries. It is the most frequently diagnosed cancer among men and the second leading cause of male cancer deaths. The identification of key molecular alterations in prostate-cancer cells implicates carcinogen defenses (GSTP1), growth-factor-signaling pathways (NKX3.1, PTEN, and p27), and androgens (AR) as critical determinants of the phenotype of prostate-cancer cells. Glutathione S-transferases (GSTP1) are detoxifying enzymes. Cells of prostatic intraepithelial neoplasia, devoid of GSTP1, undergo genomic damage mediated by carcinogens. NKX3.1, PTEN, and p27 regulate the growth and survival of prostate cells in the normal prostate. Inadequate levels of PTEN and NKX3.1 lead to a reduction in p27 levels and to increased proliferation and decreased apoptosis. Androgen receptor (AR) is a transcription factor that is normally activated by its androgen ligand. During androgen withdrawal therapy, the AR signal transduction pathway also could be activated by amplification of the AR gene, by AR gene mutations, or by altered activity of AR coactivators. Through these mechanisms, tumor cells lead to the emergence of androgen-independent prostate cancer.","Human Diseases; Cancer: specific types"
"map05216","Thyroid cancer","Thyroid cancer is the most common endocrine malignancy and accounts for the majority of endocrine cancer- related deaths each year. More than 95% of thyroid carcinomas are derived from follicular cells. Their behavior varies from the indolent growing, well-differentiated papillary and follicular carcinomas (PTC and FTC, respectively) to the extremely aggressive undifferentiated carcinoma (UC). Somatic rearrangements of RET and TRK are almost exclusively found in PTC and may be found in early stages. The most distinctive molecular features of FTC are the prominence of aneuploidy and the high prevalence of RAS mutations and PAX8-PPAR{gamma} rearrangements. p53 seems to play a crucial role in the dedifferentiation process of thyroid carcinoma.","Human Diseases; Cancer: specific types"
"map05217","Basal cell carcinoma","Cancer of the skin is the most common cancer in Caucasians and basal cell carcinomas (BCC) account for 90% of all skin cancers. The vast majority of BCC cases are sporadic, though there is a rare familial syndrome basal cell nevus syndrome (BCNS, or Gorlin syndrome) that predisposes to development of BCC. In addition, there is strong epidemiological and genetic evidence that demonstrates UV exposure as a risk factor of prime importance. The development of basal cell carcinoma is associated with constitutive activation of sonic hedgehog signaling. The mutations in SMOH, PTCH1, and SHH in BCCs result in continuous activation of target genes. At a cellular level, sonic hedgehog signaling promotes cell proliferation. Mutations in TP53 are also found with high frequency (>50%) in sporadic BCC.","Human Diseases; Cancer: specific types"
"map05218","Melanoma","Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. Melanoma arises from the malignant transformation of pigment-producing cells, melanocytes. The only known environmental risk factor is exposure to ultraviolet (UV) light and in people with fair skin the risk is greatly increased. Melanoma pathogenesis is also driven by genetic factors. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Melanoma development has been shown to be strongly associated with inactivation of the p16INK4a/cyclin dependent kinases 4 and 6/retinoblastoma protein (p16INK4a/CDK4,6/pRb) and p14ARF/human double minute 2/p53 (p14ARF/HMD2/p53) tumor suppressor pathways. MITF and TP53 are implicated in further melanoma progression.","Human Diseases; Cancer: specific types"
"map05219","Bladder cancer","The urothelium covers the luminal surface of almost the entire urinary tract, extending from the renal pelvis, through the ureter and bladder, to the proximal urethra. The majority of urothelial carcinoma are bladder carcinomas, and urothelial carcinomas of the renal pelvis and ureter account for only approximately 7% of the total. Urothelial tumours arise and evolve through divergent phenotypic pathways. Some tumours progress from urothelial hyperplasia to low-grade non-invasive superficial papillary tumours. More aggressive variants arise either from flat, high-grade carcinoma in situ (CIS) and progress to invasive tumours, or they arise de novo as invasive tumours. Low-grade papillary tumors frequently show a constitutive activation of the receptor tyrosine kinase-Ras pathway, exhibiting activating mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes. In contrast, CIS and invasive tumors frequently show alterations in the TP53 and RB genes and pathways. Invasion and metastases are promoted by several factors that alter the tumour microenvironment, including the aberrant expression of E-cadherins (E-cad), matrix metalloproteinases (MMPs), angiogenic factors such as vascular endothelial growth factor (VEGF).","Human Diseases; Cancer: specific types"
"map05220","Chronic myeloid leukemia","Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell. The natural history of CML has a triphasic clinical course comprising of an initial chronic phase (CP), which is characterized by expansion of functionally normal myeloid cells, followed by an accelerated phase (AP) and finally a more aggressive blast phase (BP), with loss of terminal differentiation capacity. On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22. The BCR/ABL fusion gene encodes p210 BCR/ABL, an oncoprotein, which, unlike the normal p145 c-Abl, has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. While fusion of c-ABL and BCR is believed to be the primary cause of the chronic phase of CML, progression to blast crisis requires other molecular changes. Common secondary abnormalities include mutations in TP53, RB, and p16/INK4A, or overexpression of genes such as EVI1. Additional chromosome translocations are also observed,such as t(3;21)(q26;q22), which generates AML1-EVI1.","Human Diseases; Cancer: specific types"
"map05221","Acute myeloid leukemia","Acute myeloid leukemia (AML) is a disease that is characterized by uncontrolled proliferation of clonal neoplastic cells and accumulation in the bone marrow of blasts with an impaired differentiation program. AML accounts for approximately 80% of all adult leukemias and remains the most common cause of leukemia death. Two major types of genetic events have been described that are crucial for leukemic transformation. A proposed necessary first event is disordered cell growth and upregulation of cell survival genes. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Alterations in myeloid transcription factors governing hematopoietic differentiation provide second necessary event for leukemogenesis. Transcription factor fusion proteins such as AML-ETO, PML-RARalpha or PLZF-RARalpha block myeloid cell differentiation by repressing target genes. In other cases, the transcription factors themselves are mutated.","Human Diseases; Cancer: specific types"
"map05222","Small cell lung cancer","Lung cancer is a leading cause of cancer death among men and women in industrialized countries. Small cell lung carcinoma (SCLC) is a highly aggressive neoplasm, which accounts for approximately 25% of all lung cancer cases. Molecular mechanisms altered in SCLC include induced expression of oncogene, MYC, and loss of tumorsuppressor genes, such as p53, PTEN, RB, and FHIT. The overexpression of MYC proteins in SCLC is largely a result of gene amplification. Such overexpression leads to more rapid proliferation and loss of terminal differentiation. Mutation or deletion of p53 or PTEN can lead to more rapid proliferation and reduced apoptosis. The retinoblastoma gene RB1 encodes a nuclear phosphoprotein that helps to regulate cell-cycle progression. The fragile histidine triad gene FHIT encodes the enzyme diadenosine triphosphate hydrolase, which is thought to have an indirect role in proapoptosis and cell-cycle control.","Human Diseases; Cancer: specific types"
"map05223","Non-small cell lung cancer","Lung cancer is a leading cause of cancer death among men and women in industrialized countries. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS, EGFR and EML4-ALK, and inactivation of tumorsuppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Mutations or overexpression of EGFR leads to a proliferative advantage. EML4-ALK fusion leads to constitutive ALK activation, which causes cell proliferation, invasion, and inhibition of apoptosis. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC. RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector.Therefore loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect.","Human Diseases; Cancer: specific types"
"map05224","Breast cancer","Breast cancer is the leading cause of cancer death among women worldwide. The vast majority of breast cancers are carcinomas that originate from cells lining the milk-forming ducts of the mammary gland. The molecular subtypes of breast cancer, which are based on the presence or absence of hormone receptors (estrogen and progesterone subtypes) and human epidermal growth factor receptor-2 (HER2), include: hormone receptor positive and HER2 negative (luminal A subtype), hormone receptor positive and HER2 positive (luminal B subtype), hormone receptor negative and HER2 positive (HER2 positive), and hormone receptor negative and HER2 negative (basal-like or triple-negative breast cancers (TNBCs)). Hormone receptor positive breast cancers are largely driven by the estrogen/ER pathway. In HER2 positive breast tumours, HER2 activates the PI3K/AKT and the RAS/RAF/MAPK pathways, and stimulate cell growth, survival and differentiation. In patients suffering from TNBC, the deregulation of various signalling pathways (Notch and Wnt/beta-catenin), EGFR protein have been confirmed. In the case of breast cancer only 8% of all cancers are hereditary, a phenomenon linked to genetic changes in BRCA1 or BRCA2. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers.","Human Diseases; Cancer: specific types"
"map05225","Hepatocellular carcinoma","Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the rare human neoplasms etiologically linked to viral factors. It has been shown that, after HBV/HCV infection and alcohol or aflatoxin B1 exposure, genetic and epigenetic changes occur. The recurrent mutated genes were found to be highly enriched in multiple key driver signaling processes, including telomere maintenance, TP53, cell cycle regulation, the Wnt/beta-catenin pathway (CTNNB1 and AXIN1), the phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Recent studies using whole-exome sequencing have revealed recurrent mutations in new driver genes involved in the chromatin remodelling (ARID1A and ARID2) and the oxidative stress (NFE2L2) pathways.","Human Diseases; Cancer: specific types"
"map05226","Gastric cancer","Gastric cancer (GC) is one of the world's most common cancers. According to Lauren's histological classification gastric cancer is divided into two distinct histological groups - the intestinal and diffuse types. Several genetic changes have been identified in intestinal-type GC. The intestinal metaplasia is characterized by mutations in p53 gene, reduced expression of retinoic acid receptor beta (RAR-beta) and hTERT expression. Gastric adenomas furthermore display mutations in the APC gene, reduced p27 expression and cyclin E amplification. In addition, amplification and overexpression of c-ErbB2, reduced TGF-beta receptor type I (TGFBRI) expression and complete loss of p27 expression are commonly observed in more advanced GC. The main molecular changes observed in diffuse-type GCs include loss of E-cadherin function by mutations in CDH1 and amplification of MET and FGFR2F.","Human Diseases; Cancer: specific types"
"map05230","Central carbon metabolism in cancer","Malignant transformation of cells requires specific adaptations of cellular metabolism to support growth and survival. In the early twentieth century, Otto Warburg established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. He showed that cancer cells consume a large amount of glucose, maintain high rate of glycolysis and convert a majority of glucose into lactic acid even under normal oxygen concentrations (Warburg's Effects). More recently, it has been recognized that the 'Warburg effect' encompasses a similarly increased utilization of glutamine. From the intermediate molecules provided by enhanced glycolysis and glutaminolysis, cancer cells synthesize most of the macromolecules required for the duplication of their biomass and genome. These cancer-specific alterations represent a major consequence of genetic mutations and the ensuing changes of signalling pathways in cancer cells. Three transcription factors, c-MYC, HIF-1 and p53, are key regulators and coordinate regulation of cancer metabolism in different ways, and many other oncogenes and tumor suppressor genes cluster along the signaling pathways that regulate c-MYC, HIF-1 and p53.","Human Diseases; Cancer: overview"
"map05231","Choline metabolism in cancer","Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, oncogenic signalling via pathways such as the RAS and PI3K-AKT pathways, and transcription factors associated with oncogenesis such as hypoxia-inducible factor 1 (HIF1) mediate overexpression and activation of choline cycle enzymes, which causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These products of choline phospholipid metabolism, such as phosphocholine (PCho), diacylglycerol (DAG) and phosphatidic acid, may function as second messengers that are essential for the mitogenic activity of growth factors, particularly in the activation of the ras-raf-1-MAPK cascade and protein kinase C pathway.","Human Diseases; Cancer: overview"
"map05235","PD-L1 expression and PD-1 checkpoint pathway in cancer","Programmed cell death 1 (PD1) and its ligand (PDL1) are key regulatory physiological immune checkpoints that maintain self-tolerance in the organism by regulating the degree of activation of T and B  cells amongst other immune cell types. In solid tumors, the PD-1/PD-L1 inhibitory pathway can be (mis-)used to silence the immune system by increasing the expression of PD-L1 on the tumor cell surface. Up-regulation of PD-L1 is caused by activation of pro-survival pathways MAPK and PI3K/Akt as well as transcriptional factors HIF-1, STAT3 and NF-kappa B. The MAPK and PI3K signalling pathways are activated by gene mutations and growth factors. PD-L1 on tumor cells may then engage the PD-1 receptors resulting in suppression of T-cell mediated immune response. Therapeutic antibodies blocking the PD-1/PD-L1 pathway by targeting PD-L1 or PD-1 are highly effective in rescuing T cell anti-tumor effector functions.","Human Diseases; Cancer: overview"
"map05310","Asthma","Asthma is a complex syndrome with many clinical phenotypes in both adults and children. Its major characteristics include a variable degree of airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Inhaled allergens encounter antigen presenting cells (APC) that line the airway. Upon recognition of the antigen and activation by APC, naive T cells differentiate into TH2 cells. Activated TH2 stimulate the formation of IgE by B cells. IgE molecules bind to IgE receptors located on mast cells. The crosslinking of mast-cell-bound IgE by allergens leads to the release of biologically active mediators (histamine, leukotrienes) by means of degranulation and, so, to the immediate symptoms of allergy. Mast cells also release chemotactic factors that contribute to the recruitment of inflammatory cells, particularly eosinophils, whose proliferation and differentiation from bone marrow progenitors is promoted by IL-5. The activation of eosinophils leads to release of toxic granules and oxygen free radicals that lead to tissue damage and promote the development of chronic inflammation.","Human Diseases; Immune disease"
"map05320","Autoimmune thyroid disease","The classification of autoimmune throid disease (AITD) includes Hashimoto's thyroiditis (HT) or chronic autoimmune thyroiditis and its variants, Graves' disease (GD) and autoimmune atrophic thyroiditis or primary myxedema. HT is characterized by the presence of goitre, thyroid autoantibodies against thyroid peroxidase (TPO) and thyroglobulin (Tg) in serum and varying degrees of thyroid dysfunction. During HT, self-reactive CD4+ T lymphocytes (Th) recruit B cells and CD8+ T cells (CTL) into the thyroid. Disease progression leads to the death of thyroid cells and hypothyroidism. Both autoantibodies and thyroid-specific cytotoxic T lymphocytes (CTLs) have been proposed to be responsible for autoimmune thyrocyte depletion. In GD, the TSH-R is the most important autoantigen. Antibodies directed against it mimic the effects of the hormone on thyroid cells, TSH, stimulating autonomous production of thyroxine and triiodothyronine and causing hyperthyroidism. The presence of TSH-R-blocking antibodies that bind the TSH receptor in a similar fashion to the antibodies in patients with Grave's disease but that block rather than activate the receptor explains some cases of atrophic hypothyroidism.","Human Diseases; Immune disease"
"map05321","Inflammatory bowel disease","Inflammatory bowel disease (IBD), which includes Crohn disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract due to environmental and genetic factors, infectious microbes, and the dysregulated immune system. Although many environmental factors (for example, geographic locations, smoking, etc.) affect the development of IBD, the most crucial might be the luminal (external) environment of the epithelial cells. There are pathogens that are found in increasing frequency in IBD. The microbial components such as flagellin, peptidoglycan, and lipopolysaccharide are recognized by receptors such as toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) proteins, and also by antigen-presenting cells (APCs) in genetically susceptible host. The TLR recognition triggers the activation of NF-kappaB, leading to an inflammatory response. APC-expressed gene NOD2 has been associated with Crohn disease. In case of mutations of NOD2, negative regulation of IL-12 production is reduced with the stimulation of muramyl dipeptide (MDP), leading to CD. In addition, the APC mediates the differentiation of naive T cells into effector T cells (Th1, Th17, Th2) and natural killer T (NKT) cells. Th1 and Th17 cells produce high levels of IFN-gamma and IL-17, -22, respectively, both of which promote CD. In contrast, Th2 cells produce IL-4, -5, -10, which together with IL-13 from NKT induce UC.","Human Diseases; Immune disease"
"map05322","Systemic lupus erythematosus","Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterised by the production of IgG autoantibodies that are specific for self-antigens, such as DNA, nuclear proteins and certain cytoplasmic components, in association with a diverse array of clinical manifestations. The primary pathological findings in patients with SLE are those of inflammation, vasculitis, immune complex deposition, and vasculopathy. Immune complexes comprising autoantibody and self-antigen is deposited particulary in the renal glomeruli and mediate a systemic inflammatory response by activating complement or via Fc{gamma}R-mediated neutrophil and macrophage activation. Activation of complement (C5) leads to injury both through formation of the membrane attack complex (C5b-9) or by generation of the anaphylatoxin and cell activator C5a. Neutrophils and macrophages cause tissue injury by the release of oxidants and proteases.","Human Diseases; Immune disease"
"map05323","Rheumatoid arthritis","Rheumatoid arthritis (RA) is a chronic autoimmune joint disease where persistent inflammation affects bone remodeling leading to progressive bone destruction. In RA, abnormal activation of the immune system elevates pro-inflammatory cytokines and chemokines levels, which can promote synovial angiogenesis and leukocyte infiltration. The synovium forms a hyperplastic pannus with infiltrated macrophage-like and fibroblast-like synoviocytes and invades joints by secreting proteinases and inducing osteoclast differentiation.","Human Diseases; Immune disease"
"map05330","Allograft rejection","Allograft rejection is the consequence of the recipient's alloimmune response to nonself antigens expressed by donor tissues. After transplantation of organ allografts, there are two pathways of antigen presentation. In the direct pathway, recipient T cells react to intact allogeneic MHC molecules expressed on the surface of donor cells. This pathway would activate host CD4 or CD8 T cells. In contrast, donor MHC molecules (and all other proteins) shed from the graft can be taken up by host APCs and presented to recipient T cells in the context of self-MHC molecules - the indirect pathway. Such presentation activates predominantly CD4 T cells. A direct cytotoxic T-cell attack on graft cells can be made only by T cells that recognize the graft MHC molecules directly. Nontheless, T cells with indirect allospecificity can contribute to graft rejection by activating macrophages, which cause tissue injury and fibrosis, and are also likely to be important in the development of an alloantibody response to graft.","Human Diseases; Immune disease"
"map05332","Graft-versus-host disease","Graft-versus-host disease (GVHD) is a lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT) where immunocompetent donor T cells attack the genetically disparate host cells. GVHD pathophysiology can be summerized in a three-step process. Step 1 involves the development of an inflammatory milieu resulting from damage in the host tissues induced by the preparative chemotherapy or radiotherapy regimen. Damaged tissues secrete inflammatory cytokines, including interleukin 1 (IL-1), and tumor necrosis factor (TNF-alpha ). During step 2, antigen-presenting cells (APCs) trigger the activation of donor-derived T cells, which induce further T-cell expansion, induce cytotoxic T lymphocytes (CTL) and natural killer (NK) cells responses and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. Also, nitric oxide (NO) is produced by activated macrophages, and it may contribute to the tissue damage seen during step 3. During step 3, the effector phase, activated CTL and NK cells mediate cytotoxicity against target host cells through Fas-Fas ligand interactions and perforin-granzyme B.","Human Diseases; Immune disease"
"map05340","Primary immunodeficiency","Primary immunodeficiencies (PIs) are a heterogeneous group of disorders, which affect cellular and humoral immunity or non-specific host defense mechanisms mediated by complement proteins, and cells such as phagocytes and natural killer (NK) cells. These disorders of the immune system cause increased susceptibility to infection, autoimmune disease, and malignancy. Most of PIs are due to genetic defects that affect cell maturation or function at different levels during hematopoiesis. Disruption of the cellular immunity is observed in patients with defects in T cells or both T and B cells. These cellular immunodeficiencies comprise 20% of all PIs. Disorders of humoral immunity affect B-cell differentiation and antibody production. They account for 70% of all PIs.","Human Diseases; Immune disease"
"map05410","Hypertrophic cardiomyopathy","Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological features of myocyte hypertrophy, myfibrillar disarray, and interstitial fibrosis. HCM is one of the most common inherited cardiac disorders, with a prevalence in young adults of 1 in 500. Hundreds of mutations in the genes that encode protein constituents of the sarcomere have been identified in HCM. These mutations increase the Ca2+ sensitivity of cardiac myofilaments. Increased myofilament Ca2+ sensitivity is expected to increase the ATP utilization by actomyosin at submaximal Ca2+ concentrations, which might cause an imbalance in energy supply and demand in the heart under severe stress. The inefficient use of ATP suggests that an inability to maintain normal ATP levels could be the central abnormality. This theory might be supported by the discovery of the role of a mutant PRKAG2 gene in HCM, which in active form acts as a central sensing mechanism protecting cells from depletion of ATP supplies. The increase in the myfilament Ca2+ sensitivity well account for the diastolic dysfunction of model animals as well as human patients of HCM. It has been widely proposed that left ventricular hypertrophy is not a primary manifestation but develops as compensatory response to sarcomere dysfunction.","Human Diseases; Cardiovascular disease"
"map05412","Arrhythmogenic right ventricular cardiomyopathy","Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that may result in arrhythmia, heart failure, and sudden death. The hallmark pathological findings are progressive myocyte loss and fibrofatty replacement, with a predilection for the right ventricle. A number of genetic studies have identified mutations in various components of the cardiac desmosome that have important roles in the pathogenesis of ARVC. Disruption of desmosomal function by defective proteins might lead to death of myocytes under mechanical stress. The myocardial injury may be accompanied by inflammation. Since regeneration of cardiac myocytes is limited, repair by fibrofatty replacement occurs. Several studies have implicated that desmosome dysfunction results in the delocalization and nuclear translocation of plakoglobin. As a result, competition between plakoglobin and beta-catenin will lead to the inhibition of Wnt/beta-catenin signaling, resulting in a shift from a myocyte fate towards an adipocyte fate of cells. The ryanodine receptor plays a crucial part in electromechanical coupling by control of release of calcium from the sarcoplasmic reticulum into the cytosol. Therefore, defects in this receptor could result in an imbalance of calcium homeostasis that might trigger cell death.","Human Diseases; Cardiovascular disease"
"map05414","Dilated cardiomyopathy","Dilated cardiomyopathy (DCM) is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac death from ventricular arrhythmia. Genetically inherited forms of DCM (familial DCM) have been identified in 25-35% of patients presenting with this disease, and the inherited gene defects are an important cause of familial DCM. The pathophysiology may be separated into two categories: defects in force generation and defects in force transmission. In cases where an underlying pathology cannot be identified, the patient is diagnosed with an idiopathic DCM. Current hypotheses regarding causes of idiopathic DCM focus on myocarditis induced by enterovirus and subsequent autoimmune myocardium impairments. Antibodies to the beta1-adrenergic receptor (beta1AR), which are detected in a substantial number of patients with idiopathic DCM, may increase the concentration of intracellular cAMP and intracellular Ca2+, a condition often leading to a transient hyper-performance of the heart followed by depressed heart function and heart failure.","Human Diseases; Cardiovascular disease"
"map05415","Diabetic cardiomyopathy","Diabetic cardiomyopathy has been defined as left ventricular dysfunction that occurs among patients with diabetes mellitus independent of a recognized cause such as coronary artery disease or hypertension. The pathogenesis of diabetic cardiomyopathy broadly involves hyperglycemia, increased circulating fatty acids, and insulin resistance contributing to reactive oxygen species (ROS) generation, mitochondrial dysfunction, impaired calcium metabolism, Renin-Angiotensin System (RAS) activation, and altered substrate metabolism. These effects result in cardiac fibrosis, hypertrophy, cardiomyocyte death, contractile dysfunction, endothelial cell damage and eventually heart failure. In the process of cardiac fibrosis, cardiac fibroblasts are the final effector cell.","Human Diseases; Cardiovascular disease"
"map05416","Viral myocarditis","Myocarditis is a cardiac disease associated with inflammation and injury of the myocardium. It results from various etiologies, both noninfectious and infectious, but coxsackievirus B3 (CVB3) is still considered the dominant etiological agent. Myocarditis may be caused by direct cytopathic effects of virus, a pathologic immune response to persistent virus, or autoimmunity triggered by the viral infection. The virus enters the myocyte through internalization of the coxsackie-adenoviral receptor (CAR) and its coreceptor, decay-accelerating factor (DAF). Viral proteases cleave various proteins in the host cell. One example is viral protease 2A, which cleaves eukaryote initiation factor 4G (eIF4G) and the dystrophin protein, resulting in a complete shutdown of cap-dependent RNA translation and cytoskeletal destruction in infected cardiomyocytes, respectively. CVB3 also cleaves the member of the Bcl-2 family Bid, leading to apoptosis. CVB3 infection also induces the cleavage of cyclin D protein through a proteasome-dependent pathway, leading to the host cell-growth arrest. Viral infection and necrosis of myocytes may lead to the release of intracellular antigens, resulting in activation of self-reactive T cells. CVB infection is a significant cause of dilated cardiomyopathy (DCM) as well as myocarditis. Epidemiologically, myocarditis underlies a significant portion of patients with DCM.","Human Diseases; Cardiovascular disease"
"map05417","Lipid and atherosclerosis","Atherosclerosis is a chronic inflammatory disease marked by a narrowing of the arteries from lipid-rich plaques present within the walls of arterial blood vessels. It represents the root cause of the majority of cardiovascular diseases (CVDs) and their complications, including conditions such as coronary artery disease, myocardial infarction and stroke.  An elevated level of low density lipoprotein (LDL) cholesterol constitutes a major risk factor for genesis of atherosclerosis. LDL can accumulate within the blood vessel wall and undergo modification by oxidation. Oxidized LDL (oxLDL) leads to endothelial dysfunction leading to expression of adhesion molecules and recruitment of monocyte in subendothelial space. The monocytes proliferate, differentiate into macrophages, and take up the lipoproteins, forming cholesterol-engorged foam cells. With the time, the foam cells die, leaving a 'necrotic core' of crystalline cholesterol and cell debris. Smooth muscle cells proliferate and migrate into the region, laying down a protective cap over the lesion. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), which mediates the recognition and internalization of oxLDL, is involved in all of these events critical in the pathogenesis of atherosclerosis.","Human Diseases; Cardiovascular disease"
"map05418","Fluid shear stress and atherosclerosis","Shear stress represents the frictional force that the flow of blood exerts at the endothelial surface of the vessel wall and plays a central role in vascular biology and contributes to the progress of atherosclerosis. Sustained laminar flow with high shear stress upregulates expressions of endothelial cell (EC) genes and proteins that are protective against atherosclerosis. The key shear stress-induced transcription factors that govern the expression of these genes are Kruppel-like factor 2 (KLF2) and nuclear factor erythroid 2-like 2 (Nrf2). On the other hand, disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote oxidative and inflammatory states in the artery wall, resulting in atherogenesis. Important transcriptional events that reflect this condition of ECs in disturbed flow include the activation of activator protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB).","Human Diseases; Cardiovascular disease"
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