G6PC1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005783 endoplasmic reticulum	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetically inferred localization to the endoplasmic reticulum, where G6PC1 is an integral ER membrane enzyme. Correct but non-core; the specific ER membrane term (GO:0005789) is the informative location. Reason: G6PC1 is anchored to the ER membrane and its active site faces the ER lumen. The IBA localization to ER is accurate but generic relative to the experimentally supported endoplasmic reticulum membrane term, which is captured as a core function. Supporting Evidence: PMID:12093795 is anchored PMID:9497333 termini facing the endoplasmic reticulum lumen and the cytoplasm
GO:0006094 gluconeogenesis	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred involvement in gluconeogenesis. G6PC1 catalyzes the terminal, committed step of gluconeogenesis, so this is a core biological process. Reason: The final step of gluconeogenesis is hydrolysis of glucose-6-phosphate to free glucose, catalyzed by G6PC1; this is well supported by biochemistry and the GSD1a disease phenotype. Supporting Evidence: PMID:9332655 the final common step of glycogenolysis and gluconeogenesis
GO:0004346 glucose-6-phosphatase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred glucose-6-phosphatase activity, the core molecular function of G6PC1. Reason: G6PC1 is the catalytic subunit of glucose-6-phosphatase (EC 3.1.3.9), hydrolyzing glucose-6-phosphate to glucose and phosphate. This is directly supported by biochemical and mutagenesis studies and is the enzyme's defining function. Supporting Evidence: PMID:12093795 a key enzyme in glucose homeostasis
GO:0016020 membrane	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Generic membrane localization inferred phylogenetically. G6PC1 is a multi-pass membrane protein, but the informative location is the ER membrane. Reason: G6PC1 is an integral membrane protein, but the generic membrane term is uninformatively broad. The specific endoplasmic reticulum membrane term (GO:0005789) captures the true location and is retained as a core function. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Supporting Evidence: PMID:9497333 an odd number of transmembrane helices
GO:0004346 glucose-6-phosphatase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of glucose-6-phosphatase activity (EC 3.1.3.9 / RHEA:16689). Consistent with the experimentally established core function. Reason: Automated EC/RHEA-based inference matches the experimentally validated catalytic activity of G6PC1. Supporting Evidence: PMID:12093795 a key enzyme in glucose homeostasis
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Electronic assignment (UniProt subcellular-location mapping) of localization to the endoplasmic reticulum membrane, the correct and core location of G6PC1. Reason: G6PC1 is a multi-pass ER membrane protein with a luminal active site; this specific location is experimentally supported and is a core function. Supporting Evidence: PMID:9497333 termini facing the endoplasmic reticulum lumen and the cytoplasm
GO:0048878 chemical homeostasis	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: ARBA-derived electronic annotation to the broad chemical-homeostasis term. G6PC1 contributes specifically to blood glucose homeostasis; the generic parent term is over-broad. Reason: The specific and experimentally supported role is glucose homeostasis (GO:0042593), retained as a core function; chemical homeostasis is an uninformative parent term. Supporting Evidence: PMID:9497333 the key enzyme in
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: IntAct-curated yeast two-hybrid interactions from a neurodegenerative-disease interactome screen (partners WFS1/O76024 and RNF11/Q9Y3C5). Bare protein-binding is uninformative about molecular function. Reason: Per curation guidelines, protein binding (GO:0005515) provides no information about G6PC1's actual function. The high-throughput Y2H interactions have no established functional consequence for glucose-6-phosphatase activity. Supporting Evidence: PMID:32814053 systematic yeast two-hybrid interaction screening
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-projected localization to the endoplasmic reticulum from a rodent ortholog. Correct but non-core relative to the specific ER membrane term. Reason: G6PC1 resides in the ER membrane; the ER compartment annotation is accurate but generic. The ER membrane term (GO:0005789) is the informative core location. Supporting Evidence: PMID:9497333 termini facing the endoplasmic reticulum lumen and the cytoplasm
GO:0006094 gluconeogenesis	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (UniPathway/ARBA) assignment of involvement in gluconeogenesis, consistent with the enzyme's terminal role in the pathway. Reason: G6PC1 catalyzes the last step of gluconeogenesis; automated pathway inference agrees with experimental evidence. Supporting Evidence: PMID:9332655 the final common step of glycogenolysis and gluconeogenesis
GO:0009743 response to carbohydrate	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-projected from rat ortholog. Reflects nutritional/transcriptional regulation of the gene rather than a molecular function of the protein. Reason: G6PC1 transcription is regulated by carbohydrate/nutrient status, but this is a regulatory-response context, not part of the enzyme's core catalytic role. Supporting Evidence: PMID:8211187 the key enzyme in glucose homeostasis
GO:0016773 phosphotransferase activity, alcohol group as acceptor	IEA GO_REF:0000107	REMOVE	Summary: Ensembl-projected molecular function term. G6PC1 is a phosphohydrolase (phosphatase), not a phosphotransferase; this branch is incorrect for the enzyme's mechanism. Reason: G6PC1 hydrolyzes glucose-6-phosphate to glucose + phosphate (a hydrolase, EC 3.1.3.9), transferring the phosphate to water via a phosphohistidine intermediate. Phosphotransferase activity with an alcohol group as acceptor (kinase-like transfer to an alcohol) mischaracterizes the reaction and is a wrong-branch electronic inference. Supporting Evidence: PMID:12093795 His(176) is the phosphate acceptor in G6Pase
GO:0031667 response to nutrient levels	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-projected from rat ortholog. Reflects nutrient-dependent transcriptional regulation of G6PC1 rather than the protein's molecular function. Reason: G6PC1 expression responds to fasting/feeding and nutrient status; this is a physiological-regulation context, not the enzyme's core function. Supporting Evidence: PMID:8211187 the key enzyme in glucose homeostasis
GO:0032094 response to food	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-projected from rat ortholog. Feeding-state regulatory context of gene expression, not a core molecular function. Reason: Reflects nutritional regulation of G6PC1 expression rather than the enzyme's catalytic role; retained as non-core. Supporting Evidence: PMID:8211187 the key enzyme in glucose homeostasis
GO:0032868 response to insulin	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-projected from rat ortholog. G6PC1 is a canonical insulin-repressed gluconeogenic gene, but this reflects transcriptional regulation, not a core molecular function. Reason: Insulin suppresses G6PC1 transcription; this regulatory-response annotation is physiologically real but peripheral to the enzyme's core catalytic function. Supporting Evidence: PMID:8211187 the key enzyme in glucose homeostasis
GO:0032869 cellular response to insulin stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-projected from rat ortholog. As with response to insulin, this captures insulin-dependent transcriptional regulation of the gene, not the protein's core function. Reason: Reflects insulin-signaling regulation of G6PC1 expression; retained as non-core context. Supporting Evidence: PMID:8211187 the key enzyme in glucose homeostasis
GO:0051156 glucose 6-phosphate metabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-projected process term. Accurately reflects that G6PC1 acts on glucose-6-phosphate, though it is broader than the specific gluconeogenesis and glucose-homeostasis roles. Reason: G6PC1's substrate is glucose-6-phosphate, so involvement in glucose 6-phosphate metabolism is correct but generic relative to its specific role in gluconeogenesis and blood glucose homeostasis. Supporting Evidence: PMID:9332655 the final common step of glycogenolysis and gluconeogenesis
GO:0055088 lipid homeostasis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-projected from rat ortholog. G6PC1 deficiency causes hyperlipidemia secondarily, but a direct role of the enzyme in lipid homeostasis is not established. Reason: Hyperlipidemia is a downstream metabolic consequence of GSD1a rather than a direct function of G6PC1; kept as non-core physiological context. Supporting Evidence: PMID:8211187 the key enzyme in glucose homeostasis
GO:1904638 response to resveratrol	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-projected from rat ortholog based on a pharmacological transcriptional response. This is a highly specific experimental-treatment term with no bearing on G6PC1's core function in humans. Reason: Response to resveratrol is a narrow drug-response term projected from a rodent expression study; it does not describe a molecular or physiological function of human G6PC1 and is an over-annotation. Supporting Evidence: PMID:8211187 the key enzyme in glucose homeostasis
GO:0006094 gluconeogenesis	TAS Reactome:R-HSA-70263	ACCEPT	Summary: Reactome traceable assignment placing G6PC1 in gluconeogenesis, where it catalyzes the terminal hydrolysis of glucose-6-phosphate to glucose. Core. Reason: Reactome curates G6PC1 as the enzyme performing the final step of gluconeogenesis, consistent with all biochemical evidence. Supporting Evidence: PMID:9332655 the final common step of glycogenolysis and gluconeogenesis
GO:0004346 glucose-6-phosphatase activity	EXP PMID:12093795 The catalytic center of glucose-6-phosphatase. HIS176 is the...	ACCEPT	Summary: Experimental characterization of the catalytic center of G6Pase, identifying His-176 as the nucleophile forming the phosphohistidine-enzyme intermediate. Direct evidence for glucose-6-phosphatase activity; core. Reason: This study biochemically dissects the G6Pase catalytic mechanism (His-176 nucleophile, His-119 proton donor), directly supporting the enzyme's core molecular function. Supporting Evidence: PMID:12093795 His(176) is the phosphate acceptor in G6Pase
GO:0004346 glucose-6-phosphatase activity	TAS Reactome:R-HSA-3274540	ACCEPT	Summary: Reactome traceable assignment of glucose-6-phosphatase activity (in the context of loss-of-function disease variants). Consistent with the core function. Reason: Reactome curates G6PC1 as glucose-6-phosphatase; the disease-variant model documents the same catalytic activity. Core function. Supporting Evidence: PMID:12093795 a key enzyme in glucose homeostasis
GO:0004346 glucose-6-phosphatase activity	EXP PMID:10960498 Glucose-6-phosphatase mutation G188R confers an atypical gly...	ACCEPT	Summary: Experimental study of the G188R variant establishing G6Pase catalytic deficiency, supporting the enzyme's glucose-6-phosphatase activity. Core. Reason: Characterization of a loss-of-function G6PC1 variant confirms the enzyme's glucose-6-phosphatase catalytic activity. Supporting Evidence: PMID:10960498 a deficiency in
GO:0004346 glucose-6-phosphatase activity	EXP PMID:15542400 Glycogen storage disease type Ia in Argentina: two novel glu...	ACCEPT	Summary: Site-directed mutagenesis and expression assays of T16R and Y209C variants show abolished enzymatic activity, directly demonstrating G6Pase catalytic function. Core. Reason: Expression assays of disease variants that abolish activity provide direct evidence for G6PC1 glucose-6-phosphatase activity. Supporting Evidence: PMID:15542400 mutations abolished enzymatic activity
GO:0004346 glucose-6-phosphatase activity	EXP PMID:9332655 Glycogen storage disease type 1a in Israel: biochemical, cli...	ACCEPT	Summary: Expression of the V166G variant in COS-1 cells caused complete inactivation of G6Pase, demonstrating the enzyme's glucose-6-phosphatase activity. Core. Reason: Site-directed mutagenesis abolishing catalytic activity directly supports G6PC1 glucose-6-phosphatase function. Supporting Evidence: PMID:9332655 complete inactivation of the G6Pase
GO:0004346 glucose-6-phosphatase activity	EXP PMID:9497333 Transmembrane topology of glucose-6-phosphatase.	ACCEPT	Summary: Transmembrane-topology and active-site study identifying His-176 as the residue that covalently binds the phosphoryl moiety during catalysis. Direct support for glucose-6-phosphatase activity; core. Reason: This study maps the G6Pase active site and catalytic residues, directly supporting the enzyme's core molecular function. Supporting Evidence: PMID:9497333 the key enzyme in
GO:0005789 endoplasmic reticulum membrane	NAS PMID:9497333 Transmembrane topology of glucose-6-phosphatase.	ACCEPT	Summary: Non-traceable/author-statement localization to the ER membrane, backed by the transmembrane-topology study showing an odd number of TM helices with the N terminus in the ER lumen. Correct, core location. Reason: The topology study establishes G6PC1 as a multi-pass ER membrane protein with its active site facing the ER lumen; ER membrane is the core location. Supporting Evidence: PMID:9497333 termini facing the endoplasmic reticulum lumen and the cytoplasm
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-3274540	ACCEPT	Summary: Reactome traceable assignment of ER membrane localization. Consistent with the experimentally established core location. Reason: Reactome curates G6PC1 as associated with the ER membrane; this matches the topology data and is a core location. Supporting Evidence: PMID:9497333 an odd number of transmembrane helices
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-71825	ACCEPT	Summary: Reactome traceable assignment (liver G6P hydrolysis reaction) placing G6PC1 at the ER membrane. Core location. Reason: Reactome curates G6PC1 associated with the inner face of the ER membrane catalyzing G6P hydrolysis; consistent with the core location. Supporting Evidence: PMID:9497333 an odd number of transmembrane helices
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-9944724	ACCEPT	Summary: Reactome traceable assignment associated with a gene-regulation event (TCF19:NuRD repression); the localization to the ER membrane is correct for the encoded protein. Core location. Reason: The encoded G6PC1 protein localizes to the ER membrane; the localization is accurate regardless of the transcriptional-regulation context of the model. Supporting Evidence: PMID:9497333 an odd number of transmembrane helices
GO:0004346 glucose-6-phosphatase activity	IDA PMID:10318794 Transmembrane topology of human glucose 6-phosphate transpor...	ACCEPT	Summary: IDA for glucose-6-phosphatase activity. The cited paper's abstract foregrounds the G6P transporter (G6PT/SLC37A4), but per curation policy the experimental MF annotation for the correct core function of G6PC1 is retained. Reason: Glucose-6-phosphatase activity is the well-established core function of G6PC1. The abstract emphasizes the transporter topology, but I cannot see the full text and do not overrule the experimental MF annotation; the assigned function is correct for this gene. Supporting Evidence: PMID:10318794 the active site of glucose
GO:0004346 glucose-6-phosphatase activity	IDA PMID:8211187 Mutations in the glucose-6-phosphatase gene that cause glyco...	ACCEPT	Summary: Direct assay of the expressed human G6Pase protein (indistinguishable from microsomal G6Pase), with disease mutations that completely inactivate the enzyme. Core function. Reason: The expressed protein was shown to have glucose-6-phosphatase activity and disease mutations abolish it, directly supporting the core molecular function. Supporting Evidence: PMID:8211187 completely inactivate the enzyme
GO:0005789 endoplasmic reticulum membrane	TAS PMID:10318794 Transmembrane topology of human glucose 6-phosphate transpor...	ACCEPT	Summary: TAS for ER membrane localization. The paper concerns the ER-lumen-facing active site of glucose-6-phosphatase within the ER membrane system. Core location. Reason: G6PC1 is an integral ER membrane protein with its active site facing the ER lumen; the ER membrane localization is correct and core. Supporting Evidence: PMID:10318794 the active site of glucose
GO:0006094 gluconeogenesis	IMP PMID:8211187 Mutations in the glucose-6-phosphatase gene that cause glyco...	ACCEPT	Summary: Mutational (IMP) evidence in which inactivating G6PC1 mutations cause GSD1a and impair the terminal step of gluconeogenesis. Core biological process. Reason: Loss-of-function mutations that inactivate the enzyme establish G6PC1's involvement in gluconeogenesis via the GSD1a phenotype. Supporting Evidence: PMID:8211187 completely inactivate the enzyme
GO:0016020 membrane	IDA PMID:10318794 Transmembrane topology of human glucose 6-phosphate transpor...	MARK AS OVER ANNOTATED	Summary: IDA for the generic membrane term. G6PC1 is an integral membrane protein, but the specific ER membrane term is the informative location. Reason: The generic membrane term is uninformatively broad; the experimentally supported ER membrane term (GO:0005789) captures the true localization and is retained as core. Supporting Evidence: PMID:9497333 an odd number of transmembrane helices
GO:0042301 phosphate ion binding	IMP PMID:12093795 The catalytic center of glucose-6-phosphatase. HIS176 is the...	KEEP AS NON CORE	Summary: IMP-based phosphate ion binding, reflecting the catalytic phosphohistidine intermediate (His-176 covalently binds phosphate; Arg-83 positions it). This is a mechanistic sub-aspect of catalysis rather than an independent core function. Reason: Phosphate binding is intrinsic to the glucose-6-phosphatase catalytic cycle (phosphohistidine-enzyme intermediate) and is subsumed by the core MF GO:0004346; kept as non-core to avoid redundancy while noting mechanistic detail. Supporting Evidence: PMID:12093795 His(176) is the phosphate acceptor in G6Pase
GO:0042593 glucose homeostasis	IMP PMID:8211187 Mutations in the glucose-6-phosphatase gene that cause glyco...	ACCEPT	Summary: IMP evidence that inactivating G6PC1 mutations disrupt glucose homeostasis (GSD1a with fasting hypoglycemia). G6PC1 is the key enzyme for blood glucose homeostasis. Core. Reason: G6PC1 is described as the key enzyme in glucose homeostasis; loss-of-function mutations cause hypoglycemia, directly supporting this process. Core function. Supporting Evidence: PMID:8211187 the key enzyme in glucose homeostasis
GO:0004346 glucose-6-phosphatase activity	IDA PMID:15661744 Brain contains a functional glucose-6-phosphatase complex ca...	ACCEPT	Summary: MGI-assigned IDA for glucose-6-phosphatase activity. The cited abstract foregrounds the paralog glucose-6-phosphatase-beta (G6PC3), but the assigned molecular function is correct for G6PC1 and I do not overrule the experimental annotation on the abstract alone. Reason: Glucose-6-phosphatase activity is the core, well-established function of G6PC1. Per curation policy, an experimental MF annotation whose full text I cannot verify is retained when the function is clearly correct for the gene. Supporting Evidence: PMID:15661744 hydrolysis of glucose-6-phosphate
GO:0005977 glycogen metabolic process	TAS PMID:8211187 Mutations in the glucose-6-phosphatase gene that cause glyco...	KEEP AS NON CORE	Summary: TAS for glycogen metabolic process. G6PC1 catalyzes the terminal step of glycogenolysis (hydrolysis of glucose-6-phosphate derived from glycogen breakdown), and its deficiency causes glycogen accumulation in GSD1a. Correct but broader than the specific glycogenolysis role. Reason: G6PC1 acts at the terminal step of glycogenolysis; involvement in glycogen metabolism is accurate. It is retained as non-core because the enzyme does not metabolize glycogen directly but processes the glucose-6-phosphate liberated from it, and its defining roles (glucose-6-phosphatase activity, gluconeogenesis, glucose homeostasis) are captured as core. Supporting Evidence: PMID:9332655 the final common step of glycogenolysis and gluconeogenesis

Gene Description

Existing Annotations Review

Core Functions

Catalyzes the hydrolysis of D-glucose-6-phosphate to D-glucose and inorganic phosphate (EC 3.1.3.9) at the luminal face of the endoplasmic reticulum membrane, the terminal and committed step of gluconeogenesis and glycogenolysis.

References

📚 Additional Documentation

Notes

📄 View Raw YAML