Glucose-6-phosphate dehydrogenase is a soluble, predominantly cytosolic enzyme that oxidizes glucose 6-phosphate to 6-phosphogluconolactone while reducing NADP+ to NADPH. This reaction initiates the oxidative pentose-phosphate pathway and supplies reducing power for cellular redox buffering and biosynthesis. G6PD has catalytic and structural NADP+ binding sites and forms active homodimeric and tetrameric assemblies. Regulatory protein interactions and lysine acetylation modulate its activity, and a peripheral membrane-associated pool is documented. Deficiency particularly compromises erythrocyte redox homeostasis and can cause hemolytic anemia. Alternative splicing produces the canonical 515-residue protein and longer 561- and 545-residue products.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004345 glucose-6-phosphate dehydrogenase activity | EXP PMID:24769394 Regulation of G6PD acetylation by SIRT2 and KAT9 modulates N... | ACCEPT | Summary: Regulated human G6PD acetylation changes its measured catalytic activity. Reason: The retained original PMID:24769394 measures G6PD activity with wild-type, K403 substitutions and site-specifically acetylated constructs. Acetylation impairs active-dimer formation, whereas SIRT2-mediated deacetylation restores activity. These experiments establish the core enzyme function; acetylation mimics and engineered proteins are not natural splice isoforms. Supporting Evidence: |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | EXP PMID:26479991 Severe G6PD Deficiency Due to a New Missense Mutation in an ... | ACCEPT | Summary: A human Arg198Ser case has severely reduced measured G6PD activity. Reason: The authentic PMID:26479991 case-report abstract identifies a male infant with very low G6PD enzymatic activity and a sequenced Arg198Ser variant, alongside ongoing hemolysis. This is supporting loss-of-function evidence for an independently established catalytic activity. It is not a purified-protein kinetic assay or evidence that every variant behaves identically. Supporting Evidence: |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The experimentally grounded ancestral G6PD activity is retained in human G6PD. Reason: The actual PTHR23429 tree places human AN68/PTN002512035 below the IBD origin AN0/PTN000604427. The canonical 515-residue sequence matches the target leaf and alignment; no retained loss assertion lies on its path. Human structural and biochemical experiments independently establish NADP-dependent G6P oxidation. P11413 among the descendant evidences is legitimate experimental grounding, not circularity. |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IDA PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | ACCEPT | Summary: Human G6PD structures and kinetics support the catalytic activity. Reason: The selected original PMID:15858258 examines human G6PD complexes with G6P and NADP+, including an engineered N-terminal deletion construct with activity comparable to wild type. Its structural and kinetic evidence supports G6P oxidation. Engineered DeltaG6PD and Canton-variant structures are distinguished from the three natural splice products; the study does not assay all products equivalently. Supporting Evidence: |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IDA PMID:35122041 Aldolase B suppresses hepatocellular carcinogenesis by inhib... | ACCEPT | Summary: The ALDOB study measures regulation of the established G6PD catalytic reaction. Reason: The PMID:35122041 abstract explicitly identifies G6PD activity and PPP metabolism as increased after Aldob loss and suppressed by restoring the inhibitory interaction. Retain the enzyme activity, independently established by human biochemistry. The accessible abstract combines human tumor observations and mouse experiments; the exact human assay construct was not independently recovered. The later correction concerns an Extended Data image and source data, not a retraction. |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IDA PMID:38066190 Substitution of arginine 219 by glycine compromises stabilit... | ACCEPT | Summary: Purified recombinant human G6PD catalyzes NADP-dependent G6P oxidation. Reason: The original PMID:38066190 Methods use bacterially expressed His-tagged human wild-type and R219G G6PD and monitor NADPH formation at 340 nm with G6P and NADP+. Table 1 reports wild-type kcat 326 s−1 versus 6 s−1 for R219G. This directly supports the catalytic activity; the pathogenic substitution and its altered oligomeric state do not define the wild-type enzyme or natural splice products. Supporting Evidence: |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic sources identify the established G6PD reaction. Reason: The literal ARBA, InterPro, rat ortholog, EC:1.1.1.49 and RHEA:15841 sources converge on oxidation of D-glucose 6-phosphate coupled to NADP+ reduction. Direct human experiments establish the same chemistry. Retain every supplied source identifier; the unrelated NAADP-direction error in UniProt FUNCTION prose does not alter this correctly represented NADP reaction. |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IMP PMID:2420826 Ribose metabolism and nucleic acid synthesis in normal and g... | ACCEPT | Summary: Human erythrocyte G6PD deficiency removes the oxidative contribution to pentose production. Reason: The authentic PMID:2420826 abstract compares normal and Mediterranean-type G6PD-deficient human erythrocytes infected with P. falciparum. Isotope incorporation shows oxidative-pathway pentose production in normal cells and none in deficient cells. This supports the established G6PD activity, while the parasite-growth phenotype also involves glutathione-dependent PRPP synthetase and is not attributed solely to oxidative stress. Supporting Evidence: |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IMP PMID:5643703 Biochemical variants of glucose-6-phosphate dehydrogenase gi... | ACCEPT | Summary: The classic variant annotation agrees with independently established G6PD catalysis. Reason: Only PMID:5643703 metadata and title were accessible, so its exact variant assays have not been independently reconstructed. Retain this experimental annotation because the same G6PD activity is directly established by later human structural and purified-enzyme studies. This acceptance does not claim to have read the unavailable 1968 experiments or validate its distinct ligand and maturation assertions. |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IMP PMID:743300 Glucose 6-phosphate dehydrogenase activity in membranes of e... | ACCEPT | Summary: The erythrocyte-membrane activity annotation is compatible with known G6PD catalysis. Reason: PMID:743300 identifies G6PD activity in erythrocyte membranes from normal and Mediterranean-deficient subjects, but the original methods were not accessible. The catalytic identity is independently established, so retain the experimental activity assertion without inventing fractionation controls or quantitative membrane partitioning from the title. |
| GO:0005515 protein binding | IPI PMID:21157431 ATM activates the pentose phosphate pathway promoting anti-o... | KEEP AS NON CORE | Summary: Human HSPB1/Hsp27 associates with G6PD during the irradiation response. Reason: The retained PMID:21157431 original shows reciprocal human Hsp27/G6PD co-immunoprecipitation in irradiated AG02603 fibroblasts and functional effects on G6PD activity. Its initial extract experiments and recombinant Xenopus G6PD clone are separate experimental contexts. Retain the positive human association under the standing generic-binding policy; it does not establish that G6PD is a DNA-repair enzyme or confer Hsp27 chaperone activity on G6PD. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:24769394 Regulation of G6PD acetylation by SIRT2 and KAT9 modulates N... | KEEP AS NON CORE | Summary: SIRT2 associates with G6PD in the acetylation-dependent regulatory mechanism. Reason: The original PMID:24769394 supports G6PD–SIRT2 association, oxidative-stress-dependent regulation and deacetylation of G6PD Lys403. G6PD is the regulated enzyme, not the deacetylase. Preserve the named positive interaction as non-core generic binding rather than replacing it with SIRT2's enzymatic function. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:35122041 Aldolase B suppresses hepatocellular carcinogenesis by inhib... | KEEP AS NON CORE | Summary: The reported ALDOB–G6PD–p53 complex supports a scoped TP53 association. Reason: PMID:35122041 explicitly reports that ALDOB potentiates p53-mediated inhibition of G6PD in a ternary complex, and UniProt retains the P04637 association. The accessible abstract supports association but does not resolve all human construct or binary-interface details. Preserve the literal TP53 partner and non-core interaction without inferring transcription-factor activity or treating co-complex evidence as an independently inspected purified binary assay. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:35122041 Aldolase B suppresses hepatocellular carcinogenesis by inhib... | KEEP AS NON CORE | Summary: ALDOB is a reported inhibitory G6PD-binding partner. Reason: The PMID:35122041 abstract directly reports ALDOB binding and inhibition of G6PD and a scaffolding effect independent of ALDOB catalytic activity. Human tumor correlations and mouse genetic experiments are explicitly distinct; the exact human construct was not recovered. Preserve the P05062 partner and positive association as non-core generic binding, without assigning ALDOB's aldolase or scaffolding activity to G6PD. Supporting Evidence: |
| GO:0005536 D-glucose binding | IDA PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | UNDECIDED | Summary: The human structural source establishes G6P contacts but does not settle the free-D-glucose annotation. Reason: Selected original PMID:15858258 sections describe G6P in the human active site. Its discussion of free-glucose discrimination includes a Leuconostoc H178N mutant, which is not a human free-glucose binding experiment. GO:0005536 is not simply a synonym for glucose-6-phosphate binding. Retain uncertainty pending reconstruction of the curator's precise ligand evidence; do not infer absence of binding solely from the phosphorylated physiological substrate. Supporting Evidence: |
| GO:0005536 D-glucose binding | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat-source evidence does not yet adjudicate binding of free D-glucose by human G6PD. Reason: The original electronic transfer names rat P05370 and ENSRNOP00000075297. Its mapped PMID:16325866 and PMID:17447164 abstracts report tissue G6PD activity or kinetics in metabolic interventions, but the exact free-glucose binding evidence was not accessible. GO:0005536 names D-glucose, whereas the established human ligand is glucose 6-phosphate. Neither substrate identity alone nor the rat abstracts establish or refute all free-glucose binding, so preserve the transfer as unresolved rather than remove it. |
| GO:0005536 D-glucose binding | IMP PMID:5643703 Biochemical variants of glucose-6-phosphate dehydrogenase gi... | UNDECIDED | Summary: Free-D-glucose binding cannot be adjudicated from the inaccessible 1968 variant experiments. Reason: PMID:5643703 was recovered only as metadata/title, not usable experimental text. The known physiological substrate is G6P, but that fact alone cannot justify removing an experimental free-glucose-binding assertion whose assays were not read. Preserve the original ligand term and evidence while requesting the relevant original experiment. |
| GO:0005737 cytoplasm | IDA GO_REF:0000054 | TOO GENERAL | Summary: The fusion-protein cytoplasm observation is compatible with the more precise established cytosol location. Reason: GO_REF:0000054 records intracellular localization of expressed fusion proteins. Cytoplasm is broader than the repeatedly supported cytosol compartment for this soluble enzyme. Mark the general compartment too broad for the core summary without treating the observed fusion-protein signal as false or assuming that every construct represents every natural splice product. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: The actual ancestral cytosolic localization is retained on the human G6PD lineage. Reason: Human AN68/PTN002512035 descends from the cytosol IBD at AN2/PTN000604429. The retained cytosol-loss assertion lies on the separate H6PD lineage rather than the target path; P11413 self evidence is legitimate grounding. Human localization records and the cytosolic PPP chemistry support this core compartment. Supporting Evidence: |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: The curated immunofluorescence annotation supports the established cytosol compartment. Reason: GO_REF:0000052 records curation of immunofluorescence localization. Retain the cytosol assertion because it agrees with independent localization and enzymatic context. The underlying image/antibody experiment was not re-inspected, so no cell-line, natural-product or exclusive-localization claim is added. |
| GO:0005829 cytosol | IDA PMID:35122041 Aldolase B suppresses hepatocellular carcinogenesis by inhib... | ACCEPT | Summary: The ALDOB-study cytosol annotation agrees with independent G6PD localization. Reason: The original PMID:35122041 annotation and curated UniProt cytosol record are consistent with the soluble enzyme's established compartment. The exact human localization construct and full original microscopy were not recovered from the accessible abstract; retain the correct location without inventing those details or treating mouse genetic experiments as human imaging. |
| GO:0005829 cytosol | IDA PMID:743300 Glucose 6-phosphate dehydrogenase activity in membranes of e... | ACCEPT | Summary: The erythrocyte-source cytosol annotation is retained as a well-supported location. Reason: PMID:743300 is linked by the curator to cytosol and a peripheral membrane pool. Its full fractionation methods remain inaccessible, but independent localization and the cytosolic enzyme context support the annotation. Neither exclusivity nor a measured cytosol-to-membrane fraction is inferred from the title. Supporting Evidence: |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt location mapping correctly identifies cytosol. Reason: The literal SL-0091 mapping agrees with the curated G6PD cytosol location, direct source-linked observations and the actual cytosol IBD. A documented peripheral-membrane pool does not contradict a nonexclusive cytosol annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-70377 | ACCEPT | Summary: The Reactome G6PD oxidation reaction is modeled in the cytosol. Reason: The retained R-HSA-70377 human summary explicitly places G6PD multimers and their G6P/NADP+ reaction in the cytosol, consistent with independent localization. Accept this location without interpreting every pathway-associated regulator as a G6PD catalytic function. Supporting Evidence: Reactome:R-HSA-70377 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9761849 | ACCEPT | Summary: The expression-event annotation agrees with the established cytosol location of G6PD. Reason: The R-HSA-9761849 cache describes G6PD expression downstream of NFE2L2, although its literal display title says P6GD. Preserve that fetched title and disclose the mismatch rather than silently correcting it. The cytosol annotation is independently supported; the event does not show that G6PD is a nuclear transcription factor or itself carries out its gene's transcription. |
| GO:0006006 glucose metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: The ancestral glucose-metabolism assertion is compatible with the human oxidative PPP enzyme. Reason: Actual PTHR23429 ancestry places human AN68 below the GO:0006006 IBD at AN0/PTN000604427, with no target-lineage loss. Human isotope and biochemical studies support glucose-derived carbon entering the oxidative PPP through G6P. Retain this conserved pathway assertion; do not confuse a short donor list, self evidence or a nonexistent ontology ancestor relationship with a phylogenetic defect. |
| GO:0006006 glucose metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: G6PD contributes to glucose metabolism through the oxidative pentose-phosphate route. Reason: The InterPro assignment is consistent with G6PD oxidizing the phosphorylated glucose intermediate at the entry to the oxidative PPP. This is a broader pathway-level description, not a claim that free glucose is the enzyme's substrate. Current official ontology closures do not make GO:0006006 an ancestor of GO:0009051 or GO:0051156, so a purported parent-term redundancy is not a valid reason to reject this annotation. |
| GO:0006098 pentose-phosphate shunt | IDA PMID:2297768 Sex steroid hormone modulation of NADPH pathways in MCF-7 ce... | ACCEPT | Summary: The human MCF-7 study measures G6PD-dependent NADPH pathways. Reason: The PMID:2297768 abstract describes quantitative cytochemical G6PD activity and NADPH-utilization measurements in human MCF-7 cells under steroid treatments. This supports the established PPP role, while the hormone-specific responses and growth effects remain experimental context rather than separate core functions. Supporting Evidence: |
| GO:0006098 pentose-phosphate shunt | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic assignment correctly places G6PD in the pentose-phosphate pathway. Reason: ARBA, rat orthology and UniPathway UPA00115 describe the pathway whose oxidative entry reaction is catalyzed by G6PD. The more specific oxidative-branch assertion is retained independently; the broad pathway remains a correct core process rather than an unsupported phenotype. |
| GO:0006629 lipid metabolic process | TAS PMID:17361089 Production of inflammatory molecules in peripheral blood mon... | KEEP AS NON CORE | Summary: G6PD deficiency affects lipid handling in human immune cells through metabolic support. Reason: PMID:17361089 studies deficient and normal human PBMC and monocyte-derived macrophages, including cholesterol esterification and lipid-droplet responses. Retain the existing lipid-metabolic association as non-core, scoped to the observed perturbation and NADPH supply. G6PD does not itself catalyze fatty-acid synthesis, cholesterol esterification or the inflammatory reactions measured in this paper. Supporting Evidence: |
| GO:0006695 cholesterol biosynthetic process | IMP PMID:12027950 Cell growth and cholesterol metabolism in human glucose-6-ph... | KEEP AS NON CORE | Summary: Human G6PD deficiency alters stimulated cholesterol synthesis and esterification. Reason: PMID:12027950 directly compares lectin-stimulated PBMC from five normal and five deficient subjects, with acetate/oleate incorporation and enzyme-expression measurements. This supports a context-dependent contribution through reducing-power supply, but not a cholesterol-synthetic catalytic step by G6PD. Retain the existing process as non-core rather than convert the phenotype into an additional core enzyme activity. Supporting Evidence: |
| GO:0006739 NADP+ metabolic process | IDA PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | ACCEPT | Summary: G6PD directly interconverts NADP+ and NADPH during G6P oxidation. Reason: PMID:15858258 establishes NADP+-dependent catalysis and coenzyme recognition. NADP+ is chemically reduced in the reaction, so this process reflects direct enzyme chemistry, unlike downstream processes that merely depend on the resulting reducing power. Retain the NADP+ metabolic annotation. Supporting Evidence: |
| GO:0006749 glutathione metabolic process | IMP PMID:17516514 Mutation in G6PD gene leads to loss of cellular control of p... | KEEP AS NON CORE | Summary: G6PD-dependent reducing power supports control of glutathione and protein glutathionylation. Reason: The PMID:17516514 abstract reports G6PD-deficient E89/K1 cells, rescue by G6PD re-expression and altered glutathione/protein-glutathionylation responses after HEDS. Its exact cell and rescue-construct species are not stated in the abstract. Retain the experimentally supported redox contribution as non-core; G6PD supplies NADPH and does not itself reduce glutathione or catalyze protein deglutathionylation. Supporting Evidence: |
| GO:0006749 glutathione metabolic process | IMP PMID:2420826 Ribose metabolism and nucleic acid synthesis in normal and g... | KEEP AS NON CORE | Summary: Human erythrocyte G6PD deficiency reduces glutathione availability in the infected-cell experiment. Reason: PMID:2420826 reports low or undetectable GSH in cultured deficient human erythrocytes and consequent impairment of GSH-dependent PRPP synthetase. This supports the existing glutathione-metabolism association through NADPH supply, with the culture/parasite context explicit. It does not make G6PD a glutathione reductase or identify oxidative damage as the paper's demonstrated cause of parasite-growth inhibition. Supporting Evidence: |
| GO:0009051 pentose-phosphate shunt, oxidative branch | IBA GO_REF:0000033 | ACCEPT | Summary: The oxidative PPP is the conserved pathway directly entered by G6PD catalysis. Reason: The actual family tree places human G6PD below the GO:0009051 IBD at AN0/PTN000604427, with intact target sequence and no target-lineage loss. The target's own experimental evidence legitimately contributes to that ancestral inference. Human G6P oxidation and isotope experiments independently support this core process. |
| GO:0009051 pentose-phosphate shunt, oxidative branch | IEA GO_REF:0000107 | ACCEPT | Summary: Rat-ortholog transfer agrees with the directly established human oxidative PPP role. Reason: The literal P05370/ENSRNOP00000075297 transfer is consistent with rat biochemical activity and the same human enzyme reaction. Retain the specific oxidative-branch process; no target-specific loss or divergence is supported, and no donor-count objection is relevant. |
| GO:0009051 pentose-phosphate shunt, oxidative branch | IMP PMID:2420826 Ribose metabolism and nucleic acid synthesis in normal and g... | ACCEPT | Summary: Human G6PD deficiency eliminates the oxidative contribution to pentose synthesis in the reported setting. Reason: The PMID:2420826 isotope experiment reports that approximately one fifth of pentose in infected normal erythrocytes came from G6P oxidation, whereas none did in comparable G6PD-deficient cells. This directly supports the oxidative PPP annotation while preserving the independent GSH/PRPP-synthetase explanation of much of the growth phenotype. Supporting Evidence: |
| GO:0009898 cytoplasmic side of plasma membrane | IDA PMID:743300 Glucose 6-phosphate dehydrogenase activity in membranes of e... | KEEP AS NON CORE | Summary: A source-linked erythrocyte membrane-associated G6PD pool is retained. Reason: The original IDA and UniProt membrane/peripheral-membrane annotation cite PMID:743300. Full experimental fractionation was not recovered, so quantitative abundance and topology controls are not newly asserted. Retain this existing specialized location as non-core alongside established cytosol, consistent with the earlier OMICS manual correction; a nonexclusive membrane association is not refuted by soluble enzyme activity. Supporting Evidence: |
| GO:0010041 response to iron(III) ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rat iron exposure changes the G6PD metabolic response. Reason: The exact donor PMID:24599681 studies long-term iron exposure and rat liver G6PD/PGD expression and activity. This is positive evidence for a contextual response, not evidence that G6PD binds iron or is an iron sensor. Retain the ortholog-derived response as non-core with its species and intervention limits; absence of a matching human experiment alone does not justify removal. Supporting Evidence: |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MODIFY | Summary: Refine the broad membrane annotation using the independently retained cytoplasmic-side location. Reason: The original PMID:19946888 YTS membrane-survey reference remains unchanged, and its exact G6PD peptide row was not recovered. Independent curated UniProt peripheral-membrane support and the existing PMID:743300-linked GO:0009898 annotation establish the more specific gene-level location already retained here. Replace the general membrane term with that supported location; this does not claim that the YTS study itself identified the membrane leaflet. Full PMID:743300 fractionation and topology controls remain inaccessible, and no new quantitative partitioning or integral-membrane claim is made. The historical OMICS corrections remain preserved. Proposed replacements: cytoplasmic side of plasma membrane Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Membrane; Peripheral membrane protein |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: Refine the UniProt membrane mapping to the already retained cytoplasmic side of the plasma membrane. Reason: The literal SL-0162 source maps the curated peripheral-membrane statement to a general membrane term. The independently retained PMID:743300-linked GO:0009898 annotation supplies a more specific location: it is part_of plasma membrane, which is_a membrane in the official ontology. Replace the parent with that existing location while preserving the original mapping and the nonexclusive cytosolic pool. The complete original fractionation/topology controls were not recovered; neither measured abundance nor integral topology is newly asserted. Proposed replacements: cytoplasmic side of plasma membrane Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Membrane; Peripheral membrane protein |
| GO:0016614 oxidoreductase activity, acting on CH-OH group of donors | IEA GO_REF:0000002 | TOO GENERAL | Summary: The broad CH-OH oxidoreductase class is less informative than the established G6PD reaction. Reason: InterPro IPR001282 supports the oxidoreductase family. G6PD directly oxidizes G6P while reducing NADP+, already captured by GO:0004345. The broad catalytic class is valid but adds no specific donor/acceptor information; mark it too general without claiming a wrong catalytic class or altering its machine-supplied mapping. |
| GO:0019322 pentose biosynthetic process | IDA PMID:5643703 Biochemical variants of glucose-6-phosphate dehydrogenase gi... | UNDECIDED | Summary: The original pentose-biosynthesis experiment is unavailable for direct adjudication. Reason: G6PD feeds the oxidative route that produces pentose phosphates, but the specific IDA assertion cites PMID:5643703, for which only metadata/title were recovered. The original direct pentose measurement and construct context remain inaccessible. Preserve the annotation as unresolved rather than infer its experiment from the pathway name or remove it because G6PD catalyzes an upstream step. |
| GO:0021762 substantia nigra development | HEP PMID:22926577 Quantitative proteomic analysis of human substantia nigra in... | UNDECIDED | Summary: The substantia-nigra developmental assertion is not resolved by the accessible disease-proteomics abstract. Reason: PMID:22926577 reports quantitative protein expression in human substantia nigra in neurodegenerative diseases. The abstract does not establish a G6PD developmental mechanism, but the complete original and exact target-specific evidence were not read. Preserve the HEP assertion as unresolved instead of retaining the inherited confident REMOVE based only on an abstract-level mismatch; expression in adult disease tissue alone is not evidence of developmental participation. Supporting Evidence: |
| GO:0030246 carbohydrate binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Direct human G6P-bound structures support non-core carbohydrate recognition. Reason: Selected original human G6PD structures in PMID:15858258 directly show noncovalent contacts with glucose-6-phosphate. This is positive substrate-recognition evidence for carbohydrate binding, independently of the unresolved free-D-glucose assertions from the rat transfer. The catalytic activity term is not a binding descendant and does not entail this annotation. Retain the broad binding function as non-core without claiming free-glucose binding, a lectin function or a resolved experiment in the original rat source. PMID:2843500 separately assays soluble G6PD and microsomal hexose dehydrogenase, so its title is not evidence of wrong-protein attribution. |
| GO:0032094 response to food | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Fasting modifies G6PD-linked cardiac metabolism in the rat donor experiment. Reason: PMID:19076169 compares fed and 24-hour-fasted rat hearts and reports altered G6PDH/GSH before ischemia; ischemia itself did not increase the pathway in that study. Retain the transferred nutritional response as non-core, not as a claim that G6PD is a food sensor or that the exact intervention was repeated in humans. Supporting Evidence: |
| GO:0034599 cellular response to oxidative stress | IMP PMID:17516514 Mutation in G6PD gene leads to loss of cellular control of p... | KEEP AS NON CORE | Summary: G6PD-dependent NADPH supports the cellular response to oxidative challenge. Reason: PMID:17516514 provides perturbation and rescue evidence for control of glutathionylation and redox buffering after HEDS. This is a genuine protective metabolic contribution, with the abstract's unresolved cell/construct species stated separately. Retain the response as non-core around the minimal catalytic core; do not assign direct peroxide reduction, Ku catalysis or DNA-repair activity to G6PD. Supporting Evidence: |
| GO:0042802 identical protein binding | IPI PMID:24769394 Regulation of G6PD acetylation by SIRT2 and KAT9 modulates N... | ACCEPT | Summary: G6PD self-association forms the active homomeric enzyme. Reason: The retained PMID:24769394 experiments distinguish wild-type G6PD, K403 substitutions and site-specific acetylation, and show regulated dimer formation alongside enzyme activity. This is a defined homomeric assembly supporting identical protein binding, rather than an unidentified generic partner interaction. Preserve the literal self partner P11413. In the restored excerpt, the subject unable to form active dimers is K403-acetylated G6PD; it is not a claim that wild-type G6PD lacks dimers. Supporting Evidence: PMID:24769394 is incapable of forming active dimers and displays a complete loss of activity |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | ACCEPT | Summary: The self-interaction annotation agrees with independently demonstrated G6PD homomeric assembly. Reason: PMID:25416956 is the original human interactome survey; its exact G6PD clone-level interaction was not independently recovered. The same self-association is directly established by human biochemical and structural studies, including wild-type dimer formation. Retain the annotation with this access limitation explicit, without claiming that the high-throughput experiment alone proves a particular stoichiometry or natural isoform specificity. |
| GO:0042803 protein homodimerization activity | IPI PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | ACCEPT | Summary: Human G6PD structures support formation of active homodimers. Reason: The selected original PMID:15858258 examines human G6PD oligomeric structures and substrate/coenzyme complexes. Both dimeric and tetrameric assemblies can be active; the tetramer is a dimer of dimers. Retain homodimerization as a defined structural property without making tetramerization obligatory or treating engineered truncations as natural isoforms. Supporting Evidence: |
| GO:0042803 protein homodimerization activity | IPI PMID:38066190 Substitution of arginine 219 by glycine compromises stabilit... | ACCEPT | Summary: Purified wild-type human G6PD forms dimers in the reported chromatography experiment. Reason: PMID:38066190 compares His-tagged wild-type and R219G proteins. Size-exclusion chromatography shows wild type predominantly dimeric, whereas R219G has dimeric and monomeric populations. The experiment supports the wild-type homodimerization annotation; it does not mean every condition, disease allele or splice product has the same assembly distribution. Supporting Evidence: |
| GO:0043249 erythrocyte maturation | IMP PMID:5643703 Biochemical variants of glucose-6-phosphate dehydrogenase gi... | UNDECIDED | Summary: The erythrocyte-maturation assertion cannot be reconstructed from the inaccessible classic variant paper. Reason: PMID:5643703 has no recovered experimental text. Hemolytic disease and the known need for NADPH in erythrocyte survival do not by themselves establish the specific maturation process, but they also do not refute the curator's unseen experiment. Preserve UNDECIDED until the original maturation evidence is accessible; do not substitute mature-cell oxidative defense for maturation. Supporting Evidence: |
| GO:0043523 regulation of neuron apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: G6PD perturbation changes neuronal susceptibility to NO-related apoptosis in the donor study. Reason: PMID:12414804 reports primary neuron/astrocyte and PC12 experiments with G6PD overexpression or antisense and NO/peroxynitrite-associated apoptosis. The abstract does not specify every cell species or construct. Retain the rat-linked transferred regulatory context as non-core: metabolic NADPH/redox support can regulate apoptosis without G6PD being an apoptosis-execution enzyme. A lack of direct human experiments alone is not a basis for removal. Supporting Evidence: |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rat ethanol exposure alters G6PD and pentose-phosphate metabolism. Reason: PMID:18488910 reports G6PD/PPP responses in liver and muscle of ethanol-exposed rats. Retain the positive ortholog-derived chemical-response context as non-core, with no claim that human G6PD directly metabolizes ethanol or that a universal tissue response has been demonstrated. Supporting Evidence: |
| GO:0046390 ribose phosphate biosynthetic process | IMP PMID:2420826 Ribose metabolism and nucleic acid synthesis in normal and g... | ACCEPT | Summary: G6PD directly initiates a route producing ribose phosphates. Reason: PMID:2420826 traces glucose carbon into pentose/nucleic-acid production and distinguishes the oxidative contribution from the larger GSH-dependent PRPP-synthetase effect. G6PD performs the first oxidation in the route, rather than being a passive substrate or merely a disease marker. Retain the ribose-phosphate biosynthetic process while avoiding a claim that G6PD itself catalyzes PRPP formation. Supporting Evidence: |
| GO:0050661 NADP binding | IDA PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | ACCEPT | Summary: Human G6PD structures directly resolve catalytic and structural NADP+ binding. Reason: The selected original PMID:15858258 describes NADP+ at the catalytic coenzyme site and a separate structural site. These are direct structural observations, supported by enzyme kinetics; the engineered constructs are kept distinct from natural splice products. Retain the specific NADP-binding annotation. Supporting Evidence: |
| GO:0050661 NADP binding | IEA GO_REF:0000120 | ACCEPT | Summary: NADP binding is an intrinsic coenzyme and structural property of G6PD. Reason: The literal rat and InterPro mappings are consistent with human structures showing catalytic and structural NADP+ sites. Retain this specific ligand-binding function alongside G6PD catalysis. The existence of a structural nucleotide site is not inferred merely from an NADP-related sequence motif. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Binds two molecules of NADP. |
| GO:0051156 glucose 6-phosphate metabolic process | IDA PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | ACCEPT | Summary: The human structure/kinetics study establishes direct G6P metabolism. Reason: PMID:15858258 resolves the G6P substrate complex and measures NADP+-dependent enzyme kinetics. This supports metabolism of the phosphorylated substrate; the engineered deletion and disease-mutant constructs are explicitly distinguished from natural splice isoforms. Supporting Evidence: |
| GO:0051156 glucose 6-phosphate metabolic process | IDA PMID:38066190 Substitution of arginine 219 by glycine compromises stabilit... | ACCEPT | Summary: Purified wild-type human G6PD turns over G6P in the recombinant assay. Reason: PMID:38066190 monitors NADPH formation while varying G6P and NADP+ concentrations in assays of His-tagged wild-type and R219G proteins. These measurements directly support G6P metabolism. The reported Michaelis constants are kinetic parameters, not independently measured binding dissociation constants. Supporting Evidence: |
| GO:0051156 glucose 6-phosphate metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: The transferred G6P-metabolism term describes the substrate directly consumed by G6PD. Reason: The rat ortholog mapping agrees with direct human G6P turnover and the established reaction. Official ontology places the oxidative PPP within PPP and G6P metabolism. Retain the direct substrate-process annotation without inferring binding of free glucose. |
| GO:0051156 glucose 6-phosphate metabolic process | IMP PMID:5643703 Biochemical variants of glucose-6-phosphate dehydrogenase gi... | ACCEPT | Summary: The classic G6P-metabolism annotation agrees with independently established human substrate turnover. Reason: Although the detailed PMID:5643703 variant experiments were not recovered, direct human structural and purified-enzyme studies establish that G6PD consumes G6P. Retain this well-established process without claiming independent inspection of the old experiment or using its title to settle distinct maturation/free-glucose assertions. |
| GO:0061052 negative regulation of cell growth involved in cardiac muscle cell development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The donor experiment supports anti-hypertrophic redox effects but not the full cardiac-development scope. Reason: PMID:24190878 studies phenylephrine-induced enlargement in cultured neonatal rat ventricular myocytes. HK2 expression increases G6PDH activity, and DHEA reduces activity and blocks the HK2-associated protection against ROS and cell enlargement. The pharmacological specificity limits remain. GO:0061052 additionally requires growth contributing to progression from initial formation to the mature cardiac cell; neonatal origin and induced hypertrophy do not establish that developmental process. Mark this overextended scope without denying the positive G6PD-associated perturbation or claiming the paper only studies HK2. Supporting Evidence: |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: G6PD is listed in the retained urinary-exosome protein table. Reason: The authentic expanded NHLBI table associated with PMID:19056867 lists G6PD/NP_000393 with the historical isoform-a label. Preserve the literal part_of UBERON:0001088 urine extension. This supports detected association with the isolated urinary fraction, not vesicle biogenesis, a mandatory intravesicular topology, a present-day isoform-unique peptide claim or an established passive-packaging mechanism. Supporting Evidence: |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: The original expressed-prostatic-secretion exosome workbook contains G6PD. Reason: PMID:23533145 Supplemental Table 2, sheet SI Table 2 row 675, lists P11413/G6PD. The native cache contains the main text; the authentic supplementary workbook was independently retained and read. Keep the positive fraction-associated observation as non-core without inferring exosome biogenesis, exclusive vesicle residence or a G6PD-specific extracellular catalytic role. Supporting Evidence: |
| GO:1904879 positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: G6PD-dependent NADPH can positively regulate cardiac high-voltage calcium current. Reason: The actual PMID:23071515 Methods and Results use rat hearts/cardiomyocytes, G6PD inhibition, intracellular NADPH versus NADH and an independent G6PD-deficient mouse comparison. NADPH partly prevents the inhibitor-associated loss of L-type current; other signaling and pH contributions are discussed. The official term definition cites this paper. Retain this measured, indirect metabolic regulation as non-core, not as a claim that G6PD is a channel subunit or directly binds the channel. Supporting Evidence: |
| GO:2000378 negative regulation of reactive oxygen species metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: G6PD-associated NADPH production supports a context-dependent reduction of ROS. Reason: The mapped rat cardiac study links G6PDH activity to the HK2-associated protection against ROS after phenylephrine stimulation, with DHEA specificity limits. This supports a non-core regulatory outcome through reducing-power supply. It does not make G6PD a ROS-consuming enzyme or imply NADPH always lowers ROS in every cellular context. |
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Download this section (compressed HTML)Q: What original assays support binding of free D-glucose, as distinct from glucose 6-phosphate, in the human and rat annotation chain?
Q: Which original 1968 experiments support pentose biosynthesis and erythrocyte maturation, and what target-specific evidence supports the substantia-nigra developmental assertion?
Q: Can the UniProt FUNCTION direction for NAADP/NAADPH be reconciled with PMID:34784249 and RHEA:86243 without changing the retained source record?
Q: How do the 515-, 561- and 545-residue natural products differ in activity, assembly and localization under comparable conditions?
Experiment: Compare purified, sequence-verified natural G6PD products using matched G6P/NADP+ turnover and oligomerization assays, distinguishing kinetic parameters from direct ligand-binding constants.
Experiment: Test free D-glucose and G6P binding separately with appropriate ligand and catalytic controls rather than infer one from the other.
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