Glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49) is the committed, rate-limiting first enzyme of the oxidative branch of the pentose phosphate pathway (hexose monophosphate shunt). It oxidises D-glucose-6-phosphate to 6-phospho-D-glucono-1,5-lactone while reducing NADP+ to NADPH. G6PD is the principal cytosolic source of NADPH for reductive biosynthesis (fatty acids, cholesterol, nucleotides) and, most critically in erythrocytes, for regenerating reduced glutathione and defending cells against oxidative stress. The enzyme is active as a homodimer/homotetramer (dimer of dimers) and requires a tightly bound structural NADP+ in addition to the catalytic (cosubstrate) NADP+. G6PD deficiency is the most common human enzyme defect, affecting several hundred million people, and is X-linked; it causes acute oxidant-induced hemolytic anemia (favism from fava beans, certain drugs, and infection), neonatal jaundice, and, in severe variants, chronic nonspherocytic hemolytic anemia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core, well-supported molecular function. G6PD catalyzes the NADP+-dependent oxidation of glucose-6-phosphate, the first and rate-limiting step of the oxidative pentose phosphate pathway. The IBA call across metazoan, plant, fungal and bacterial orthologs correctly captures the conserved catalytic function. Reason: This is the primary, extensively validated molecular function of G6PD, supported by human structural, kinetic, and disease-mutation studies. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Catalyzes the rate-limiting step of the oxidative pentose- PMID:15858258 catalyses the first and rate-limiting step of the pentose phosphate shunt. |
| GO:0009051 pentose-phosphate shunt, oxidative branch | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. G6PD is the entry enzyme of the oxidative branch of the pentose phosphate pathway, converting glucose-6-phosphate toward ribulose-5-phosphate while generating NADPH. This is the correct, specific BP term for the enzyme and is conserved across the ortholog set. Reason: Directly corresponds to the pathway step catalyzed by G6PD; well supported phylogenetically and experimentally. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Catalyzes the rate-limiting step of the oxidative pentose- |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Correct subcellular localization. G6PD is a soluble cytosolic enzyme that is active in the cytosol, consistent with the localization of the pentose phosphate pathway and with direct human immunofluorescence and fractionation data. Reason: Cytosolic localization is well established for human G6PD and its orthologs. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Cytoplasm, cytosol |
| GO:0006006 glucose metabolic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: G6PD acts on glucose-6-phosphate rather than free glucose; glucose metabolic process is a correct but more general parent term. The specific and informative annotations are the pentose-phosphate shunt (oxidative branch) BP terms and the glucose-6-phosphate metabolic process term. Reason: The term is not wrong (the PPP is part of glucose catabolism) but is unnecessarily general given the more specific pentose-phosphate shunt and glucose 6-phosphate metabolic process annotations that better describe the enzyme. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000604427 · G6PD family node SUPPORTS SOURCE BUT NOT TARGET G6PD acts on glucose-6-phosphate; the family-level glucose metabolic process term is a true but uninformative parent of the specific pentose-phosphate shunt annotations. |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the core catalytic activity via ARBA/InterPro/EC 1.1.1.49/RHEA:15841. Consistent with all experimental evidence. Reason: Correct core molecular function; the IEA mapping to EC 1.1.1.49 is accurate. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location keyword mapping to cytosol, matching the curated localization. Reason: Accurate cytosolic localization consistent with experimental data. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Cytoplasm, cytosol |
| GO:0006006 glucose metabolic process | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO transfer of a general glucose metabolic process term. As with the IBA call, this is a correct but overly general parent of the specific pentose-phosphate shunt annotations. Reason: Superseded in specificity by the pentose-phosphate shunt and glucose-6-phosphate metabolic process terms. |
| GO:0016020 membrane | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: G6PD is a soluble cytosolic enzyme. A fraction can associate peripherally with the erythrocyte membrane, and UniProt records a peripheral membrane localization, but the bare "membrane" CC term is an over-annotation relative to the dominant cytosolic localization. Reason: Only a minor, peripheral membrane-associated pool exists; the generic membrane term over-represents this as a primary location. 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 | MARK AS OVER ANNOTATED | Summary: Correct but general parent of glucose-6-phosphate dehydrogenase activity. G6PD is an NADP+-dependent oxidoreductase acting on the CH-OH group of glucose-6-phosphate. Reason: The specific child term GO:0004345 is annotated and preferred; this parent term is redundant. |
| GO:0050661 NADP binding | IEA GO_REF:0000120 | ACCEPT | Summary: G6PD binds NADP+ both as catalytic cosubstrate and as a structural cofactor. Electronic assignment is accurate and independently supported by human structural studies and kinetics. Reason: NADP binding is an intrinsic, experimentally confirmed property of G6PD. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Binds two molecules of NADP. The first one is a PMID:15858258 NADP(+) binding at the coenzyme site |
| GO:0005515 protein binding | IPI PMID:21157431 ATM activates the pentose phosphate pathway promoting anti-o... | MARK AS OVER ANNOTATED | Summary: IntAct capture of a G6PD interaction with HSPB1/Hsp27 (P04792). Cosentino et al. showed that ATM promotes Hsp27 binding to G6PD, directly stimulating its activity during the oxidative-stress/DNA-damage response. The interaction is biologically meaningful (an activity-modulating partner) but the bare "protein binding" term is uninformative as a molecular function. Reason: Per curation guidelines, bare protein binding is not an informative MF. The HSPB1 interaction is retained here as documentation of a regulatory partner rather than a core molecular function. Supporting Evidence: PMID:21157431 ATM promotes Hsp27 |
| GO:0005515 protein binding | IPI PMID:24769394 Regulation of G6PD acetylation by SIRT2 and KAT9 modulates N... | MARK AS OVER ANNOTATED | Summary: IntAct capture of the G6PD-SIRT2 (Q8IXJ6) interaction. SIRT2 deacetylates G6PD at K403, activating the enzyme; the interaction is enhanced by oxidative (H2O2) stress. Regulatory partner, but bare protein binding is uninformative as MF. Reason: Uninformative generic binding term; the SIRT2 interaction is a documented regulatory relationship rather than a core molecular function. Supporting Evidence: PMID:24769394 SIRT2-mediated deacetylation and activation of G6PD |
| GO:0042802 identical protein binding | IPI PMID:24769394 Regulation of G6PD acetylation by SIRT2 and KAT9 modulates N... | ACCEPT | Summary: G6PD self-association (homodimer/homotetramer). Acetylation on K403 blocks formation of active dimers, underscoring that the oligomeric self-interaction is required for activity. Homodimerization activity (GO:0042803) is the more informative representation of this self-interaction. Reason: G6PD is a bona fide homo-oligomer; identical protein binding is accurate. 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: High-throughput (Y2H interactome map) evidence for G6PD self-interaction, consistent with its obligate homo-oligomeric quaternary structure. Reason: Corroborates the well-established homodimeric/homotetrameric assembly of G6PD. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Homotetramer; dimer of dimers |
| GO:0005536 D-glucose binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The physiological substrate of G6PD is glucose-6-phosphate, not free D-glucose. Structural work describes binding of glucose-6-phosphate at the substrate site. "D-glucose binding" is at best an imprecise proxy for substrate binding and is not the informative substrate descriptor. Reason: G6PD binds glucose-6-phosphate rather than free D-glucose; the term mischaracterizes the substrate and should not be treated as a core function. Supporting Evidence: PMID:15858258 Substrate |
| GO:0006098 pentose-phosphate shunt | IEA GO_REF:0000120 | ACCEPT | Summary: Correct pathway annotation. G6PD initiates the pentose phosphate shunt. This is a valid parent of the more specific oxidative-branch term. Reason: Accurate representation of the pathway in which G6PD functions. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Catalyzes the rate-limiting step of the oxidative pentose- |
| GO:0009051 pentose-phosphate shunt, oxidative branch | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl orthology transfer of the specific oxidative-branch PPP term, matching the experimental and IBA annotations. Reason: Specific and correct BP term for G6PD. |
| GO:0010041 response to iron(III) ion | IEA GO_REF:0000107 | REMOVE | Summary: Electronically transferred from rat ortholog (P05370) via Ensembl Compara. This is a physiological/context response term with no evidence that it reflects a molecular function or direct role of human G6PD; it appears to derive from expression/phenotype observations in rat. Reason: Over-propagated ortholog-based IEA of a context-specific response with no support for a direct G6PD role in humans. |
| GO:0030246 carbohydrate binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Generic carbohydrate binding transferred from rat ortholog. G6PD binds the specific substrate glucose-6-phosphate; a bare carbohydrate-binding MF is uninformative and over-general. Reason: Uninformative parent term; substrate binding is better captured by the catalytic activity annotation. |
| GO:0032094 response to food | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl orthology transfer from rat of a whole-organism response term. No evidence supports a direct, defined role of human G6PD in a "response to food" process; this is a physiological/nutritional context annotation. Reason: Over-propagated ortholog-based IEA of a context response, not a G6PD function. |
| GO:0043523 regulation of neuron apoptotic process | IEA GO_REF:0000107 | REMOVE | Summary: Transferred from rat ortholog. While NADPH from G6PD supports antioxidant defense and could indirectly influence neuronal survival, there is no evidence for human G6PD directly regulating neuron apoptosis; this is an over-propagated pleiotropic/context annotation. Reason: Ortholog-based IEA of an indirect physiological consequence, not a defined molecular role of human G6PD. |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl orthology transfer from rat of a whole-organism chemical-response term with no support for a direct human G6PD function. Reason: Over-propagated ortholog-based IEA context response, not a G6PD function. |
| GO:0051156 glucose 6-phosphate metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Accurate BP term - glucose-6-phosphate is the direct substrate of G6PD, so the enzyme participates in glucose-6-phosphate metabolism. Independently supported by human IDA annotations. Reason: Correctly describes the metabolic process acting on the direct substrate. |
| GO:0061052 negative regulation of cell growth involved in cardiac muscle cell development | IEA GO_REF:0000107 | REMOVE | Summary: Highly specific developmental term transferred from rat ortholog. There is no evidence for a direct, defined role of human G6PD in cardiac muscle cell growth regulation; this is an over-propagated pleiotropic annotation. Reason: Ortholog-based IEA of a narrow developmental process unsupported for human G6PD. |
| GO:1904879 positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel | IEA GO_REF:0000107 | REMOVE | Summary: Very specific ion-transport regulation term transferred from rat ortholog. No evidence supports a direct role of human G6PD in high voltage-gated calcium channel regulation. Reason: Over-propagated ortholog-based IEA of a specific process unrelated to the documented enzymatic function of human G6PD. |
| GO:2000378 negative regulation of reactive oxygen species metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred from rat ortholog. G6PD-derived NADPH supports antioxidant systems (glutathione/thioredoxin), so this captures a genuine downstream consequence of the enzyme's activity, but it is an indirect physiological effect rather than a direct molecular role. Retained as a non-core process. Reason: Reflects a real, literature-supported downstream antioxidant consequence of NADPH production, but it is an indirect/pleiotropic role rather than the core catalytic function. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for cytosolic localization, consistent with all other localization data. Reason: Confirms the established cytosolic localization of G6PD. |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | EXP PMID:24769394 Regulation of G6PD acetylation by SIRT2 and KAT9 modulates N... | ACCEPT | Summary: Experimental demonstration of G6PD catalytic activity in the context of acetylation-dependent regulation - K403 acetylation abolishes activity and SIRT2 deacetylation restores it, measured as G6PD enzymatic activity. Reason: Direct experimental confirmation of the core catalytic activity. Supporting Evidence: PMID:24769394 is a key enzyme in the pentose PMID:24769394 plays an essential role in the oxidative stress |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | EXP PMID:26479991 Severe G6PD Deficiency Due to a New Missense Mutation in an ... | ACCEPT | Summary: Clinical case demonstrating that a novel missense variant produces very low G6PD enzymatic activity, causing severe deficiency with neonatal jaundice and hemolysis - functional evidence that this protein carries G6PD catalytic activity. Reason: Loss of measured G6PD enzymatic activity in a patient variant confirms the core catalytic function. Supporting Evidence: PMID:26479991 very low glucose-6-phosphate |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IDA PMID:38066190 Substitution of arginine 219 by glycine compromises stabilit... | ACCEPT | Summary: Recombinant WT and Arg219Gly mutant G6PD were assayed directly; the mutant shows 50-fold reduced catalytic activity, confirming the assay measures the intrinsic G6PD dehydrogenase activity of the human enzyme. Reason: Direct in vitro assay of purified human G6PD confirms the catalytic activity. Supporting Evidence: PMID:38066190 catalytic activity by 50-fold while having a negligible effect on substrate |
| GO:0042803 protein homodimerization activity | IPI PMID:38066190 Substitution of arginine 219 by glycine compromises stabilit... | ACCEPT | Summary: Size-exclusion chromatography showed the WT enzyme is dimeric while the Arg219Gly mutant appears as both monomer and dimer, establishing that arginine 219 is critical for dimer formation and that homodimerization is intrinsic to G6PD. Reason: Direct biophysical demonstration of G6PD homodimer formation; a core structural/functional property required for activity. Supporting Evidence: PMID:38066190 critical role of arginine 219 in G6PD dimer formation PMID:38066190 only the latter for the wild-type form, suggesting a |
| GO:0051156 glucose 6-phosphate metabolic process | IDA PMID:38066190 Substitution of arginine 219 by glycine compromises stabilit... | ACCEPT | Summary: Direct assays of substrate (glucose-6-phosphate) turnover by WT and mutant G6PD document participation in glucose-6-phosphate metabolism. Reason: Accurate BP annotation acting on the direct substrate; experimentally supported. Supporting Evidence: PMID:38066190 catalytic activity by 50-fold while having a negligible effect on substrate |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IDA PMID:35122041 Aldolase B suppresses hepatocellular carcinogenesis by inhib... | ACCEPT | Summary: Study of ALDOB-mediated inhibition directly assays G6PD activity; identifies G6PD as the rate-limiting PPP enzyme whose activity is modulated by ALDOB and p53. Confirms the catalytic function in a hepatic/cancer context. Reason: Direct measurement of G6PD enzymatic activity supports the core function. Supporting Evidence: PMID:35122041 rate-limiting enzyme in the pentose phosphate pathway, glucose-6-phosphate |
| GO:0005515 protein binding | IPI PMID:35122041 Aldolase B suppresses hepatocellular carcinogenesis by inhib... | MARK AS OVER ANNOTATED | Summary: IntAct/UniProt capture of the direct G6PD-TP53 (P04637) interaction. Li et al. showed G6PD forms a ternary complex with ALDOB and TP53; the interaction is a documented regulatory relationship, but bare protein binding is uninformative as MF. Reason: Generic binding term is uninformative; the TP53/ALDOB ternary-complex interaction is recorded as a regulatory relationship rather than a core MF. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Forms a ternary complex with ALDOB and TP53; this |
| GO:0005515 protein binding | IPI PMID:35122041 Aldolase B suppresses hepatocellular carcinogenesis by inhib... | MARK AS OVER ANNOTATED | Summary: IntAct/UniProt capture of the direct G6PD-ALDOB (P05062, aldolase B) interaction. ALDOB directly binds and inhibits G6PD, holding oxidative PPP metabolism in check and suppressing hepatocellular carcinogenesis. Informative regulatory partner, but bare protein binding is uninformative as MF. Reason: Generic binding term; the ALDOB interaction is retained as a documented inhibitory regulator rather than a core molecular function. Supporting Evidence: PMID:35122041 directly binding and inhibiting the file:human/G6PD/G6PD-uniprot.txt ALDOB stabilizes the complex inhibiting G6PD |
| GO:0005829 cytosol | IDA PMID:35122041 Aldolase B suppresses hepatocellular carcinogenesis by inhib... | ACCEPT | Summary: Direct localization evidence placing G6PD in the cytosol, consistent with all other localization data. Reason: Confirms established cytosolic localization. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Cytoplasm, cytosol |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of G6PD in urinary/prostatic-secretion exosomes. G6PD is an abundant cytosolic enzyme frequently detected in exosome inventories; this is not a site of its enzymatic function. Reason: High-throughput mass-spec localization to exosomes; likely reflects passive incorporation of an abundant cytosolic protein rather than a functional site. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput membrane-proteome (NK cell) detection. G6PD is a soluble cytosolic enzyme that can peripherally associate with membranes; the generic membrane term over-represents this minor pool. Reason: Peripheral/incidental membrane association from a proteome-wide screen; not a primary functional localization. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Membrane; Peripheral membrane protein |
| GO:0021762 substantia nigra development | HEP PMID:22926577 Quantitative proteomic analysis of human substantia nigra in... | REMOVE | Summary: Derived from a quantitative proteomic survey of human substantia nigra in neurodegenerative disease. Detection/altered expression in a tissue does not indicate a role of G6PD in substantia nigra development; this is an expression- context over-annotation. Reason: Expression-based (HEP) annotation from a disease proteomics survey; provides no evidence for a developmental role of G6PD. Supporting Evidence: PMID:22926577 substantia nigra |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: A second high-throughput proteomic detection of G6PD in urinary exosomes, as for PMID:23533145. Reason: High-throughput exosome proteomics; incidental localization of an abundant cytosolic protein, not a functional site. |
| GO:0006739 NADP+ metabolic process | IDA PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | ACCEPT | Summary: G6PD reduces NADP+ to NADPH as part of its catalytic cycle, participating directly in NADP+ metabolism. Structural/kinetic study documents NADP+ binding and turnover. Reason: Accurate - G6PD is a major cellular NADP+/NADPH-interconverting enzyme. Supporting Evidence: PMID:15858258 NADP(+)-dependent and |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IDA PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | ACCEPT | Summary: Structural studies of human G6PD binary complexes with glucose-6-phosphate and NADP+ directly characterize the catalytic function of the human enzyme. Reason: Direct structural/biochemical evidence for the core catalytic activity. Supporting Evidence: PMID:15858258 catalyses the first and rate-limiting step of the pentose phosphate shunt. |
| GO:0051156 glucose 6-phosphate metabolic process | IDA PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | ACCEPT | Summary: G6PD acts directly on glucose-6-phosphate; structural characterization of the substrate complex supports participation in glucose-6-phosphate metabolism. Reason: Accurate BP annotation for the enzyme's direct substrate. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-70377 | ACCEPT | Summary: Reactome traceable assertion placing the G6PD dehydrogenation reaction (G6PD multimers dehydrogenate G6P) in the cytosol. Reason: Consistent with the established cytosolic localization of the PPP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9761849 | ACCEPT | Summary: Reactome traceable assertion for cytosolic localization associated with an NRF2/NFE2L2-dependent G6PD expression event. Reason: Consistent with cytosolic localization. |
| GO:0005737 cytoplasm | IDA GO_REF:0000054 | ACCEPT | Summary: Localization of an expressed GFP-fusion to the cytoplasm (LIFEdb). A correct but more general parent of the specific cytosol term. Reason: Cytoplasmic localization is correct; cytosol is the preferred, more specific term and is separately annotated. |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IMP PMID:2420826 Ribose metabolism and nucleic acid synthesis in normal and g... | ACCEPT | Summary: Comparison of normal versus G6PD-deficient (Mediterranean) erythrocytes shows loss of oxidative-branch flux in deficient cells, functional evidence for G6PD catalytic activity. Reason: Deficiency-based functional evidence supports the core catalytic activity. Supporting Evidence: PMID:2420826 approximately 20% of the pentose was produced via the |
| GO:0005536 D-glucose binding | IDA PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | MARK AS OVER ANNOTATED | Summary: Structural work describes binding at the substrate site, but the true substrate is glucose-6-phosphate rather than free D-glucose. The D-glucose binding term imprecisely represents substrate recognition. Reason: G6PD binds glucose-6-phosphate; the free-D-glucose descriptor mischaracterizes the substrate and is not a core function. Supporting Evidence: PMID:15858258 Substrate |
| GO:0006098 pentose-phosphate shunt | IDA PMID:2297768 Sex steroid hormone modulation of NADPH pathways in MCF-7 ce... | ACCEPT | Summary: Study of G6PD activity and NADPH-generating pathways in MCF-7 cells, linking G6PD to pentose phosphate shunt / NADPH production. Reason: Correct pathway annotation supported by direct measurement of G6PD activity within the shunt. Supporting Evidence: PMID:2297768 utilization pathways of NADPH generated by G6PD |
| GO:0006629 lipid metabolic process | TAS PMID:17361089 Production of inflammatory molecules in peripheral blood mon... | KEEP AS NON CORE | Summary: G6PD-derived NADPH is required for fatty acid and lipid biosynthesis, and G6PD-deficient PBMC show altered lipid/inflammatory profiles. This is an indirect, NADPH-supply role rather than a direct lipid-metabolic activity of G6PD. Reason: Reflects a genuine but indirect contribution (NADPH supply for lipid synthesis); not the core catalytic function. Supporting Evidence: PMID:17361089 glucose-6-phosphate dehydrogenase-deficient subjects |
| GO:0006695 cholesterol biosynthetic process | IMP PMID:12027950 Cell growth and cholesterol metabolism in human glucose-6-ph... | KEEP AS NON CORE | Summary: G6PD-deficient lymphomononuclear cells show reduced cholesterol synthesis, reflecting the NADPH requirement of the cholesterol biosynthetic pathway. This is an indirect (NADPH-supply) contribution rather than a direct role of G6PD in cholesterol biosynthesis. Reason: Indirect NADPH-dependent contribution to cholesterol synthesis; not a direct molecular role. Supporting Evidence: PMID:12027950 an essential enzyme involved in both |
| GO:0006749 glutathione metabolic process | IMP PMID:17516514 Mutation in G6PD gene leads to loss of cellular control of p... | ACCEPT | Summary: G6PD-derived NADPH is required to regenerate reduced glutathione; G6PD deficiency causes loss of control of protein glutathionylation, and reintroducing G6PD normalizes the phenotype. Central physiological role, though it is mediated via NADPH supply rather than direct glutathione chemistry. Reason: Well-supported involvement of G6PD in maintaining the glutathione redox system, a defining physiological role especially in erythrocytes. Supporting Evidence: PMID:17516514 control of protein glutathionylation PMID:17516514 susceptible to oxidative stress due to |
| GO:0006749 glutathione metabolic process | IMP PMID:2420826 Ribose metabolism and nucleic acid synthesis in normal and g... | ACCEPT | Summary: G6PD-deficient erythrocytes show markedly reduced glutathione (GSH), demonstrating that G6PD activity is required to maintain reduced glutathione. Reason: Deficiency-based evidence for G6PD's role in glutathione metabolism via NADPH provision. Supporting Evidence: PMID:2420826 Reduced glutathione (GSH) content of G6PD-deficient cells |
| GO:0009051 pentose-phosphate shunt, oxidative branch | IMP PMID:2420826 Ribose metabolism and nucleic acid synthesis in normal and g... | ACCEPT | Summary: In G6PD-deficient (Mediterranean) erythrocytes none of the pentose was produced via the oxidative pathway, directly demonstrating G6PD's role in the oxidative branch of the PPP. Reason: Direct deficiency-based evidence for the core oxidative-branch role. Supporting Evidence: PMID:2420826 oxidation of glucose-6-phosphate |
| GO:0019322 pentose biosynthetic process | IDA PMID:5643703 Biochemical variants of glucose-6-phosphate dehydrogenase gi... | KEEP AS NON CORE | Summary: Biochemical variant studies link G6PD activity to production of pentose phosphates via the oxidative PPP. Pentose (ribose-5-phosphate) biosynthesis is a downstream output of the pathway G6PD initiates. Reason: G6PD contributes to pentose biosynthesis by feeding the oxidative PPP, but the direct, defining function is the dehydrogenase step; pentose output is a pathway-level consequence. |
| GO:0034599 cellular response to oxidative stress | IMP PMID:17516514 Mutation in G6PD gene leads to loss of cellular control of p... | ACCEPT | Summary: G6PD deficiency sensitizes cells to oxidative stress (increased protein glutathionylation, reduced NADPH and thiol buffering); reintroducing G6PD rescues the phenotype. G6PD is central to the cellular oxidative-stress response through NADPH production. Reason: Well-supported role of G6PD in the cellular antioxidant/oxidative-stress response, a defining function especially in erythrocytes. Supporting Evidence: PMID:17516514 susceptible to oxidative stress due to |
| GO:0042803 protein homodimerization activity | IPI PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | ACCEPT | Summary: Human G6PD crystal structures show a homodimeric/tetrameric assembly (dimer of dimers), confirming homodimerization as an intrinsic structural property required for activity. Reason: Directly supported by structural data; homodimerization is essential for the active enzyme. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Homotetramer; dimer of dimers |
| GO:0043249 erythrocyte maturation | IMP PMID:5643703 Biochemical variants of glucose-6-phosphate dehydrogenase gi... | KEEP AS NON CORE | Summary: Biochemical G6PD variants cause congenital nonspherocytic hemolytic disease, reflecting the essential role of G6PD in protecting maturing/mature erythrocytes from oxidative damage. The link to erythrocyte maturation is physiological and indirect (via NADPH/antioxidant defense). Reason: G6PD is critical for erythrocyte oxidative defense; its contribution to erythrocyte maturation is an important but indirect physiological role. |
| GO:0046390 ribose phosphate biosynthetic process | IMP PMID:2420826 Ribose metabolism and nucleic acid synthesis in normal and g... | KEEP AS NON CORE | Summary: In P. falciparum-infected erythrocytes, G6PD deficiency reduces oxidative- pathway contribution to the pentose/PRPP pool, linking G6PD to ribose phosphate biosynthesis. This is a downstream pathway output rather than a direct activity. Reason: G6PD feeds ribose-phosphate biosynthesis via the oxidative PPP, but this is a pathway-level consequence, not the core catalytic function. Supporting Evidence: PMID:2420826 PRPP synthetase, which requires GSH |
| GO:0050661 NADP binding | IDA PMID:15858258 Structural studies of glucose-6-phosphate and NADP+ binding ... | ACCEPT | Summary: Structural studies directly demonstrate NADP+ binding at both the catalytic coenzyme site and the structural site of human G6PD. Reason: Directly demonstrated intrinsic NADP-binding property. Supporting Evidence: PMID:15858258 Structural NADP(+) binds in a very similar way |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IMP PMID:5643703 Biochemical variants of glucose-6-phosphate dehydrogenase gi... | ACCEPT | Summary: Characterization of biochemical G6PD variants with reduced/altered enzyme activity causing hemolytic disease provides functional evidence for the core catalytic activity. Reason: Variant-based functional evidence supports the core catalytic function. |
| GO:0004345 glucose-6-phosphate dehydrogenase activity | IMP PMID:743300 Glucose 6-phosphate dehydrogenase activity in membranes of e... | ACCEPT | Summary: Measurement of G6PD activity in erythrocyte membranes from normal versus Mediterranean-deficient subjects, functional evidence for the enzyme's catalytic activity. Reason: Deficiency-based functional evidence for the core catalytic activity. |
| GO:0005536 D-glucose binding | IMP PMID:5643703 Biochemical variants of glucose-6-phosphate dehydrogenase gi... | MARK AS OVER ANNOTATED | Summary: The physiological substrate of G6PD is glucose-6-phosphate, not free D-glucose. As for the other D-glucose binding annotations, this imprecisely represents substrate recognition. Reason: Substrate is glucose-6-phosphate; the D-glucose binding term is imprecise and not a core function. |
| GO:0005829 cytosol | IDA PMID:743300 Glucose 6-phosphate dehydrogenase activity in membranes of e... | ACCEPT | Summary: Direct evidence for G6PD in the cytosolic (soluble) fraction of erythrocytes, consistent with all other localization data. Reason: Confirms cytosolic localization. |
| 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 fraction of erythrocyte G6PD is peripherally associated with the cytoplasmic face of the plasma membrane. This is a minor membrane-associated pool; the enzyme's dominant and functional localization is cytosolic. Reason: Genuine but minor peripheral membrane association in erythrocytes; not the primary functional localization. Supporting Evidence: file:human/G6PD/G6PD-uniprot.txt Membrane; Peripheral membrane protein |
| GO:0051156 glucose 6-phosphate metabolic process | IMP PMID:5643703 Biochemical variants of glucose-6-phosphate dehydrogenase gi... | ACCEPT | Summary: G6PD variant studies link the enzyme to metabolism of its direct substrate, glucose-6-phosphate. Reason: Accurate BP annotation acting on the direct substrate. |
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