Glucose-6-phosphatase catalytic subunit 3 (G6PC3) is a widely expressed endoplasmic reticulum membrane phosphatase with nine transmembrane helices and a catalytic site facing the ER lumen. It hydrolyzes glucose 6-phosphate and several other phosphate esters, using His167 to form a covalent phosphohistidine intermediate. A well-established physiological role is removal of 1,5-anhydroglucitol 6-phosphate, a side product of hexose-phosphorylating enzymes that inhibits hexokinases when it accumulates. The ER transporter SLC37A4 supplies this substrate to G6PC3. Its dephosphorylation protects cellular glucose utilization and is particularly important for neutrophil survival and function. Biallelic loss-of-function variants cause severe congenital neutropenia type 4, sometimes accompanied by nonhematological developmental abnormalities whose relationship to the enzymeβs substrate range remains incompletely resolved.
Definition: Catalysis of the reaction: 1,5-anhydro-D-glucitol 6-phosphate + H2O = 1,5-anhydro-D-glucitol + phosphate.
Justification: Specifies the toxic-metabolite dephosphorylation directly performed by human G6PC3; broader sugar-phosphatase terms describe demonstrated substrate-class capabilities but do not name this physiological substrate.
Parent term: phosphatase activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: The phylogenetic ER assignment agrees with human enzyme topology and localization. Reason: The ER IBD at AN0/PTN000971890 lies on the verified human G6PC3 ancestry path. Its descendant evidence includes the target, which is legitimate experimental grounding rather than circularity. Human topology and biochemical evidence place G6PC3 in the ER membrane with the catalytic site facing the lumen. Accept the organelle-level annotation alongside the specific membrane location; the ER term is informative localization, not an erroneous propagation merely because a narrower component is also present. |
| GO:0006094 gluconeogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The gluconeogenesis IBA has a verified ancestral placement and experimental descendant grounding; its physiological scope remains tissue dependent. Reason: The actual IBD for gluconeogenesis lies at AN0/PTN000971890, ancestral to human G6PC3, and its literal donor set and target path were verified. Mouse G6pc3 has an experimental gluconeogenesis annotation associated with PMID:15661744; the authentic abstract reports a functional G6PC3/G6PT system supporting glucose production in astrocytes. This is positive same-role evidence and cannot be dismissed as transfer from the hepatic paralog alone. Retain the process as non-core, with the donor-species and abstract-access limits explicit. These data do not quantify human net glucose production from noncarbohydrate precursors or establish systemic hepatic glucose output as G6PC3's principal role. |
| GO:0004346 glucose-6-phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The verified ancestral glucose-6-phosphatase activity is retained as an established core molecular capability. Reason: The actual PTHR12591 tree places human Q9BUM1 at AN106/PTN002488969 beneath the glucose-6-phosphatase IBD at AN0/PTN000971890. The literal descendant sources and target path were checked; inclusion of Q9BUM1 among those sources reflects experimental evidence on the target and is not circularity. Direct human catalytic and mutant-control experiments independently establish glucose-6-phosphate hydrolysis. Accept the inherited molecular activity as core on this combined evidence; ancestral placement alone does not establish physiological substrate priority. PMID:30626647 favors 1,5-anhydroglucitol 6-phosphate as the physiological substrate, and the relative in-vivo contribution of G6P hydrolysis remains unresolved. |
| GO:0016020 membrane | IBA GO_REF:0000033 | TOO GENERAL | Summary: The ancestral membrane assertion is valid but less informative than the established ER membrane location. Reason: The membrane IBD at AN0/PTN000971890 and its path to G6PC3 were verified. G6PC3 is indeed a multipass membrane protein; there is no evidence of an erroneous phylogenetic transfer. The generic membrane term adds little localization information beyond the retained endoplasmic reticulum membrane annotation. Use a granularity judgment without treating the broader location as a biological falsehood or a failure of the PAINT node placement. |
| GO:0004346 glucose-6-phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic mapping identifies an independently demonstrated glucose-6-phosphatase molecular activity. Reason: The original combined evidence retains ARBA, InterPro, RHEA, EC and rodent identifiers. Its glucose-6-phosphate hydrolysis assignment agrees with direct human G6PC3 catalytic and mutant-control experiments. Accept the established molecular capability as core without treating these mappings as independent human assays or as evidence of physiological dominance. The enzyme also dephosphorylates 1,5-anhydroglucitol 6-phosphate, whose accumulation and toxicity are directly demonstrated in deficient cells. SLC37A4 performs the separate transport step; no transport activity is assigned to G6PC3. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt mapping captures the established ER membrane residence of G6PC3. Reason: The original SL-0097 mapping agrees with the human nine-transmembrane topology and luminal catalytic site. ER membrane is the specific cellular component used in the functional synthesis. Preserve the electronic mapping provenance, with the experimental literature supplying independent biological support rather than implying that the vocabulary mapping is itself an experiment. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse-derived ER localization is independently supported in human G6PC3. Reason: Retain the literal mouse G6pc3 ortholog source and electronic evidence code. Human topology studies place the catalytic residues in the ER lumen, and human recombinant enzyme work identifies the protein as an ER membrane phosphatase. The organelle assignment is therefore independently coherent even though every underlying donor microscopy experiment was not re-read. Accept ER localization without converting orthology evidence into a direct human imaging assay. |
| GO:0006094 gluconeogenesis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: The electronic gluconeogenesis context is compatible with a terminal dephosphorylation step, without establishing dominant human pathway flux. Reason: Preserve the original rodent ortholog and UniPathway sources. Experimental mouse G6PC3/G6PT-dependent glucose-production evidence in PMID:15661744 and the explicit human Reactome G6PC3 reaction support the biological pathway context independently of the electronic mapping. The complete original mouse assay was not recovered, and local glucose-6-phosphate recycling is not itself proof of net gluconeogenesis. Retain the supported pathway assignment as non-core without claiming a direct quantitative human flux experiment or substituting G6PC1's systemic role for G6PC3. |
| GO:0051156 glucose 6-phosphate metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: G6PC3 directly metabolizes glucose 6-phosphate, while the original rat donor's isoenzyme-specific attribution remains unresolved. Reason: The original Ensembl transfer names rat G6pc3/Q6AZ83, whose same-term IDA row cites PMID:4303362. The authentic abstract of that paper describes developing rat-kidney phosphatase activity and glucose synthesis but does not molecularly resolve the G6PC3 isoenzyme. Preserve that access limitation without asserting a wrong-gene attribution from the paper's age or title. Independent human G6PC3 assays in PMID:14718531 and PMID:25492228 directly establish hydrolysis of glucose 6-phosphate, so the process remains biologically supported as non-core. The stronger physiological substrate evidence concerns 1,5-anhydroglucitol 6-phosphate clearance. |
| GO:0006094 gluconeogenesis | TAS Reactome:R-HSA-70263 | KEEP AS NON CORE | Summary: Reactome explicitly places the normal G6PC3-catalyzed glucose-6-phosphate reaction within gluconeogenesis. Reason: The official R-HSA-3262512 page names G6PC3 as catalyst, gives glucose-6-phosphate and water as inputs and glucose and phosphate as outputs, and identifies the reaction as an event of Gluconeogenesis. This resolves the target-participation question that the broad R-HSA-70263 pathway summary alone does not answer. Retain the original TAS pathway annotation as non-core. The curated reaction hierarchy does not by itself establish the size of net gluconeogenic flux in particular human tissues or displace the directly supported physiological detoxification role. |
| GO:0004346 glucose-6-phosphatase activity | EXP PMID:14718531 Histidine 167 is the phosphate acceptor in glucose-6-phospha... | ACCEPT | Summary: G6Pase-beta forms a phosphohistidine intermediate during glucose-6-phosphate hydrolysis. Reason: The authentic PMID:14718531 abstract directly identifies His167 as the phosphate acceptor in the covalent intermediate and places the active site on the ER luminal side with Arg79 and His114. It therefore supports the experimental glucose-6-phosphatase assertion. The abstract does not state the construct species; attribution to this human target comes from the current human GOA annotation and identity. Complete original Methods were not recovered, so additional construct or kinetic details are not inferred. Accept this catalytic activity as an established molecular capability, corroborated by the independently read human assays in PMID:25492228 and PMID:30626647. This classification does not claim that G6P is the primary physiological substrate or that its hydrolysis explains neutropenia. Supporting Evidence: PMID:14718531 Glc-6-Pase-beta is also a nine-transmembrane domain protein that forms a covalently bound phosphoryl enzyme intermediate during Glc-6-P hydrolysis. |
| GO:0004346 glucose-6-phosphatase activity | TAS Reactome:R-HSA-3282876 | ACCEPT | Summary: The disease reaction records defective G6PC3 against a separately identified normal glucose-6-phosphate hydrolysis reaction. Reason: Reactome R-HSA-3282876 explicitly models loss of function in G6PC3 mutants and links the normal G6PC3-catalyzed reaction R-HSA-3262512. The disease title is not evidence that wild-type G6PC3 lacks this activity, and the original row is not a NOT annotation. Independent human biochemical and variant assays establish the normal reaction. Accept the TAS molecular capability as core, distinguishing the mutant catalyst in the disease event from the normal enzyme. Neither curated pathway membership nor acceptance of the molecular activity establishes net human gluconeogenic flux or makes G6P hydrolysis the explanation for neutropenia. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: The curated immunofluorescence ER assignment agrees with independent human biochemical evidence. Reason: GO_REF:0000052 identifies immunofluorescence-based localization curation. The individual Human Protein Atlas image and antibody experiment were not independently re-read, so no new image, cell-line or antibody claims are made. Independent human G6PC3 topology and enzyme studies support ER residence and a luminal active site. Accept the established organelle localization while retaining the original IDA provenance and the exact scope of independent verification. |
| GO:0004346 glucose-6-phosphatase activity | IMP PMID:25492228 Functional analysis of mutations in a severe congenital neut... | ACCEPT | Summary: Controlled human wild-type and variant assays directly support glucose-6-phosphate hydrolysis. Reason: Selected original Methods and Results in PMID:25492228 compare recombinant human G6PC3 and disease-associated variants in COS-1 cells using a glucose-6-phosphate phosphohydrolase assay, mock controls and protein measurements. Fourteen missense variants lacked measurable activity, while S139I and R189Q retained approximately 49% and 45% of wild-type activity. Accept the original IMP capability as an established molecular activity. Because glucose-6-phosphate was the supplied substrate, this assay does not establish physiological substrate priority or show that loss of this reaction alone explains disease. The separately demonstrated 1,5-anhydroglucitol 6-phosphate detoxification mechanism remains core. Supporting Evidence: PMID:25492228 Fourteen missense mutations completely abolish G6Pase-Ξ² enzymatic activity |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | TOO GENERAL | Summary: The high-throughput membrane assignment is compatible with G6PC3 but less specific than its established ER membrane location. Reason: The authentic PMID:19946888 abstract describes a membrane-proteome survey of the NK-like YTS cell line with 1,843 high-confidence proteins. The target-specific peptide table was not independently recovered, so no additional G6PC3 peptide or abundance claim is made. Nothing in that access limitation refutes the curated HDA annotation, and independent evidence establishes G6PC3 as a membrane protein. The appropriate judgment is lack of localization specificity relative to ER membrane, not rejection of an experimental annotation on incomplete evidence. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-3282876 | ACCEPT | Summary: The disease reaction retains an ER membrane context consistent with the normal G6PC3 location. Reason: R-HSA-3282876 describes defective G6PC3 variants in an ER membrane reaction and links the separately identified normal G6PC3 enzyme and reaction. Independent human topology evidence establishes the normal protein's ER membrane residence. Accept this location without inferring that every disease variant has normal trafficking, stability or catalytic function. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-3262512 | ACCEPT | Summary: The normal Reactome G6PC3 reaction places the enzyme at the ER membrane. Reason: R-HSA-3262512 explicitly names G6PC3 as the ER membrane catalyst of luminal glucose-6-phosphate hydrolysis. This curated location agrees with independent human topology and enzyme evidence. Accept the cellular component while keeping the reaction's catalytic capability separate from claims about the dominant physiological substrate. |
| GO:1990748 cellular detoxification | IMP PMID:30626647 Failure to eliminate a phosphorylated glucose analog leads t... | NEW | Summary: G6PC3 directly detoxifies cells by hydrolyzing the hexokinase inhibitor 1,5-anhydroglucitol 6-phosphate. Reason: Original experiments in PMID:30626647 show hydrolysis by recombinant human G6PC3 with a catalytic H167A control, accumulation of 1,5-anhydroglucitol 6-phosphate in G6PC3-deficient human cells, inhibition of hexokinases by that metabolite and altered cellular glucose utilization. G6PC3 itself performs the detoxifying chemical step; SLC37A4 supplies the separate transport step. The assertion is therefore supported by mechanistic participation as well as perturbation evidence. Human PGP, CLYBL and MAPDA provide same-role enzyme comparators annotated to toxic metabolite repair, an is_a child of cellular detoxification. Use only this single process: the narrower repair definitions currently require production of a useful metabolite, whereas a physiological role for the 1,5-anhydroglucitol product is unresolved. Do not add its detoxification parent or repair children redundantly, and do not infer apoptosis-regulator activity from downstream neutrophil consequences. Supporting Evidence: PMID:30626647 1,5AG6P accumulates in G6PC3- or G6PT-deficient cells incubated with 1,5AG |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Which phosphate esters other than 1,5-anhydroglucitol 6-phosphate are physiological G6PC3 substrates outside neutrophils, and what supplies them to the ER lumen?
Q: How much does G6PC3-mediated glucose 6-phosphate hydrolysis contribute to local endogenous glucose production in different human tissues, independently of its role in removing a hexokinase inhibitor?
Q: Do nonhematological phenotypes in G6PC3 deficiency reflect 1,5-anhydroglucitol 6-phosphate accumulation or other substrates in particular cell types?
Q: Does GO metabolite repair/toxic metabolite repair encompass detoxifying 1,5AG6P to 1,5AG despite the current useful-metabolites wording and the sourceβs statement that 1,5AG has no established physiological role, or is cellular detoxification the appropriate process annotation? No need to infer utility from the paperβs informal metabolite-repair label.
Experiment: Compare isotope-resolved metabolite turnover in G6PC3-deficient and rescued human neutrophil precursors and selected nonmyeloid cells, with separate perturbation of SLC37A4 and matched transporter-independent lysate assays.
Hypothesis: G6PC3 substrate requirements differ between tissues because the accessible ER substrate pool differs.
Experiment: Measure labeled noncarbohydrate-carbon incorporation into newly released glucose while controlling 1,5-anhydroglucitol exposure and testing wild-type versus catalytic-mutant G6PC3 rescue. Distinguish net gluconeogenesis from glucose 6-phosphate recycling.
Hypothesis: A portion of glucose 6-phosphate hydrolysis may support local glucose production independently of detoxification.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)