G6PC3 encodes the ubiquitously expressed catalytic subunit 3 of glucose-6-phosphatase (glucose-6-phosphatase-beta / G6Pase-beta; EC 3.1.3.9), a multi-pass integral membrane protein of the endoplasmic reticulum and a paralog of the liver/kidney/intestine-restricted G6PC1. It hydrolyses glucose-6-phosphate to glucose and inorganic phosphate (and the metabolite 1,5-anhydroglucitol-6-phosphate) with its active site facing the ER lumen, forming a covalent phosphohistidine intermediate at His167. It functions together with the ER glucose-6-phosphate transporter SLC37A4 (G6PT) to support intracellular glucose production and energy homeostasis, and is ~8x less active than G6Pase-alpha. Loss of G6PC3 causes severe congenital neutropenia type 4 (SCN4 / Dursun syndrome), in which neutrophils show endoplasmic-reticulum stress and enhanced apoptosis, accompanied by congenital cardiac and urogenital malformations and a prominent superficial venous pattern; unlike G6PC1 deficiency it is not a classic hepatic glycogen storage disease.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: IBA localization of G6PC3 to the endoplasmic reticulum. Correct but a generic parent of the more precise ER membrane assignment. Reason: G6PC3 is an ER-resident enzyme with its active site facing the ER lumen; ER localization is well supported experimentally, so the phylogenetic call is sound. The more specific term is endoplasmic reticulum membrane (GO:0005789), captured elsewhere and used in core_functions. Supporting Evidence: PMID:25492228 G6Pase-Ξ² is an enzyme embedded in the endoplasmic reticulum membrane that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate. |
| GO:0006094 gluconeogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA involvement in gluconeogenesis, inherited from the glucose-6-phosphatase family (including hepatic orthologs). Reason: Gluconeogenesis is a family/pathway-level assignment (the terminal dephosphorylation step is shared with the liver enzyme G6PC1). G6PC3 is ubiquitously expressed and its deficiency causes neutropenia rather than fasting hypoglycemia/glycogen storage disease, so systemic gluconeogenesis is not its core physiological role. Its ubiquitous complex with SLC37A4/G6PT supports local intracellular glucose production and energy homeostasis rather than hepatic glucose output. Retained as a valid but non-core process. Supporting Evidence: PMID:25492228 the ubiquitous G6Pase-Ξ²/G6PT complex maintains energy homeostasis and functionality in neutrophils and macrophages |
| GO:0004346 glucose-6-phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA glucose-6-phosphatase activity, the core molecular function of G6PC3, concordant with experimental evidence. Reason: This is the defining, experimentally established molecular function of G6PC3 (EC 3.1.3.9). It is corroborated by direct catalytic assays and mutagenesis of the active-site residues, and by the disease-mutation functional analysis. Represents the core molecular function. 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:0016020 membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA generic membrane localization. Correct but uninformative given the well-established ER membrane localization. Reason: G6PC3 is a multi-pass ER membrane protein, so "membrane" is not wrong, but it is a generic parent superseded by the specific endoplasmic reticulum membrane (GO:0005789) annotation. Marked as over-annotated in favor of the specific term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Supporting Evidence: file:human/G6PC3/G6PC3-uniprot.txt Multi-pass membrane protein |
| GO:0004346 glucose-6-phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (ARBA/InterPro/RHEA/EC) assignment of glucose-6-phosphatase activity, matching the experimentally established function. Reason: The IEA mapping (EC 3.1.3.9, RHEA:16689, InterPro glucose-6-phosphatase family) agrees with the direct experimental molecular function. Correct. Supporting Evidence: file:human/G6PC3/G6PC3-uniprot.txt Reaction=D-glucose 6-phosphate + H2O = D-glucose + phosphate; |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location keyword mapping to ER membrane, the precise localization of G6PC3. Reason: G6PC3 is a multi-pass ER membrane protein; this specific localization is well supported experimentally and by topology studies. This is the core cellular component. Supporting Evidence: file:human/G6PC3/G6PC3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane PMID:25492228 G6Pase-Ξ² is an enzyme embedded in the endoplasmic reticulum membrane that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl orthology-based transfer of ER localization. Correct but a generic parent of ER membrane. Reason: ER localization is well established for G6PC3. Correct, though the specific ER membrane term is more informative and captured elsewhere. Supporting Evidence: PMID:25492228 G6Pase-Ξ² is an enzyme embedded in the endoplasmic reticulum membrane that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate. |
| GO:0006094 gluconeogenesis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (UniPathway/ortholog) assignment of gluconeogenesis, a family/pathway-level process. Reason: Same rationale as the IBA gluconeogenesis annotation: a valid pathway-level assignment shared across the glucose-6-phosphatase family, but not the core physiological role of the ubiquitous G6PC3, whose deficiency causes neutropenia rather than a hepatic glucose-homeostasis disorder. Kept as non-core. Supporting Evidence: file:human/G6PC3/G6PC3-uniprot.txt Carbohydrate biosynthesis; gluconeogenesis. |
| GO:0051156 glucose 6-phosphate metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based assignment of glucose 6-phosphate metabolic process, the direct metabolic process performed by G6PC3. Reason: G6PC3 directly hydrolyses glucose-6-phosphate, so it participates in glucose 6-phosphate metabolism. This is the most directly supported biological process and is used as the core process in core_functions. Supporting Evidence: PMID:25492228 Both phosphatases catalyze the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate and both are key enzymes for intracellular glucose production. |
| GO:0006094 gluconeogenesis | TAS Reactome:R-HSA-70263 | KEEP AS NON CORE | Summary: Reactome pathway (Gluconeogenesis) traceable assignment placing G6PC3 in the gluconeogenesis pathway. Reason: Reactome places G6PC3 in the gluconeogenesis pathway (the terminal G6P dephosphorylation step). Valid at pathway level but non-core for the ubiquitous G6PC3, per the rationale above. Supporting Evidence: file:human/G6PC3/G6PC3-uniprot.txt Carbohydrate biosynthesis; gluconeogenesis. |
| GO:0004346 glucose-6-phosphatase activity | EXP PMID:14718531 Histidine 167 is the phosphate acceptor in glucose-6-phospha... | ACCEPT | Summary: Experimental demonstration of glucose-6-phosphatase (G6P hydrolase) activity, with identification of His167 as the catalytic phosphate acceptor. Reason: Direct experimental evidence: G6Pase-beta forms a covalent phosphoryl enzyme intermediate during G6P hydrolysis, and His167 (lumenal, with active-site Arg79 and His114) is the phosphate acceptor; active-site mutants lose the intermediate. Core molecular function. Supporting Evidence: PMID:14718531 we demonstrated that the phosphate acceptor in Glc-6-Pase-beta is His(167) and that it lies inside the ER lumen with the active site residues, Arg(79) and His(114). |
| GO:0004346 glucose-6-phosphatase activity | TAS Reactome:R-HSA-3282876 | ACCEPT | Summary: Reactome traceable assignment of glucose-6-phosphatase activity (context: defective G6PC3 does not hydrolyze G6P), consistent with the core function. Reason: Reactome records G6PC3 as the enzyme that hydrolyzes G6P; the paired "defective G6PC3" reaction underscores that loss of this activity is the disease mechanism. Consistent with the experimentally established function. Supporting Evidence: PMID:25492228 Fourteen missense mutations completely abolish G6Pase-Ξ² enzymatic activity |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence (IDA) localizing G6PC3 to the endoplasmic reticulum. Reason: Direct immunofluorescence localization to the ER, concordant with the established ER membrane residence of G6PC3. Correct; the specific ER membrane term is captured in core_functions. Supporting Evidence: PMID:25492228 G6Pase-Ξ² is an enzyme embedded in the endoplasmic reticulum membrane that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate. |
| GO:0004346 glucose-6-phosphatase activity | IMP PMID:25492228 Functional analysis of mutations in a severe congenital neut... | ACCEPT | Summary: IMP for glucose-6-phosphatase activity: functional analysis of SCN4 disease mutations shows they abolish or reduce G6P hydrolase activity. Reason: Mutational functional analysis in a sensitive recombinant expression assay: 14 of 16 SCN4 missense mutants completely abolish G6P hydrolytic activity (S139I and R189Q retain ~49%/45%), directly establishing that G6PC3 encodes glucose-6-phosphatase activity and that loss of this activity is pathogenic. Core molecular function. Supporting Evidence: PMID:25492228 Fourteen missense mutations completely abolish G6Pase-Ξ² enzymatic activity while the p.S139I and p.R189Q mutations retain 49% and 45%, respectively of wild type G6Pase-Ξ² activity. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput MS membrane-proteome survey of an NK-like cell line (PMID:19946888) detecting G6PC3 among membrane proteins. Reason: This is a generic "membrane" localization from a large-scale membrane proteomics dataset (1843 proteins identified) rather than a G6PC3-specific study. G6PC3 is specifically an ER membrane protein; the generic parent term is uninformative and superseded by endoplasmic reticulum membrane (GO:0005789). Marked as over-annotated. Supporting Evidence: PMID:19946888 spectrometric analysis identified 1843 proteins with high confidence scores. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-3282876 | ACCEPT | Summary: Reactome traceable assignment of ER membrane localization for G6PC3. Reason: ER membrane is the precise, well-supported localization of the multi-pass G6PC3 protein. Core cellular component. Supporting Evidence: file:human/G6PC3/G6PC3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-3262512 | ACCEPT | Summary: Reactome traceable assignment of ER membrane localization (reaction: G6PC3 hydrolyzes G6P to form Glc and Pi, ubiquitous). Reason: Duplicate ER membrane localization from a second Reactome reaction; correct and consistent with the multi-pass ER membrane residence of G6PC3. Supporting Evidence: file:human/G6PC3/G6PC3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
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