Mouse glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classic moonlighting protein that functions primarily as a key glycolytic enzyme while also participating in diverse non-metabolic processes. As a glycolytic enzyme, GAPDH catalyzes the reversible conversion of D-glyceraldehyde 3-phosphate (G3P) to 3-phospho-D-glyceroyl phosphate using NAD+ as cofactor (EC 1.2.1.12). The protein forms a homotetramer and is abundantly expressed in all tissues. Beyond glycolysis, GAPDH has moonlighting functions in translation regulation as a component of the GAIT complex, in innate immunity through interaction with TRAF2/TRAF3 to promote NF-kappaB activation and type I interferon production, and in nuclear events including transcription, RNA transport, DNA replication, and apoptosis. The nuclear functions are mediated by S-nitrosylase activity that transfers NO groups to nuclear targets SIRT1, HDAC2, and PRKDC. S-nitrosylation at Cys-150 promotes interaction with SIAH1 and nuclear translocation. GAPDH also associates with microtubules via CHP1 and modulates cytoskeletal organization. Sulfhydration at Cys-150 increases catalytic activity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004365 glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity | IDA PMID:19903941 H2S signals through protein S-sulfhydration | ACCEPT | Summary: Direct enzymatic activity demonstrated via sulfhydration studies. Reason: This is the core enzymatic function of GAPDH. Study demonstrates catalytic activity and its regulation by sulfhydration at Cys-150. Supporting Evidence: UniProtKB:P16858 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 file:mouse/Gapdh/Gapdh-deep-research-perplexity.md GAPDH is a ubiquitous and essential enzyme encoded by the *Gapdh* gene in mouse that catalyzes the sixth step of glycolysis, converting glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate while generating NADH[2][7]. file:mouse/Gapdh/Gapdh-deep-research-falcon.md the catalytic **Cys150** nucleophilically attacks the aldehyde of G3P forming a hemithioacetal; hydride transfer to NAD+ produces NADH and a thioacyl (thioester) intermediate |
| GO:0004365 glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic annotation for GAPDH activity. Reason: Redundant with IDA evidence but consistent. Supporting Evidence: UniProtKB:P16858 GO; GO:0004365; F:glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity; IDA:UniProtKB. |
| GO:0004365 glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation for GAPDH activity. Reason: Redundant with IDA evidence but consistent. Supporting Evidence: UniProtKB:P16858 GO; GO:0004365; F:glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity; IDA:UniProtKB. |
| GO:0004365 glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity | ISO GO_REF:0000096 | ACCEPT | Summary: Transfer from rat ortholog. Reason: Consistent with direct evidence. Supporting Evidence: UniProtKB:P16858 GO; GO:0004365; F:glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity; IDA:UniProtKB. |
| GO:0004365 glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity | IDA PMID:28258188 Lysine post-translational modification of glyceraldehyde-3-p... | ACCEPT | Summary: Direct evidence for GAPDH activity in metabolic regulation. Reason: Consistent with core function. Supporting Evidence: PMID:28258188 mutation of all 4 lysine residues (4K-R GAPDH) to mimic their unmodified state reduced GAPDH glycolytic activity and glycolytic flux and increased gluconeogenic GAPDH activity and glucose production. |
| GO:0004365 glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity | IDA PMID:176725 Human glyceraldehyde-3-phosphate dehydrogenase in man-rodent... | ACCEPT | Summary: Historical direct evidence for GAPDH activity. Reason: Early demonstration of enzymatic activity. Supporting Evidence: PMID:176725 The human enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) forms heteropolymers with the rodent enzyme in man-rodent somatic cell hybrids. |
| GO:0004365 glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity | IMP PMID:15665293 Glycolytic enzymes can modulate cellular life span | ACCEPT | Summary: Core GAPDH enzymatic activity supported by curated annotations. Reason: Core GAPDH activity is well established across curated resources. Supporting Evidence: UniProtKB:P16858 GO; GO:0004365; F:glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity; IDA:UniProtKB. |
| GO:0004365 glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence similarity to human GAPDH. Reason: Consistent with direct evidence. Supporting Evidence: UniProtKB:P16858 GO; GO:0004365; F:glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity; IDA:UniProtKB. |
| GO:0004365 glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity | IMP PMID:3796661 Linear dose-response relationship of erythrocyte enzyme-acti... | ACCEPT | Summary: Core GAPDH enzymatic activity supported by curated annotations. Reason: Core GAPDH activity is well established across curated resources. Supporting Evidence: UniProtKB:P16858 GO; GO:0004365; F:glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity; IDA:UniProtKB. |
| GO:0061621 canonical glycolysis | IDA PMID:12581789 Influence of age and caloric restriction on liver glycolytic... | ACCEPT | Summary: Direct evidence for role in glycolysis in mouse liver. Reason: Core biological process for GAPDH. Supporting Evidence: UniProtKB:P16858 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 file:mouse/Gapdh/Gapdh-deep-research-falcon.md catalyzes the oxidative phosphorylation step of glycolysis converting **glyceraldehyde-3-phosphate (G3P)** to **1,3-bisphosphoglycerate (1,3‑BPG)** while reducing **NAD+ to NADH** |
| GO:0061621 canonical glycolysis | ISO GO_REF:0000119 | ACCEPT | Summary: Transfer from human ortholog. Reason: Consistent with direct evidence. Supporting Evidence: UniProtKB:P16858 GO; GO:0061621; P:canonical glycolysis; IDA:MGI. |
| GO:0061621 canonical glycolysis | IMP PMID:10777777 Zinc-induced cortical neuronal death: contribution of energy... | ACCEPT | Summary: Mutant phenotype showing glycolysis impairment. Reason: Genetic evidence supporting glycolytic function. Supporting Evidence: PMID:10777777 levels of intracellular free Zn(2+) associated with neurotoxicity may be sufficient to inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH) |
| GO:0061621 canonical glycolysis | IMP PMID:28918937 A Predictive Model for Selective Targeting of the Warburg Ef... | ACCEPT | Summary: Mutant phenotype evidence for glycolysis. Reason: GAPDH inhibition affects glycolytic flux. Supporting Evidence: PMID:28918937 we establish a natural product, koningic acid (KA), to be a selective inhibitor of GAPDH |
| GO:0006096 glycolytic process | IBA GO_REF:0000033 | MODIFY | Summary: Phylogenetic annotation for glycolysis. Reason: The more specific term GO:0061621 (canonical glycolysis) should be used. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000089475 SUPPORTS TRANSFER A deep GAPDH node seeded across animals, fungi and plants. PTN000089475 itself is not in the local PAINT cache, so this row's seed set is read from the GOA WITH/FROM; the family is cached, and PTHR10836-paint.tsv's GO:0006096 IBD (PTN008507066) carries the same span. On the gene names, stating exactly what is established: PTHR10836-entries.csv shows the FAMILY contains D. melanogaster Gapdh1 (P07486) and Gapdh2 (P07487) and budding-yeast TDH1/TDH2/TDH3 (P00360/P00358/P00359). The taxon column matters here: the family also carries Gapdh2 for D. pseudoobscura (O44104) and D. subobscura (O44105), so a match on gene name alone picks the wrong species. That corroborates the fly/yeast span, but it does NOT resolve the WITH/FROM's own identifiers - entries.csv is UniProt-accession-keyed and contains no FB or SGD id, so "FB:FBgn0001091 is Gapdh1" remains an inference from organism and gene name rather than a lookup. Read the names as likely, not as established. Arabidopsis, rat and human GAPDH are also in the span. Glycolysis is ancestral across it, so the propagation is about as secure as an IBA gets; the term is simply the general parent of the canonical pathway term. MGI:MGI:95640 · mouse Gapdh (the review target itself) SUPPORTS TRANSFER The target's own MGI record is among the IBD seeds, marking experimental grounding on the target itself; this is expected and is not circular. Note the seed set also carries MGI:MGI:95653, a second mouse gene - so the target's presence is not the node's only murine evidence. Proposed replacements: canonical glycolysis Supporting Evidence: UniProtKB:P16858 Carbohydrate degradation; glycolysis; pyruvate from D- glyceraldehyde 3-phosphate: step 1/5. |
| GO:0006096 glycolytic process | IEA GO_REF:0000120 | MODIFY | Summary: Automated annotation for glycolysis. Reason: Use more specific term GO:0061621. Proposed replacements: canonical glycolysis Supporting Evidence: UniProtKB:P16858 Carbohydrate degradation; glycolysis; pyruvate from D- glyceraldehyde 3-phosphate: step 1/5. |
| GO:0006094 gluconeogenesis | IDA PMID:28258188 Lysine post-translational modification of glyceraldehyde-3-p... | ACCEPT | Summary: Direct evidence for GAPDH role in gluconeogenesis. Reason: GAPDH catalyzes a reversible reaction that operates in both glycolysis and gluconeogenesis directions. Supporting Evidence: UniProtKB:P16858 Carbohydrate degradation; glycolysis; pyruvate from D- glyceraldehyde 3-phosphate |
| GO:0006094 gluconeogenesis | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine learning annotation. Reason: Consistent with direct evidence. |
| GO:0005829 cytosol | IDA PMID:23512986 Cytosolic proteins lose solubility as amyloid deposits in a ... | ACCEPT | Summary: Direct evidence for cytosolic localization. Reason: The cytosol is the primary location for GAPDH glycolytic function. Supporting Evidence: UniProtKB:P16858 Cytoplasm, cytosol {ECO:0000250|UniProtKB:P04797} file:mouse/Gapdh/Gapdh-deep-research-falcon.md Canonical GAPDH catalysis occurs in the **cytoplasm** as part of glycolysis |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic annotation for cytosol. Reason: Consistent with direct evidence. Supporting Evidence: UniProtKB:P16858 Cytoplasm, cytosol {ECO:0000250|UniProtKB:P04797} |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation for cytosol. Reason: Consistent with direct evidence. Supporting Evidence: UniProtKB:P16858 Cytoplasm, cytosol {ECO:0000250|UniProtKB:P04797} |
| GO:0005829 cytosol | ISO GO_REF:0000119 | ACCEPT | Summary: Transfer from human ortholog. Reason: Consistent with direct evidence. |
| GO:0005829 cytosol | ISO GO_REF:0000096 | ACCEPT | Summary: Transfer from rat ortholog. Reason: Consistent with direct evidence. |
| GO:0005829 cytosol | IDA PMID:21347706 Identification of the target proteins of rosiglitazone in 3T... | ACCEPT | Summary: Cytosolic localization supported by curated annotations. Reason: Cytosol is the primary cellular location for GAPDH glycolytic function. Supporting Evidence: UniProtKB:P16858 GO; GO:0005829; C:cytosol; IDA:MGI. |
| GO:0005829 cytosol | IDA PMID:24137001 The primary microRNA-208b interacts with Polycomb-group prot... | ACCEPT | Summary: Direct evidence for cytosol localization. Reason: Consistent with primary location. Supporting Evidence: PMID:24137001 The nuclear and cytosolic fractions were verified by immunoblot procedure using anti-Brm and anti-MeCP2 (nuclear markers) as well as anti-glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (cytoplasmic marker) antibodies. |
| GO:0005829 cytosol | TAS Reactome:R-MMU-9631076 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with primary location. |
| GO:0005829 cytosol | TAS Reactome:R-MMU-9631080 | ACCEPT | Summary: Reactome pathway annotation. Reason: Consistent with primary location. |
| GO:0005829 cytosol | ISO PMID:24101517 Mitochondrial disulfide relay mediates translocation of p53 ... | ACCEPT | Summary: Cytosolic localization consistent with core GAPDH function; PMID is not directly informative for localization. Reason: Multiple lines of evidence support cytosolic localization; use canonical UniProt subcellular annotation. Supporting Evidence: UniProtKB:P16858 Cytoplasm, cytosol {ECO:0000250|UniProtKB:P04797} |
| GO:0005829 cytosol | IDA PMID:23530063 MCJ/DnaJC15, an endogenous mitochondrial repressor of the re... | ACCEPT | Summary: Cytosolic localization supported by curated annotations. Reason: Cytosol is the primary cellular location for GAPDH glycolytic function. Supporting Evidence: UniProtKB:P16858 GO; GO:0005829; C:cytosol; IDA:MGI. |
| GO:0005829 cytosol | IDA PMID:21413931 Protor-1 is required for efficient mTORC2-mediated activatio... | ACCEPT | Summary: Cytosolic localization supported by curated annotations. Reason: Cytosol is the primary cellular location for GAPDH glycolytic function. Supporting Evidence: UniProtKB:P16858 GO; GO:0005829; C:cytosol; IDA:MGI. |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence similarity annotation. Reason: Consistent with primary location. |
| GO:0005737 cytoplasm | IDA PMID:32483152 Long noncoding RNA SAM promotes myoblast proliferation throu... | ACCEPT | Summary: Direct evidence for cytoplasmic localization. Reason: GAPDH is primarily cytoplasmic. Supporting Evidence: PMID:32483152 cellular fractionation assay in ASCs (Fig. 1g) or C2C12 (Supplementary Fig. 1f) also showed that SAM transcripts were enriched in cytoplasmic extracts, in a similar pattern as Gapdh transcripts, whereas lncRNA Malat1 was only found in nuclear extracts16. |
| GO:0005737 cytoplasm | ISO GO_REF:0000119 | ACCEPT | Summary: Transfer from human ortholog. Reason: Consistent with direct evidence. |
| GO:0005737 cytoplasm | ISO GO_REF:0000096 | ACCEPT | Summary: Transfer from rat ortholog. Reason: Consistent with direct evidence. |
| GO:0005737 cytoplasm | IDA PMID:18698006 Characterization of glycolytic enzyme interactions with muri... | ACCEPT | Summary: Direct evidence from erythrocyte studies. Reason: Consistent with primary location. Supporting Evidence: PMID:18698006 GEs were found to localize to the membrane in oxygenated erythrocytes but redistributed to the cytoplasm upon deoxygenation, as seen in human erythrocytes. |
| GO:0005737 cytoplasm | IDA PMID:21539824 Pinpointing the expression of piRNAs and function of the PIW... | ACCEPT | Summary: Cytoplasmic localization supported by curated annotations. Reason: GAPDH is primarily cytoplasmic for glycolytic function. Supporting Evidence: UniProtKB:P16858 GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence similarity annotation. Reason: Consistent with primary location. |
| GO:0005737 cytoplasm | IDA PMID:17962088 The protein profile of mouse mature cumulus-oocyte complex | ACCEPT | Summary: Cytoplasmic localization supported by curated annotations. Reason: GAPDH is primarily cytoplasmic for glycolytic function. Supporting Evidence: UniProtKB:P16858 GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. |
| GO:0005737 cytoplasm | IDA PMID:19470756 SIRT1 promotes cell survival under stress by deacetylation-d... | ACCEPT | Summary: Cytoplasmic localization supported by curated annotations. Reason: GAPDH is primarily cytoplasmic for glycolytic function. Supporting Evidence: UniProtKB:P16858 GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. |
| GO:0005737 cytoplasm | IDA PMID:19075228 A postnatal switch of CELF and MBNL proteins reprograms alte... | ACCEPT | Summary: Cytoplasmic localization supported by curated annotations. Reason: GAPDH is primarily cytoplasmic for glycolytic function. Supporting Evidence: UniProtKB:P16858 GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. |
| GO:0005737 cytoplasm | IDA PMID:15159393 Cyclin A2 mediates cardiomyocyte mitosis in the postmitotic ... | ACCEPT | Summary: Cytoplasmic localization supported by curated annotations. Reason: GAPDH is primarily cytoplasmic for glycolytic function. Supporting Evidence: UniProtKB:P16858 GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Nuclear localization based on sequence similarity; falcon synthesis frames this as a PTM-triggered (S-nitrosylation/acetylation) conditional relocalization that disrupts the glycolytic tetramer, i.e. a moonlighting state rather than the core cytosolic glycolytic function. Reason: Nuclear translocation of GAPDH is well-established and occurs upon S-nitrosylation and binding to SIAH1, but it is a conditionally enabled, PTM-dependent moonlighting state and not the core glycolytic function of GAPDH. Falcon synthesis explicitly characterizes non-glycolytic roles as condition-dependent states enabled when PTMs disrupt the tetramer and drive nuclear relocalization. Supporting Evidence: UniProtKB:P16858 Translocates to the nucleus following S-nitrosylation and interaction with SIAH1, which contains a nuclear localization signal file:mouse/Gapdh/Gapdh-deep-research-falcon.md **S-nitrosylation** of catalytic **Cys150**, inhibiting glycolytic activity, preventing NAD+ binding and tetramer stability, and enabling interaction with **Siah1** (E3 ligase) file:mouse/Gapdh/Gapdh-deep-research-falcon.md many non-glycolytic roles are proposed/observed when PTMs disrupt the tetrameric glycolytic state and promote relocalization (e.g., to nucleus) |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Automated annotation for nucleus. Reason: Consistent with known nuclear translocation, but this is a conditional, PTM-dependent moonlighting localization rather than the core cytosolic glycolytic function. Supporting Evidence: UniProtKB:P16858 Nucleus {ECO:0000250|UniProtKB:P04797}. |
| GO:0005634 nucleus | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Transfer from human ortholog. Reason: Conditional, PTM-dependent moonlighting localization, not the core glycolytic function. |
| GO:0005634 nucleus | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Transfer from rat ortholog. Reason: Conditional, PTM-dependent moonlighting localization, not the core glycolytic function. |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | ACCEPT | Summary: Automated annotation for cytoskeleton. Reason: GAPDH associates with cytoskeleton via CHP1 interaction. Supporting Evidence: UniProtKB:P16858 Modulates the organization and assembly of the cytoskeleton |
| GO:0015630 microtubule cytoskeleton | ISO GO_REF:0000096 | ACCEPT | Summary: Transfer from rat ortholog. Reason: GAPDH associates with microtubules via CHP1. |
| GO:0015630 microtubule cytoskeleton | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence similarity annotation. Reason: Consistent with CHP1-dependent microtubule association. |
| GO:0005886 plasma membrane | IDA PMID:18698006 Characterization of glycolytic enzyme interactions with muri... | KEEP AS NON CORE | Summary: Direct evidence for plasma membrane association in erythrocytes. Reason: Membrane association is a minor localization; GAPDH is primarily cytosolic. Supporting Evidence: PMID:18698006 GEs were found to localize to the membrane in oxygenated erythrocytes but redistributed to the cytoplasm upon deoxygenation, as seen in human erythrocytes. |
| GO:0005886 plasma membrane | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Transfer from human ortholog. Reason: Minor localization. |
| GO:0005739 mitochondrion | HDA PMID:14651853 Integrated analysis of protein composition, tissue diversity... | KEEP AS NON CORE | Summary: Mitochondrion localization supported by curated annotations. Reason: Mitochondrial association may occur but is not the primary location. Supporting Evidence: UniProtKB:P16858 GO; GO:0005739; C:mitochondrion; HDA:MGI. |
| GO:0043209 myelin sheath | HDA PMID:17634366 Proteolipid protein is required for transport of sirtuin 2 i... | KEEP AS NON CORE | Summary: Myelin sheath localization supported by curated annotations. Reason: Tissue-specific localization in CNS myelin. Supporting Evidence: UniProtKB:P16858 GO; GO:0043209; C:myelin sheath; HDA:UniProtKB. |
| GO:0005811 lipid droplet | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Transfer from human ortholog. Reason: Minor localization. |
| GO:0031906 late endosome lumen | TAS Reactome:R-MMU-9631080 | KEEP AS NON CORE | Summary: Reactome annotation for endosomal localization. Reason: Related to chaperone-mediated autophagy pathway. |
| GO:0031965 nuclear membrane | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Transfer from human ortholog. Reason: Minor localization during nuclear translocation. |
| GO:0098978 glutamatergic synapse | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Transfer from rat ortholog for synaptic localization. Reason: Tissue-specific localization in neurons. |
| GO:0099092 postsynaptic density, intracellular component | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Transfer from rat ortholog. Reason: Neuron-specific localization. |
| GO:0097452 GAIT complex | IDA PMID:23071094 Heterotrimeric GAIT complex drives transcript-selective tran... | ACCEPT | Summary: Direct experimental evidence for GAPDH as component of GAIT complex in murine macrophages. Reason: GAPDH is a core component of the GAIT complex that mediates interferon-gamma-induced transcript-selective translation inhibition. Supporting Evidence: UniProtKB:P16858 Component of the GAIT (gamma interferon- activated inhibitor of translation) complex which mediates interferon- gamma-induced transcript-selective translation inhibition in inflammation processes |
| GO:0097452 GAIT complex | ISO GO_REF:0000119 | ACCEPT | Summary: Transfer from human ortholog. Reason: Consistent with direct evidence. |
| GO:0017148 negative regulation of translation | IDA PMID:23071094 Heterotrimeric GAIT complex drives transcript-selective tran... | ACCEPT | Summary: Direct evidence for translation regulation via GAIT complex. Reason: GAPDH participates in transcript-selective translation inhibition as part of the GAIT complex. Supporting Evidence: UniProtKB:P16858 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 |
| GO:0017148 negative regulation of translation | ISO GO_REF:0000119 | ACCEPT | Summary: Transfer from human ortholog. Reason: Consistent with direct evidence. |
| GO:1990904 ribonucleoprotein complex | ISO GO_REF:0000119 | ACCEPT | Summary: GAPDH is part of GAIT ribonucleoprotein complex. Reason: GAIT complex is a ribonucleoprotein complex. |
| GO:0003723 RNA binding | TAS PMID:23071094 Heterotrimeric GAIT complex drives transcript-selective tran... | NEW | Summary: GAPDH binds GAIT element RNA as part of GAIT complex function. Reason: As a component of the GAIT complex, GAPDH participates in binding to GAIT element-containing mRNAs. The complex binds to stem loop-containing GAIT elements in the 3'-UTR of inflammatory mRNAs. Supporting Evidence: UniProtKB:P16858 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 |
| GO:0035605 peptidyl-cysteine S-nitrosylase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: S-nitrosylase activity based on sequence similarity. Reason: Moonlighting function - GAPDH can transfer NO groups to target proteins including SIRT1, HDAC2, and PRKDC. Supporting Evidence: UniProtKB:P16858 Nuclear functions are probably due to the nitrosylase activity that mediates cysteine S-nitrosylation of nuclear target proteins such as SIRT1, HDAC2 and PRKDC file:mouse/Gapdh/Gapdh-deep-research-falcon.md GAPDH-SNO can function as a **transnitrosylase**, transferring NO from the S-nitrosylated active-site cysteine to nuclear proteins such as **HDAC2, ATM, and SIRT1** |
| GO:0035605 peptidyl-cysteine S-nitrosylase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Rhea-based annotation for nitrosylase. Reason: Moonlighting function consistent with UniProt annotation. |
| GO:0035605 peptidyl-cysteine S-nitrosylase activity | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Transfer from rat ortholog. Reason: Moonlighting function. |
| GO:0035606 peptidyl-cysteine S-trans-nitrosylation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: S-trans-nitrosylation process annotation. Reason: Moonlighting function related to nitrosylase activity. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: NF-kappaB regulation based on sequence similarity. Reason: Moonlighting function - GAPDH promotes TNF-induced NF-kappaB activation via TRAF2 interaction. Supporting Evidence: UniProtKB:P16858 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 |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Transfer from human ortholog. Reason: Moonlighting function. |
| GO:0032481 positive regulation of type I interferon production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Interferon regulation based on sequence similarity. Reason: Moonlighting function via TRAF3 interaction. |
| GO:0032481 positive regulation of type I interferon production | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Transfer from human ortholog. Reason: Moonlighting function. |
| GO:0045087 innate immune response | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: Keyword-based annotation for innate immunity. Reason: GAPDH has moonlighting roles in innate immunity via TRAF2/TRAF3. |
| GO:0071346 cellular response to type II interferon | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Response to IFN-gamma for GAIT complex assembly. Reason: Related to GAIT complex function which is activated by IFN-gamma. |
| GO:0001819 positive regulation of cytokine production | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Cytokine regulation via innate immunity functions. Reason: Related to NF-kappaB and interferon signaling. |
| GO:0050832 defense response to fungus | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Antifungal activity annotation. Reason: Part of innate immunity moonlighting function. |
| GO:0061844 antimicrobial humoral immune response mediated by antimicrobial peptide | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Antimicrobial activity annotation. Reason: Part of innate immunity moonlighting function. |
| GO:0031640 killing of cells of another organism | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Antimicrobial killing activity. Reason: Part of innate immunity moonlighting function. |
| GO:0008017 microtubule binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Microtubule binding based on sequence similarity. Reason: GAPDH modulates cytoskeletal organization via CHP1-dependent microtubule association. Supporting Evidence: UniProtKB:P16858 Facilitates the CHP1-dependent microtubule and membrane associations through its ability to stimulate the binding of CHP1 to microtubules |
| GO:0008017 microtubule binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Transfer from rat ortholog. Reason: Moonlighting function. |
| GO:0000226 microtubule cytoskeleton organization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cytoskeleton organization annotation. Reason: Related to microtubule association moonlighting function. |
| GO:0051402 neuron apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuronal apoptosis annotation. Reason: GAPDH participates in nuclear apoptotic events via nitrosylase activity; a PTM-enabled moonlighting role and not the core glycolytic function. Supporting Evidence: UniProtKB:P16858 Participates in nuclear events including transcription, RNA transport, DNA replication and apoptosis file:mouse/Gapdh/Gapdh-deep-research-falcon.md connects nuclear GAPDH to stress-response pathways including apoptosis (NO/GAPDH/Siah1 axis) and autophagy regulation |
| GO:0019899 enzyme binding | IPI PMID:19903941 H2S signals through protein S-sulfhydration | ACCEPT | Summary: GAPDH is modified in H2S signaling, indicating enzyme interaction context. Reason: S-sulfhydration of GAPDH supports a regulated interaction context in H2S signaling. Supporting Evidence: PMID:19903941 About 10 to 25% of many liver proteins, including actin, tubulin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), are sulfhydrated under physiological conditions. |
| GO:0042802 identical protein binding | ISO GO_REF:0000119 | ACCEPT | Summary: Homotetrameric assembly based on ortholog evidence. Reason: GAPDH forms a homotetramer essential for catalytic activity. Supporting Evidence: UniProtKB:P16858 Homotetramer (PubMed:23071094) file:mouse/Gapdh/Gapdh-deep-research-falcon.md a functional catalytic form as an **NAD+-bound homotetramer** |
| GO:0042802 identical protein binding | ISO GO_REF:0000096 | ACCEPT | Summary: Transfer from rat ortholog. Reason: Consistent with homotetramer formation. |
| GO:0097718 disordered domain specific binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Binding to disordered domains annotation. Reason: Related to diverse protein interactions. |
| GO:0010951 negative regulation of endopeptidase activity | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Endopeptidase inhibition annotation. Reason: Moonlighting function. |
| GO:0019828 aspartic-type endopeptidase inhibitor activity | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Aspartic protease inhibitor annotation. Reason: Moonlighting function. |
| GO:0051287 NAD binding | IEA GO_REF:0000002 | ACCEPT | Summary: NAD binding based on InterPro domain annotation. Reason: NAD+ is the essential cofactor for GAPDH catalytic activity. Supporting Evidence: UniProtKB:P16858 D-glyceraldehyde 3-phosphate + phosphate + NAD(+) = (2R)-3- phospho-glyceroyl phosphate + NADH + H(+) file:mouse/Gapdh/Gapdh-deep-research-falcon.md an N‑terminal region mediating **NAD+ binding** (approx. residues 1–150) |
| GO:0050661 NADP binding | IEA GO_REF:0000002 | REMOVE | Summary: InterPro-based annotation for NADP binding. Reason: GAPDH uses NAD+ not NADP as cofactor. The NADP binding annotation is based on domain similarity but is not functionally accurate for this enzyme. |
| GO:0006006 glucose metabolic process | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based glucose metabolism annotation. Reason: Too general - more specific glycolysis term should be used. Proposed replacements: canonical glycolysis |
| GO:0016620 oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based oxidoreductase annotation. Reason: Too general - the specific GAPDH activity term should be used. Proposed replacements: glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity |
| GO:0046166 glyceraldehyde-3-phosphate biosynthetic process | ISO PMID:18662986 Glyceroneogenesis is the dominant pathway for triglyceride g... | KEEP AS NON CORE | Summary: G3P biosynthesis annotation supported by curated annotations. Reason: Related to gluconeogenesis where G3P is produced. Supporting Evidence: UniProtKB:P16858 GO; GO:0046166; P:glyceraldehyde-3-phosphate biosynthetic process; ISO:MGI. |
| GO:0050821 protein stabilization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Protein stabilization annotation. Reason: Moonlighting function. |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000043 | MODIFY | Summary: Keyword-based annotation for oxidoreductase activity. Reason: Too general - the specific GAPDH activity term GO:0004365 should be used. Proposed replacements: glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: Keyword-based annotation for transferase activity. Reason: Related to the nitrosylase moonlighting function (EC 2.6.99.-); falcon describes GAPDH-SNO transnitrosylase NO-group transfer to nuclear targets. Supporting Evidence: file:mouse/Gapdh/Gapdh-deep-research-falcon.md GAPDH-SNO can function as a **transnitrosylase**, transferring NO from the S-nitrosylated active-site cysteine to nuclear proteins such as **HDAC2, ATM, and SIRT1** |
| GO:0002376 immune system process | IEA GO_REF:0000043 | MODIFY | Summary: Keyword-based annotation for immune system process. Reason: Too general - more specific innate immunity terms are already present. Proposed replacements: innate immune response |
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: Keyword-based annotation for apoptosis. Reason: GAPDH participates in nuclear apoptotic events via nitrosylase activity; falcon frames this as a condition-dependent, PTM-enabled moonlighting role rather than a core function. Supporting Evidence: file:mouse/Gapdh/Gapdh-deep-research-falcon.md connects nuclear GAPDH to stress-response pathways including apoptosis (NO/GAPDH/Siah1 axis) and autophagy regulation |
| GO:0006417 regulation of translation | IEA GO_REF:0000043 | MODIFY | Summary: Keyword-based annotation for translation regulation. Reason: Too general - the more specific negative regulation of translation term is already present. Proposed replacements: negative regulation of translation |
| GO:0051873 obsolete killing by host of symbiont cells | ISO GO_REF:0000119 | REMOVE | Summary: Transfer from human ortholog for antimicrobial term. Reason: This is an obsolete GO term that should not be used. The antimicrobial function is covered by GO:0061844 (antimicrobial humoral immune response). |
| GO:0005515 protein binding | IPI PMID:19423573 A protein interaction network for the large conductance Ca(2... | REMOVE | Summary: Physical interaction detected in protein interaction study. Reason: Protein binding is not an informative GO term per curation guidelines. Supporting Evidence: PMID:19423573 coimmunoprecipitation and two-dimensional PAGE, combined with mass spectrometry, were used to reveal 174 putative BKAPs from cytoplasmic and membrane/cytoskeletal fractions of mouse cochlea. |
| GO:0005515 protein binding | IPI PMID:27461448 Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite... | REMOVE | Summary: Physical interaction with GluA2. Reason: Protein binding is not informative; specific interaction terms preferred. Supporting Evidence: PMID:27461448 Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development. |
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Download this section (compressed HTML)Q: What is the relative contribution of glycolytic vs moonlighting functions to overall GAPDH cellular role?
Q: How is the switch between cytosolic glycolytic function and nuclear translocation regulated at the molecular level?
Experiment: Quantitative proteomics to measure GAPDH redistribution between cytosol, nucleus, and membrane compartments under inflammatory and stress conditions
Hypothesis: GAPDH localization changes dynamically based on cellular stress, with S-nitrosylation driving nuclear accumulation.
Type: Quantitative proteomics
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