| IED ID | IndEnz0002005829 |
| Enzyme Type ID | protease005829 |
| Protein Name |
Glyceraldehyde-3-phosphate dehydrogenase GAPDH EC 1.2.1.12 Peptidyl-cysteine S-nitrosylase GAPDH EC 2.6.99.- |
| Gene Name | GAPDH GAPD CDABP0047 OK/SW-cl.12 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MGKVKVGVNGFGRIGRLVTRAAFNSGKVDIVAINDPFIDLNYMVYMFQYDSTHGKFHGTVKAENGKLVINGNPITIFQERDPSKIKWGDAGAEYVVESTGVFTTMEKAGAHLQGGAKRVIISAPSADAPMFVMGVNHEKYDNSLKIISNASCTTNCLAPLAKVIHDNFGIVEGLMTTVHAITATQKTVDGPSGKLWRDGRGALQNIIPASTGAAKAVGKVIPELNGKLTGMAFRVPTANVSVVDLTCRLEKPAKYDDIKKVVKQASEGPLKGILGYTEHQVVSSDFNSDTHSSTFDAGAGIALNDHFVKLISWYDNEFGYSNRVVDLMAHMASKE |
| Enzyme Length | 335 |
| Uniprot Accession Number | P04406 |
| Absorption | |
| Active Site | ACT_SITE 152; /note=Nucleophile; /evidence=ECO:0000269|PubMed:25086035 |
| Activity Regulation | ACTIVITY REGULATION: Glyceraldehyde-3-phosphate dehydrogenase activity is inhibited by fumarate, via the formation of S-(2-succinyl)cysteine residues. {ECO:0000250|UniProtKB:P04797}. |
| Binding Site | BINDING 35; /note="NAD"; /evidence="ECO:0000269|PubMed:16239728, ECO:0000269|PubMed:16510976"; BINDING 80; /note="NAD; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:16239728, ECO:0000269|PubMed:16510976"; BINDING 122; /note="NAD"; /evidence="ECO:0000269|PubMed:16239728, ECO:0000269|PubMed:16510976"; BINDING 182; /note="Glyceraldehyde 3-phosphate"; /evidence="ECO:0000250|UniProtKB:P22513"; BINDING 234; /note="Glyceraldehyde 3-phosphate"; /evidence="ECO:0000250|UniProtKB:P22513"; BINDING 316; /note="NAD"; /evidence="ECO:0000269|PubMed:16239728, ECO:0000269|PubMed:16510976" |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=D-glyceraldehyde 3-phosphate + NAD(+) + phosphate = (2R)-3-phospho-glyceroyl phosphate + H(+) + NADH; Xref=Rhea:RHEA:10300, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474, ChEBI:CHEBI:57540, ChEBI:CHEBI:57604, ChEBI:CHEBI:57945, ChEBI:CHEBI:59776; EC=1.2.1.12; Evidence={ECO:0000255|PROSITE-ProRule:PRU10009, ECO:0000269|PubMed:3170585}; CATALYTIC ACTIVITY: Reaction=L-cysteinyl-[protein] + S-nitroso-L-cysteinyl-[GAPDH] = L-cysteinyl-[GAPDH] + S-nitroso-L-cysteinyl-[protein]; Xref=Rhea:RHEA:66684, Rhea:RHEA-COMP:10131, Rhea:RHEA-COMP:17089, Rhea:RHEA-COMP:17090, Rhea:RHEA-COMP:17091, ChEBI:CHEBI:29950, ChEBI:CHEBI:149494; Evidence={ECO:0000250|UniProtKB:P04797};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66685; Evidence={ECO:0000250|UniProtKB:P04797}; |
| DNA Binding | |
| EC Number | 1.2.1.12; 2.6.99.- |
| Enzyme Function | FUNCTION: Has both glyceraldehyde-3-phosphate dehydrogenase and nitrosylase activities, thereby playing a role in glycolysis and nuclear functions, respectively (PubMed:3170585, PubMed:11724794). Glyceraldehyde-3-phosphate dehydrogenase is a key enzyme in glycolysis that catalyzes the first step of the pathway by converting D-glyceraldehyde 3-phosphate (G3P) into 3-phospho-D-glyceroyl phosphate (PubMed:3170585, PubMed:11724794). Modulates the organization and assembly of the cytoskeleton (By similarity). Facilitates the CHP1-dependent microtubule and membrane associations through its ability to stimulate the binding of CHP1 to microtubules (By similarity). Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma-induced transcript-selective translation inhibition in inflammation processes (PubMed:23071094). Upon interferon-gamma treatment assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation (PubMed:23071094). Also plays a role in innate immunity by promoting TNF-induced NF-kappa-B activation and type I interferon production, via interaction with TRAF2 and TRAF3, respectively (PubMed:23332158, PubMed:27387501). Participates in nuclear events including transcription, RNA transport, DNA replication and apoptosis (By similarity). Nuclear functions are probably due to the nitrosylase activity that mediates cysteine S-nitrosylation of nuclear target proteins such as SIRT1, HDAC2 and PRKDC (By similarity). {ECO:0000250|UniProtKB:P04797, ECO:0000269|PubMed:11724794, ECO:0000269|PubMed:23071094, ECO:0000269|PubMed:23332158, ECO:0000269|PubMed:27387501, ECO:0000269|PubMed:3170585}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | PATHWAY: Carbohydrate degradation; glycolysis; pyruvate from D-glyceraldehyde 3-phosphate: step 1/5. |
| nucleotide Binding | NP_BIND 13..14; /note="NAD"; /evidence="ECO:0000269|PubMed:16239728, ECO:0000269|PubMed:16510976" |
| Features | Active site (1); Alternative sequence (1); Beta strand (20); Binding site (6); Chain (1); Cross-link (1); Glycosylation (2); Helix (13); Initiator methionine (1); Modified residue (45); Motif (1); Mutagenesis (14); Natural variant (2); Nucleotide binding (1); Region (3); Sequence conflict (1); Site (1); Turn (7) |
| Keywords | 3D-structure;ADP-ribosylation;Acetylation;Alternative splicing;Apoptosis;Cytoplasm;Cytoskeleton;Direct protein sequencing;Glycolysis;Glycoprotein;Immunity;Innate immunity;Isopeptide bond;Membrane;Methylation;NAD;Nucleus;Oxidation;Oxidoreductase;Phosphoprotein;Reference proteome;S-nitrosylation;Transferase;Translation regulation;Ubl conjugation |
| Interact With | Q6UY14-3; Q9UIJ7; P05067; Q9UQM7; Q14194; P35222; Q9BPW9-4; P00533; O00471; O75344; P06241; Itself; Q8NEA9; P42858; Q92993-2; P35228; P12004; P00558; P48147; P17612; A0A0C4DFM3; Q9UHX1-2; P15927; P05109; Q96GZ6; P00441; Q9BSI4; P10599 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:12829261}. Nucleus {ECO:0000250|UniProtKB:P04797}. Cytoplasm, perinuclear region {ECO:0000269|PubMed:12829261}. Membrane {ECO:0000269|PubMed:12829261}. Cytoplasm, cytoskeleton {ECO:0000250|UniProtKB:P04797}. Note=Translocates to the nucleus following S-nitrosylation and interaction with SIAH1, which contains a nuclear localization signal (By similarity). Postnuclear and Perinuclear regions (PubMed:12829261). {ECO:0000250|UniProtKB:P04797, ECO:0000269|PubMed:12829261}. |
| Modified Residue | MOD_RES 5; /note="N6,N6-dimethyllysine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 9; /note="Deamidated asparagine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 42; /note="Phosphotyrosine"; /evidence="ECO:0007744|PubMed:15592455"; MOD_RES 46; /note="Methionine sulfoxide; in vitro"; /evidence="ECO:0000305|PubMed:25086035"; MOD_RES 61; /note="N6-acetyllysine"; /evidence="ECO:0007744|PubMed:19608861"; MOD_RES 64; /note="Deamidated asparagine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 66; /note="N6,N6-dimethyllysine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 70; /note="Deamidated asparagine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 75; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:18183946, ECO:0007744|PubMed:20068231"; MOD_RES 83; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"; MOD_RES 122; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 148; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 149; /note="Deamidated asparagine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 151; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163"; MOD_RES 152; /note="ADP-ribosylcysteine; by autocatalysis; in irreversibly inhibited form"; /evidence="ECO:0000250|UniProtKB:P04797"; MOD_RES 152; /note="Cysteine persulfide"; /evidence="ECO:0000250|UniProtKB:P16858"; MOD_RES 152; /note="S-(2-succinyl)cysteine"; /evidence="ECO:0000250|UniProtKB:P04797"; MOD_RES 152; /note="S-nitrosocysteine; in reversibly inhibited form"; /evidence="ECO:0000250|UniProtKB:P04797"; MOD_RES 153; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 155; /note="Deamidated asparagine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 177; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:24275569"; MOD_RES 182; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:24275569"; MOD_RES 184; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:24275569"; MOD_RES 194; /note="N6,N6-dimethyllysine; alternate"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 194; /note="N6-acetyllysine; alternate"; /evidence="ECO:0007744|PubMed:19608861"; MOD_RES 194; /note="N6-malonyllysine; alternate"; /evidence="ECO:0000269|PubMed:21908771"; MOD_RES 211; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:19690332"; MOD_RES 215; /note="N6,N6-dimethyllysine; alternate"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 215; /note="N6-malonyllysine; alternate"; /evidence="ECO:0000269|PubMed:21908771"; MOD_RES 219; /note="N6-acetyllysine"; /evidence="ECO:0007744|PubMed:19608861"; MOD_RES 225; /note="Deamidated asparagine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 227; /note="N6,N6-dimethyllysine; alternate"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 227; /note="N6-acetyllysine; alternate"; /evidence="ECO:0007744|PubMed:19608861"; MOD_RES 229; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:18183946, ECO:0007744|PubMed:23186163"; MOD_RES 237; /note="Phosphothreonine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 241; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:24275569"; MOD_RES 247; /note="S-(2-succinyl)cysteine"; /evidence="ECO:0000250|UniProtKB:P04797"; MOD_RES 247; /note="S-nitrosocysteine"; /evidence="ECO:0000269|PubMed:22771119, ECO:0000269|PubMed:25417112"; MOD_RES 254; /note="N6-acetyllysine"; /evidence="ECO:0007744|PubMed:19608861"; MOD_RES 260; /note="N6,N6-dimethyllysine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 263; /note="N6,N6-dimethyllysine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 312; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:18183946, ECO:0007744|PubMed:19690332"; MOD_RES 316; /note="Deamidated asparagine"; /evidence="ECO:0000269|PubMed:18183946"; MOD_RES 333; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 334; /note="N6,N6-dimethyllysine"; /evidence="ECO:0000269|PubMed:18183946" |
| Post Translational Modification | PTM: S-nitrosylation of Cys-152 leads to interaction with SIAH1, followed by translocation to the nucleus (By similarity). S-nitrosylation of Cys-247 is induced by interferon-gamma and LDL(ox) implicating the iNOS-S100A8/9 transnitrosylase complex and seems to prevent interaction with phosphorylated RPL13A and to interfere with GAIT complex activity (PubMed:22771119, PubMed:25417112). {ECO:0000250|UniProtKB:P04797, ECO:0000269|PubMed:22771119, ECO:0000269|PubMed:25417112}.; PTM: ISGylated. {ECO:0000305|PubMed:16815975}.; PTM: Sulfhydration at Cys-152 increases catalytic activity. {ECO:0000250|UniProtKB:P16858}.; PTM: Oxidative stress can promote the formation of high molecular weight disulfide-linked GAPDH aggregates, through a process called nucleocytoplasmic coagulation. Such aggregates can be observed in vivo in the affected tissues of patients with Alzheimer disease or alcoholic liver cirrhosis, or in cell cultures during necrosis. Oxidation at Met-46 may play a pivotal role in the formation of these insoluble structures. This modification has been detected in vitro following treatment with free radical donor (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide. It has been proposed to destabilize nearby residues, increasing the likelihood of secondary oxidative damages, including oxidation of Tyr-45 and Met-105. This cascade of oxidations may augment GAPDH misfolding, leading to intermolecular disulfide cross-linking and aggregation. {ECO:0000305|PubMed:25086035}.; PTM: Succination of Cys-152 and Cys-247 by the Krebs cycle intermediate fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits glyceraldehyde-3-phosphate dehydrogenase activity. Fumarate concentration as well as succination of cysteine residues in GAPDH is significantly increased in muscle of diabetic mammals. It was proposed that the S-(2-succinyl)cysteine chemical modification may be a useful biomarker of mitochondrial and oxidative stress in diabetes and that succination of GAPDH and other thiol proteins by fumarate may contribute to the metabolic changes underlying the development of diabetes complications. {ECO:0000250|UniProtKB:P04797}.; PTM: (Microbial infection) Glycosylated by C.rodentium protein NleB, enteropathogenic E.coli protein NleB1 and S.typhimurium protein Ssek1: arginine GlcNAcylation prevents the interaction with TRAF2 and TRAF3 (PubMed:23332158, PubMed:27387501, PubMed:28522607). This leads to reduced ubiquitination of TRAF2 and TRAF3, and subsequent inhibition of NF-kappa-B signaling and type I interferon production, respectively (PubMed:23332158, PubMed:27387501). {ECO:0000269|PubMed:23332158, ECO:0000269|PubMed:27387501, ECO:0000269|PubMed:28522607}. |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (12) |
| Cross Reference PDB | 1U8F; 1ZNQ; 3GPD; 4WNC; 4WNI; 6ADE; 6IQ6; 6M61; 6YND; 6YNE; 6YNF; 6YNH; |
| Mapped Pubmed ID | 10714828; 14743216; 15047060; 15161933; 15383276; 15507493; 16055720; 16097032; 16169070; 16263121; 16799092; 17027006; 17174955; 17353931; 17446270; 17488287; 17500595; 17599067; 17620599; 17955473; 18309294; 183598; 18624398; 18910716; 18910717; 18985028; 19119138; 19135240; 19338310; 19367725; 19417104; 19463016; 19683529; 19805454; 20029029; 20392205; 20467437; 20562859; 20849852; 21044950; 21080425; 21163940; 21182205; 21565611; 21900206; 21979951; 21988832; 22106087; 22304920; 22623428; 22810585; 23348613; 23386615; 23414517; 23602568; 23653351; 23823123; 23902751; 24189400; 24421388; 24658140; 25451934; 25609649; 25852190; 26496610; 26514267; 26626483; 26629320; 26752685; 2793178; 31387164; 32802964; 7144574; |
| Motif | MOTIF 245..250; /note=[IL]-x-C-x-x-[DE] motif; /evidence=ECO:0000305|PubMed:25417112 |
| Gene Encoded By | |
| Mass | 36,053 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:10300; RHEA:66684; RHEA:66685 |
| Cross Reference Brenda | 1.2.1.12; |