G6PD

UniProt ID: P11413
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

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.

Existing Annotations Review

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.

Core Functions

NADP+-dependent oxidation of glucose-6-phosphate to 6-phospho-D-glucono-1,5-lactone, the committed, rate-limiting first step of the oxidative branch of the pentose phosphate pathway, generating NADPH.

Molecular Function:
glucose-6-phosphate dehydrogenase activity
Directly Involved In:
pentose-phosphate shunt, oxidative branch
Cellular Locations:
cytosol
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.
  • PMID:2420826
    oxidation of glucose-6-phosphate

Provision of NADPH reducing power for antioxidant defense, most critically regeneration of reduced glutathione, protecting cells (especially erythrocytes) from oxidative stress.

Molecular Function:
glucose-6-phosphate dehydrogenase activity
Directly Involved In:
glutathione metabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/G6PD/G6PD-uniprot.txt
    provide reducing power (NADPH) and pentose phosphates for fatty acid
  • PMID:17516514
    control of protein glutathionylation
  • PMID:2420826
    Reduced glutathione (GSH) content of G6PD-deficient cells

NADP+ binding, both as catalytic cosubstrate and as a tightly bound structural cofactor required for stability of the active homodimer/homotetramer.

Molecular Function:
NADP binding
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/G6PD/G6PD-uniprot.txt
    Binds two molecules of NADP. The first one is a
  • PMID:15858258
    Structural NADP(+) binds in a very similar way

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000054
Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins in living cells
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
file:human/G6PD/G6PD-uniprot.txt
UniProt text export for G6PD (P11413)
PMID:12027950
Cell growth and cholesterol metabolism in human glucose-6-phosphate dehydrogenase deficient lymphomononuclear cells.
PMID:15858258
Structural studies of glucose-6-phosphate and NADP+ binding to human glucose-6-phosphate dehydrogenase.
PMID:17361089
Production of inflammatory molecules in peripheral blood mononuclear cells from severely glucose-6-phosphate dehydrogenase-deficient subjects.
PMID:17516514
Mutation in G6PD gene leads to loss of cellular control of protein glutathionylation: mechanism and implication.
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:21157431
ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair.
PMID:22926577
Quantitative proteomic analysis of human substantia nigra in Alzheimer's disease, Huntington's disease and Multiple sclerosis.
PMID:2297768
Sex steroid hormone modulation of NADPH pathways in MCF-7 cells.
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
PMID:2420826
Ribose metabolism and nucleic acid synthesis in normal and glucose-6-phosphate dehydrogenase-deficient human erythrocytes infected with Plasmodium falciparum.
PMID:24769394
Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:26479991
Severe G6PD Deficiency Due to a New Missense Mutation in an Infant of Northern European Descent.
PMID:35122041
Aldolase B suppresses hepatocellular carcinogenesis by inhibiting G6PD and pentose phosphate pathways.
PMID:38066190
Substitution of arginine 219 by glycine compromises stability, dimerization, and catalytic activity in a G6PD mutant.
PMID:5643703
Biochemical variants of glucose-6-phosphate dehydrogenase giving rise to congenital nonspherocytic hemolytic disease.
PMID:743300
Glucose 6-phosphate dehydrogenase activity in membranes of erythrocytes from normal individuals and subjects with Mediterranean G6PD deficiency.
Reactome:R-HSA-70377
G6PD multimers dehydrogenate G6P
Reactome:R-HSA-9761849
AcK-NFE2L2-dependent P6GD gene expression

📚 Additional Documentation

Notes

(G6PD-notes.md)

G6PD (human, P11413) review notes

Summary of verified biology

G6PD is glucose-6-phosphate dehydrogenase (EC 1.1.1.49), the committed, rate-limiting
first enzyme of the oxidative branch of the pentose phosphate pathway (PPP / hexose
monophosphate shunt). It oxidises D-glucose-6-phosphate to 6-phospho-D-glucono-1,5-lactone,
reducing NADP+ to NADPH (Rhea:RHEA:15841). It is the principal cytosolic source of NADPH for
reductive biosynthesis (fatty acids, cholesterol, nucleotides) and, critically in erythrocytes,
for regenerating reduced glutathione and defending against oxidative stress.

  • UniProt FUNCTION: "Catalyzes the rate-limiting step of the oxidative pentose-phosphate pathway,
    which represents a route for the dissimilation of carbohydrates besides glycolysis. The main
    function of this enzyme is to provide reducing power (NADPH) and pentose phosphates for fatty
    acid and nucleic acid synthesis." [file:human/G6PD/G6PD-uniprot.txt]
  • Active as a homodimer / homotetramer (dimer of dimers) requiring a tightly bound
    structural NADP+ for stability, in addition to the catalytic (cosubstrate) NADP+.
    UniProt MISCELLANEOUS: "Binds two molecules of NADP. The first one is a cosubstrate (bound to
    the N-terminal domain), the second is bound to the C-terminal domain and functions as a
    structural element." [file:human/G6PD/G6PD-uniprot.txt]
  • Cytosolic (UniProt SUBCELLULAR LOCATION: Cytoplasm, cytosol).
  • G6PD deficiency is the most common human enzyme defect (~400 million people), X-linked
    (CNSHA1, MIM:300908), causing acute oxidant-induced hemolytic anemia (favism, drugs,
    infection), neonatal jaundice, and in severe class-I variants chronic nonspherocytic
    hemolytic anemia.

Key experimental references (cached)

  • PMID:15858258 (Kotaka 2005, Acta Cryst D): crystal structures of human G6PD binary
    complexes with G6P and with NADP+; substrate + cosubstrate + structural NADP+ binding;
    tetramer interface. Supports GO:0004345, GO:0050661 NADP binding, GO:0005536 D-glucose
    binding, GO:0042803 homodimerization. (abstract-only cache)
  • PMID:24769394 (Wang 2014, EMBO J): G6PD acetylation on K403 by KAT9/ELP3 blocks dimer
    formation and abolishes activity; SIRT2 deacetylates and activates G6PD; PPP/NADPH homeostasis
    during oxidative stress; SIRT2 interaction (Q8IXJ6). Supports GO:0004345 (EXP), GO:0005515
    (SIRT2), GO:0042802.
  • PMID:26479991 (Warny 2015): case report, severe G6PD deficiency, novel Arg198Ser missense;
    very low enzymatic activity, neonatal jaundice + hemolysis. Supports GO:0004345 (EXP).
  • PMID:38066190 (Zgheib 2023, Commun Biol, full text): Arg219Gly mutant — 50-fold reduced
    catalytic activity, impaired dimerization/stability; WT is dimeric. Supports GO:0004345 (IDA),
    GO:0042803 homodimerization, GO:0051156 G6P metabolic process.
  • PMID:35122041 (Li 2020, Nat Cancer): ALDOB directly binds and inhibits G6PD, forming a
    ternary complex with p53 (TP53); restrains PPP in liver; suppresses HCC. Supports GO:0004345
    (IDA), GO:0005515 (TP53 P04637; ALDOB P05062), GO:0005829.
  • PMID:743300 (Benatti 1978): G6PD activity in erythrocyte membranes, normal vs Mediterranean
    deficiency. Supports GO:0004345 (IMP), and the membrane-associated (GO:0009898) / cytosol
    localization annotations.
  • PMID:5643703 (Beutler 1968, Blood): biochemical G6PD variants causing CNSHA; classic
    deficiency phenotype work. Supports GO:0004345, GO:0005536, GO:0051156, GO:0043249 erythrocyte
    maturation, GO:0019322 pentose biosynthesis (IMP/IDA). (abstract-only cache)
  • PMID:2420826 (Roth 1986, JCI): ribose/PRPP metabolism in normal vs G6PD-deficient
    P. falciparum-infected RBCs; oxidative-branch contribution to pentose. Supports GO:0004345,
    GO:0006749 glutathione metabolism, GO:0009051 oxidative branch, GO:0046390 ribose-phosphate
    biosynthesis.
  • PMID:17516514 (Ayene 2008): G6PD deficiency → loss of control of protein glutathionylation;
    reduced NADPH; reintroducing G6PD normalises phenotype. Supports GO:0006749, GO:0034599
    cellular response to oxidative stress.
  • PMID:2297768 (Thomas 1990): hormonal modulation of G6PD and NADPH utilization in MCF-7;
    cited for GO:0006098 pentose-phosphate shunt (IDA).
  • PMID:21157431 (Cosentino 2011, EMBO J, full text): ATM activates PPP; Hsp27 (HSPB1, P04792)
    binds and directly stimulates G6PD. Basis of the GO:0005515 IPI with HSPB1.
  • PMID:12027950 (Batetta 2002): G6PD-deficient PBMC show reduced cholesterol synthesis;
    basis of GO:0006695 cholesterol biosynthetic process (IMP) — indirect / NADPH-supply role.
  • PMID:17361089 (Sanna 2007): inflammatory molecules in severely G6PD-deficient PBMC;
    cited for GO:0006629 lipid metabolic process (TAS) — indirect.

Localization / proteomics (high-throughput, non-core)

  • PMID:23533145, PMID:19056867: extracellular exosome (HDA) — mass-spec exosome inventories.
  • PMID:19946888: membrane (HDA) — NK cell membrane proteome; G6PD is a soluble cytosolic enzyme
    that can associate peripherally with membranes (cf. PMID:743300).
  • PMID:22926577: substantia nigra proteomics (HEP) — GO:0021762 substantia nigra development is
    an expression-context over-annotation, not a G6PD function.

Curation stance

  • Core: GO:0004345 glucose-6-phosphate dehydrogenase activity (MF); GO:0009051 pentose-phosphate
    shunt, oxidative branch and GO:0006098 pentose-phosphate shunt (BP); GO:0005829 cytosol (CC);
    GO:0050661 NADP binding; GO:0042803 homodimerization.
  • Ensembl orthology IEA transfers (GO_REF:0000107) from rat P05370 import several
    context/phenotype terms (response to iron(III), response to food, response to ethanol,
    regulation of neuron apoptotic process, negative regulation of cardiac muscle cell growth,
    positive regulation of HVGCC calcium transport) that are downstream/pleiotropic physiological
    responses, not molecular functions of the human enzyme → MARK_AS_OVER_ANNOTATED or REMOVE
    (clearly wrong-context IEA).
  • Do NOT REMOVE experimental annotations whose full text I cannot verify; bare protein binding
    IPIs → MARK_AS_OVER_ANNOTATED (informative interactors noted: HSPB1, SIRT2, TP53, ALDOB).

📄 View Raw YAML

 
id: P11413
gene_symbol: G6PD
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: Short
  id: P11413-1
- name: Long
  id: P11413-2
  sequence_note: VSP_001592
- name: '3'
  id: P11413-3
  sequence_note: VSP_037802
existing_annotations:
- term:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: This is the primary, extensively validated molecular function of G6PD,
      supported by human structural, kinetic, and disease-mutation studies.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Catalyzes the rate-limiting step of the oxidative pentose-
    - reference_id: PMID:15858258
      supporting_text: catalyses the first and rate-limiting step of the pentose phosphate shunt.
- term:
    id: GO:0009051
    label: pentose-phosphate shunt, oxidative branch
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Directly corresponds to the pathway step catalyzed by G6PD; well supported
      phylogenetically and experimentally.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Catalyzes the rate-limiting step of the oxidative pentose-
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    reason: Cytosolic localization is well established for human G6PD and its orthologs.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0006006
    label: glucose metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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
      source_entities:
      - source_id: PANTHER:PTN000604427
        source_label: G6PD family node
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: 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.
- term:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of the core catalytic activity via ARBA/InterPro/EC
      1.1.1.49/RHEA:15841. Consistent with all experimental evidence.
    action: ACCEPT
    reason: Correct core molecular function; the IEA mapping to EC 1.1.1.49 is accurate.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt subcellular-location keyword mapping to cytosol, matching the
      curated localization.
    action: ACCEPT
    reason: Accurate cytosolic localization consistent with experimental data.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0006006
    label: glucose metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Superseded in specificity by the pentose-phosphate shunt and
      glucose-6-phosphate metabolic process terms.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Only a minor, peripheral membrane-associated pool exists; the generic
      membrane term over-represents this as a primary location.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Membrane; Peripheral membrane protein
- term:
    id: GO:0016614
    label: oxidoreductase activity, acting on CH-OH group of donors
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific child term GO:0004345 is annotated and preferred; this parent
      term is redundant.
- term:
    id: GO:0050661
    label: NADP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: NADP binding is an intrinsic, experimentally confirmed property of G6PD.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Binds two molecules of NADP. The first one is a
    - reference_id: PMID:15858258
      supporting_text: NADP(+) binding at the coenzyme site
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21157431
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:21157431
      supporting_text: ATM promotes Hsp27
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24769394
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic binding term; the SIRT2 interaction is a documented
      regulatory relationship rather than a core molecular function.
    supported_by:
    - reference_id: PMID:24769394
      supporting_text: SIRT2-mediated deacetylation and activation of G6PD
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:24769394
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: G6PD is a bona fide homo-oligomer; identical protein binding is accurate.
    supported_by:
    - reference_id: PMID:24769394
      supporting_text: is incapable of forming active dimers and displays a complete loss of activity
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: High-throughput (Y2H interactome map) evidence for G6PD self-interaction,
      consistent with its obligate homo-oligomeric quaternary structure.
    action: ACCEPT
    reason: Corroborates the well-established homodimeric/homotetrameric assembly of G6PD.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Homotetramer; dimer of dimers
- term:
    id: GO:0005536
    label: D-glucose binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:15858258
      supporting_text: Substrate
- term:
    id: GO:0006098
    label: pentose-phosphate shunt
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Correct pathway annotation. G6PD initiates the pentose phosphate shunt.
      This is a valid parent of the more specific oxidative-branch term.
    action: ACCEPT
    reason: Accurate representation of the pathway in which G6PD functions.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Catalyzes the rate-limiting step of the oxidative pentose-
- term:
    id: GO:0009051
    label: pentose-phosphate shunt, oxidative branch
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl orthology transfer of the specific oxidative-branch PPP term,
      matching the experimental and IBA annotations.
    action: ACCEPT
    reason: Specific and correct BP term for G6PD.
- term:
    id: GO:0010041
    label: response to iron(III) ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: REMOVE
    reason: Over-propagated ortholog-based IEA of a context-specific response with no
      support for a direct G6PD role in humans.
- term:
    id: GO:0030246
    label: carbohydrate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative parent term; substrate binding is better captured by the
      catalytic activity annotation.
- term:
    id: GO:0032094
    label: response to food
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: REMOVE
    reason: Over-propagated ortholog-based IEA of a context response, not a G6PD function.
- term:
    id: GO:0043523
    label: regulation of neuron apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: REMOVE
    reason: Ortholog-based IEA of an indirect physiological consequence, not a defined
      molecular role of human G6PD.
- term:
    id: GO:0045471
    label: response to ethanol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl orthology transfer from rat of a whole-organism chemical-response
      term with no support for a direct human G6PD function.
    action: REMOVE
    reason: Over-propagated ortholog-based IEA context response, not a G6PD function.
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Correctly describes the metabolic process acting on the direct substrate.
- term:
    id: GO:0061052
    label: negative regulation of cell growth involved in cardiac muscle cell development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: REMOVE
    reason: Ortholog-based IEA of a narrow developmental process unsupported for human
      G6PD.
- term:
    id: GO:1904879
    label: positive regulation of calcium ion transmembrane transport via high voltage-gated
      calcium channel
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: REMOVE
    reason: Over-propagated ortholog-based IEA of a specific process unrelated to the
      documented enzymatic function of human G6PD.
- term:
    id: GO:2000378
    label: negative regulation of reactive oxygen species metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for cytosolic localization,
      consistent with all other localization data.
    action: ACCEPT
    reason: Confirms the established cytosolic localization of G6PD.
- term:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  evidence_type: EXP
  original_reference_id: PMID:24769394
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Direct experimental confirmation of the core catalytic activity.
    supported_by:
    - reference_id: PMID:24769394
      supporting_text: is a key enzyme in the pentose
    - reference_id: PMID:24769394
      supporting_text: plays an essential role in the oxidative stress
- term:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  evidence_type: EXP
  original_reference_id: PMID:26479991
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Loss of measured G6PD enzymatic activity in a patient variant confirms the
      core catalytic function.
    supported_by:
    - reference_id: PMID:26479991
      supporting_text: very low glucose-6-phosphate
- term:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:38066190
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Direct in vitro assay of purified human G6PD confirms the catalytic activity.
    supported_by:
    - reference_id: PMID:38066190
      supporting_text: catalytic activity by 50-fold while having a negligible effect on substrate
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:38066190
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Direct biophysical demonstration of G6PD homodimer formation; a core
      structural/functional property required for activity.
    supported_by:
    - reference_id: PMID:38066190
      supporting_text: critical role of arginine 219 in G6PD dimer formation
    - reference_id: PMID:38066190
      supporting_text: only the latter for the wild-type form, suggesting a
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:38066190
  qualifier: involved_in
  review:
    summary: Direct assays of substrate (glucose-6-phosphate) turnover by WT and mutant
      G6PD document participation in glucose-6-phosphate metabolism.
    action: ACCEPT
    reason: Accurate BP annotation acting on the direct substrate; experimentally supported.
    supported_by:
    - reference_id: PMID:38066190
      supporting_text: catalytic activity by 50-fold while having a negligible effect on substrate
- term:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:35122041
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Direct measurement of G6PD enzymatic activity supports the core function.
    supported_by:
    - reference_id: PMID:35122041
      supporting_text: rate-limiting enzyme in the pentose phosphate pathway, glucose-6-phosphate
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35122041
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic binding term is uninformative; the TP53/ALDOB ternary-complex
      interaction is recorded as a regulatory relationship rather than a core MF.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Forms a ternary complex with ALDOB and TP53; this
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35122041
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic binding term; the ALDOB interaction is retained as a documented
      inhibitory regulator rather than a core molecular function.
    supported_by:
    - reference_id: PMID:35122041
      supporting_text: directly binding and inhibiting the
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: ALDOB stabilizes the complex inhibiting G6PD
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:35122041
  qualifier: located_in
  review:
    summary: Direct localization evidence placing G6PD in the cytosol, consistent with
      all other localization data.
    action: ACCEPT
    reason: Confirms established cytosolic localization.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: High-throughput mass-spec localization to exosomes; likely reflects passive
      incorporation of an abundant cytosolic protein rather than a functional site.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Peripheral/incidental membrane association from a proteome-wide screen; not
      a primary functional localization.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Membrane; Peripheral membrane protein
- term:
    id: GO:0021762
    label: substantia nigra development
  evidence_type: HEP
  original_reference_id: PMID:22926577
  qualifier: involved_in
  review:
    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.
    action: REMOVE
    reason: Expression-based (HEP) annotation from a disease proteomics survey; provides
      no evidence for a developmental role of G6PD.
    supported_by:
    - reference_id: PMID:22926577
      supporting_text: substantia nigra
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: A second high-throughput proteomic detection of G6PD in urinary exosomes,
      as for PMID:23533145.
    action: KEEP_AS_NON_CORE
    reason: High-throughput exosome proteomics; incidental localization of an abundant
      cytosolic protein, not a functional site.
- term:
    id: GO:0006739
    label: NADP+ metabolic process
  evidence_type: IDA
  original_reference_id: PMID:15858258
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Accurate - G6PD is a major cellular NADP+/NADPH-interconverting enzyme.
    supported_by:
    - reference_id: PMID:15858258
      supporting_text: NADP(+)-dependent and
- term:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:15858258
  qualifier: enables
  review:
    summary: Structural studies of human G6PD binary complexes with glucose-6-phosphate
      and NADP+ directly characterize the catalytic function of the human enzyme.
    action: ACCEPT
    reason: Direct structural/biochemical evidence for the core catalytic activity.
    supported_by:
    - reference_id: PMID:15858258
      supporting_text: catalyses the first and rate-limiting step of the pentose phosphate shunt.
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:15858258
  qualifier: involved_in
  review:
    summary: G6PD acts directly on glucose-6-phosphate; structural characterization of
      the substrate complex supports participation in glucose-6-phosphate metabolism.
    action: ACCEPT
    reason: Accurate BP annotation for the enzyme's direct substrate.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70377
  qualifier: located_in
  review:
    summary: Reactome traceable assertion placing the G6PD dehydrogenation reaction
      (G6PD multimers dehydrogenate G6P) in the cytosol.
    action: ACCEPT
    reason: Consistent with the established cytosolic localization of the PPP.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9761849
  qualifier: located_in
  review:
    summary: Reactome traceable assertion for cytosolic localization associated with an
      NRF2/NFE2L2-dependent G6PD expression event.
    action: ACCEPT
    reason: Consistent with cytosolic localization.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: Localization of an expressed GFP-fusion to the cytoplasm (LIFEdb). A correct
      but more general parent of the specific cytosol term.
    action: ACCEPT
    reason: Cytoplasmic localization is correct; cytosol is the preferred, more specific
      term and is separately annotated.
- term:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  evidence_type: IMP
  original_reference_id: PMID:2420826
  qualifier: enables
  review:
    summary: Comparison of normal versus G6PD-deficient (Mediterranean) erythrocytes
      shows loss of oxidative-branch flux in deficient cells, functional evidence for
      G6PD catalytic activity.
    action: ACCEPT
    reason: Deficiency-based functional evidence supports the core catalytic activity.
    supported_by:
    - reference_id: PMID:2420826
      supporting_text: approximately 20% of the pentose was produced via the
- term:
    id: GO:0005536
    label: D-glucose binding
  evidence_type: IDA
  original_reference_id: PMID:15858258
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: G6PD binds glucose-6-phosphate; the free-D-glucose descriptor mischaracterizes
      the substrate and is not a core function.
    supported_by:
    - reference_id: PMID:15858258
      supporting_text: Substrate
- term:
    id: GO:0006098
    label: pentose-phosphate shunt
  evidence_type: IDA
  original_reference_id: PMID:2297768
  qualifier: involved_in
  review:
    summary: Study of G6PD activity and NADPH-generating pathways in MCF-7 cells,
      linking G6PD to pentose phosphate shunt / NADPH production.
    action: ACCEPT
    reason: Correct pathway annotation supported by direct measurement of G6PD activity
      within the shunt.
    supported_by:
    - reference_id: PMID:2297768
      supporting_text: utilization pathways of NADPH generated by G6PD
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: TAS
  original_reference_id: PMID:17361089
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Reflects a genuine but indirect contribution (NADPH supply for lipid
      synthesis); not the core catalytic function.
    supported_by:
    - reference_id: PMID:17361089
      supporting_text: glucose-6-phosphate dehydrogenase-deficient subjects
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:12027950
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Indirect NADPH-dependent contribution to cholesterol synthesis; not a direct
      molecular role.
    supported_by:
    - reference_id: PMID:12027950
      supporting_text: an essential enzyme involved in both
- term:
    id: GO:0006749
    label: glutathione metabolic process
  evidence_type: IMP
  original_reference_id: PMID:17516514
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Well-supported involvement of G6PD in maintaining the glutathione redox
      system, a defining physiological role especially in erythrocytes.
    supported_by:
    - reference_id: PMID:17516514
      supporting_text: control of protein glutathionylation
    - reference_id: PMID:17516514
      supporting_text: susceptible to oxidative stress due to
- term:
    id: GO:0006749
    label: glutathione metabolic process
  evidence_type: IMP
  original_reference_id: PMID:2420826
  qualifier: involved_in
  review:
    summary: G6PD-deficient erythrocytes show markedly reduced glutathione (GSH),
      demonstrating that G6PD activity is required to maintain reduced glutathione.
    action: ACCEPT
    reason: Deficiency-based evidence for G6PD's role in glutathione metabolism via
      NADPH provision.
    supported_by:
    - reference_id: PMID:2420826
      supporting_text: Reduced glutathione (GSH) content of G6PD-deficient cells
- term:
    id: GO:0009051
    label: pentose-phosphate shunt, oxidative branch
  evidence_type: IMP
  original_reference_id: PMID:2420826
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Direct deficiency-based evidence for the core oxidative-branch role.
    supported_by:
    - reference_id: PMID:2420826
      supporting_text: oxidation of glucose-6-phosphate
- term:
    id: GO:0019322
    label: pentose biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:5643703
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:17516514
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Well-supported role of G6PD in the cellular antioxidant/oxidative-stress
      response, a defining function especially in erythrocytes.
    supported_by:
    - reference_id: PMID:17516514
      supporting_text: susceptible to oxidative stress due to
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:15858258
  qualifier: enables
  review:
    summary: Human G6PD crystal structures show a homodimeric/tetrameric assembly (dimer
      of dimers), confirming homodimerization as an intrinsic structural property
      required for activity.
    action: ACCEPT
    reason: Directly supported by structural data; homodimerization is essential for the
      active enzyme.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Homotetramer; dimer of dimers
- term:
    id: GO:0043249
    label: erythrocyte maturation
  evidence_type: IMP
  original_reference_id: PMID:5643703
  qualifier: involved_in
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: G6PD is critical for erythrocyte oxidative defense; its contribution to
      erythrocyte maturation is an important but indirect physiological role.
- term:
    id: GO:0046390
    label: ribose phosphate biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:2420826
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: G6PD feeds ribose-phosphate biosynthesis via the oxidative PPP, but this is
      a pathway-level consequence, not the core catalytic function.
    supported_by:
    - reference_id: PMID:2420826
      supporting_text: PRPP synthetase, which requires GSH
- term:
    id: GO:0050661
    label: NADP binding
  evidence_type: IDA
  original_reference_id: PMID:15858258
  qualifier: enables
  review:
    summary: Structural studies directly demonstrate NADP+ binding at both the catalytic
      coenzyme site and the structural site of human G6PD.
    action: ACCEPT
    reason: Directly demonstrated intrinsic NADP-binding property.
    supported_by:
    - reference_id: PMID:15858258
      supporting_text: Structural NADP(+) binds in a very similar way
- term:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  evidence_type: IMP
  original_reference_id: PMID:5643703
  qualifier: enables
  review:
    summary: Characterization of biochemical G6PD variants with reduced/altered enzyme
      activity causing hemolytic disease provides functional evidence for the core
      catalytic activity.
    action: ACCEPT
    reason: Variant-based functional evidence supports the core catalytic function.
- term:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  evidence_type: IMP
  original_reference_id: PMID:743300
  qualifier: enables
  review:
    summary: Measurement of G6PD activity in erythrocyte membranes from normal versus
      Mediterranean-deficient subjects, functional evidence for the enzyme's catalytic
      activity.
    action: ACCEPT
    reason: Deficiency-based functional evidence for the core catalytic activity.
- term:
    id: GO:0005536
    label: D-glucose binding
  evidence_type: IMP
  original_reference_id: PMID:5643703
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Substrate is glucose-6-phosphate; the D-glucose binding term is imprecise and
      not a core function.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:743300
  qualifier: located_in
  review:
    summary: Direct evidence for G6PD in the cytosolic (soluble) fraction of
      erythrocytes, consistent with all other localization data.
    action: ACCEPT
    reason: Confirms cytosolic localization.
- term:
    id: GO:0009898
    label: cytoplasmic side of plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:743300
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Genuine but minor peripheral membrane association in erythrocytes; not the
      primary functional localization.
    supported_by:
    - reference_id: file:human/G6PD/G6PD-uniprot.txt
      supporting_text: Membrane; Peripheral membrane protein
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IMP
  original_reference_id: PMID:5643703
  qualifier: involved_in
  review:
    summary: G6PD variant studies link the enzyme to metabolism of its direct substrate,
      glucose-6-phosphate.
    action: ACCEPT
    reason: Accurate BP annotation acting on the direct substrate.
core_functions:
- description: NADP+-dependent oxidation of glucose-6-phosphate to
    6-phospho-D-glucono-1,5-lactone, the committed, rate-limiting first step of the
    oxidative branch of the pentose phosphate pathway, generating NADPH.
  molecular_function:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  directly_involved_in:
  - id: GO:0009051
    label: pentose-phosphate shunt, oxidative branch
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/G6PD/G6PD-uniprot.txt
    supporting_text: Catalyzes the rate-limiting step of the oxidative pentose-
  - reference_id: PMID:15858258
    supporting_text: catalyses the first and rate-limiting step of the pentose phosphate shunt.
  - reference_id: PMID:2420826
    supporting_text: oxidation of glucose-6-phosphate
- description: Provision of NADPH reducing power for antioxidant defense, most critically
    regeneration of reduced glutathione, protecting cells (especially erythrocytes) from
    oxidative stress.
  molecular_function:
    id: GO:0004345
    label: glucose-6-phosphate dehydrogenase activity
  directly_involved_in:
  - id: GO:0006749
    label: glutathione metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/G6PD/G6PD-uniprot.txt
    supporting_text: provide reducing power (NADPH) and pentose phosphates for fatty acid
  - reference_id: PMID:17516514
    supporting_text: control of protein glutathionylation
  - reference_id: PMID:2420826
    supporting_text: Reduced glutathione (GSH) content of G6PD-deficient cells
- description: NADP+ binding, both as catalytic cosubstrate and as a tightly bound
    structural cofactor required for stability of the active homodimer/homotetramer.
  molecular_function:
    id: GO:0050661
    label: NADP binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/G6PD/G6PD-uniprot.txt
    supporting_text: Binds two molecules of NADP. The first one is a
  - reference_id: PMID:15858258
    supporting_text: Structural NADP(+) binds in a very similar way
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations
    of expressed fusion proteins in living cells
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/G6PD/G6PD-uniprot.txt
  title: UniProt text export for G6PD (P11413)
  findings: []
- id: PMID:12027950
  title: Cell growth and cholesterol metabolism in human glucose-6-phosphate dehydrogenase
    deficient lymphomononuclear cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; supports an indirect NADPH-supply role of G6PD in
      cholesterol synthesis (G6PD-deficient PBMC show reduced cholesterol synthesis).
- id: PMID:15858258
  title: Structural studies of glucose-6-phosphate and NADP+ binding to human glucose-6-phosphate
    dehydrogenase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified human G6PD structural study; directly supports catalytic
      activity, NADP binding (catalytic and structural sites), substrate binding, and
      homo-oligomerization.
- id: PMID:17361089
  title: Production of inflammatory molecules in peripheral blood mononuclear cells
    from severely glucose-6-phosphate dehydrogenase-deficient subjects.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified; supports only an indirect lipid/inflammatory phenotype
      of G6PD deficiency, not a direct lipid-metabolic function.
- id: PMID:17516514
  title: 'Mutation in G6PD gene leads to loss of cellular control of protein glutathionylation:
    mechanism and implication.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; strongly supports G6PD's role in glutathione metabolism
      and the cellular oxidative-stress response via NADPH.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput exosome proteomics; incidental localization of an
      abundant cytosolic enzyme.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput membrane proteomics; peripheral/incidental membrane
      association, not a primary functional site.
- id: PMID:21157431
  title: ATM activates the pentose phosphate pathway promoting anti-oxidant defence
    and DNA repair.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified full text; documents HSPB1/Hsp27 binding and direct
      stimulation of G6PD activity in the ATM oxidative-stress/DNA-damage response.
- id: PMID:22926577
  title: Quantitative proteomic analysis of human substantia nigra in Alzheimer's
    disease, Huntington's disease and Multiple sclerosis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: Disease proteomics survey; detection/altered expression does not support
      a substantia nigra developmental role for G6PD (HEP annotation over-interpreted).
- id: PMID:2297768
  title: Sex steroid hormone modulation of NADPH pathways in MCF-7 cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; measures G6PD activity and NADPH-generating pathways,
      supporting the pentose phosphate shunt annotation.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput exosome proteomics; incidental localization of an
      abundant cytosolic enzyme.
- id: PMID:2420826
  title: Ribose metabolism and nucleic acid synthesis in normal and glucose-6-phosphate
    dehydrogenase-deficient human erythrocytes infected with Plasmodium falciparum.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; deficiency-based evidence for the oxidative-branch PPP
      role, glutathione maintenance, and ribose-phosphate contribution.
- id: PMID:24769394
  title: Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis
    and cell survival during oxidative stress.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; supports catalytic activity, K403 acetylation-dependent
      regulation, homodimerization requirement, and the SIRT2 interaction.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome map; corroborates G6PD self-interaction
      (identical protein binding).
- id: PMID:26479991
  title: Severe G6PD Deficiency Due to a New Missense Mutation in an Infant of Northern
    European Descent.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified case report; very low enzymatic activity of a novel
      variant supports the catalytic function and X-linked deficiency phenotype.
- id: PMID:35122041
  title: Aldolase B suppresses hepatocellular carcinogenesis by inhibiting G6PD and
    pentose phosphate pathways.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; identifies G6PD as the rate-limiting PPP enzyme,
      directly assays its activity, and documents the ALDOB-G6PD-TP53 ternary complex.
- id: PMID:38066190
  title: Substitution of arginine 219 by glycine compromises stability, dimerization,
    and catalytic activity in a G6PD mutant.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified full text; direct biochemical/biophysical evidence for
      catalytic activity, dimerization, and substrate binding of human G6PD.
- id: PMID:5643703
  title: Biochemical variants of glucose-6-phosphate dehydrogenase giving rise to
    congenital nonspherocytic hemolytic disease.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified classic study; variant enzymes causing CNSHA support
      the catalytic function and erythrocyte oxidative-defense role.
- id: PMID:743300
  title: Glucose 6-phosphate dehydrogenase activity in membranes of erythrocytes from
    normal individuals and subjects with Mediterranean G6PD deficiency.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; supports catalytic activity, cytosolic localization,
      and a minor peripheral membrane-associated pool in erythrocytes.
- id: Reactome:R-HSA-70377
  title: G6PD multimers dehydrogenate G6P
  findings: []
- id: Reactome:R-HSA-9761849
  title: AcK-NFE2L2-dependent P6GD gene expression
  findings: []