G6PC1

UniProt ID: P35575
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

Glucose-6-phosphatase catalytic subunit 1 (G6PC1; EC 3.1.3.9) is the liver/kidney/intestine catalytic subunit of the glucose-6-phosphatase system. It is a multi-pass integral endoplasmic reticulum membrane protein (nine transmembrane helices) whose catalytic active site faces the ER lumen. G6PC1 hydrolyzes D-glucose-6-phosphate to D-glucose and inorganic phosphate, the terminal, committed step shared by both gluconeogenesis and glycogenolysis, enabling hepatic and renal glucose output into the blood. It acts together with the ER glucose-6-phosphate transporter SLC37A4/G6PT, which supplies luminal glucose-6-phosphate to the active site. Catalysis proceeds via a phosphohistidine-enzyme intermediate in which His-176 is the nucleophile and His-119 the proton donor. Loss-of-function variants in G6PC1 cause glycogen storage disease type Ia (von Gierke disease), characterized by fasting hypoglycemia, hepatomegaly, nephromegaly, lactic acidemia, hyperlipidemia, and hyperuricemia.

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

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.

Molecular Function:
glucose-6-phosphatase activity
Directly Involved In:
gluconeogenesis glucose homeostasis
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:

References

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:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10318794
Transmembrane topology of human glucose 6-phosphate transporter.
PMID:10960498
Glucose-6-phosphatase mutation G188R confers an atypical glycogen storage disease type 1b phenotype.
PMID:12093795
The catalytic center of glucose-6-phosphatase. HIS176 is the nucleophile forming the phosphohistidine-enzyme intermediate during catalysis.
PMID:15542400
Glycogen storage disease type Ia in Argentina: two novel glucose-6-phosphatase mutations affecting protein stability.
PMID:15661744
Brain contains a functional glucose-6-phosphatase complex capable of endogenous glucose production.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:8211187
Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a.
PMID:9332655
Glycogen storage disease type 1a in Israel: biochemical, clinical, and mutational studies.
PMID:9497333
Transmembrane topology of glucose-6-phosphatase.
Reactome:R-HSA-3274540
Defective G6PC does not hydrolyze glucose 6-phosphate
Reactome:R-HSA-70263
Gluconeogenesis
Reactome:R-HSA-71825
G6PC hydrolyzes G6P to Glc and Pi (liver)
Reactome:R-HSA-9944724
TCF19:NuRD represses G6PC gene expression

📚 Additional Documentation

Notes

(G6PC1-notes.md)

G6PC1 (Glucose-6-phosphatase catalytic subunit 1) — review notes

UniProt: P35575 (G6PC1_HUMAN); formerly G6PC / G6PC1; EC 3.1.3.9.
HGNC:4056. 357 aa. Chromosome 17.

Core biology

G6PC1 is the liver/kidney/intestine catalytic subunit of glucose-6-phosphatase, a
multi-pass integral endoplasmic reticulum (ER) membrane protein (nine transmembrane
helices) whose catalytic active site faces the ER lumen. It hydrolyzes
D-glucose-6-phosphate + H2O -> D-glucose + phosphate (Rhea:16689), the terminal,
committed step shared by gluconeogenesis and glycogenolysis, thereby enabling
hepatic/renal glucose output into blood. It functions together with the ER
glucose-6-phosphate transporter SLC37A4/G6PT, which supplies luminal G6P.

Key UniProt FUNCTION line:
"Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. Forms with
the glucose-6-phosphate transporter (SLC37A4/G6PT) the complex responsible for glucose
production in the terminal step of glycogenolysis and gluconeogenesis. Hence, it is the
key enzyme in homeostatic regulation of blood glucose levels."
(ECO:0000269|PubMed:10960498, 12093795, 15542400, 9332655, 9497333)

Structure / topology / active site (PMID:9497333, PMID:12093795)

  • Nine transmembrane helices; N terminus lumenal, C terminus cytoplasmic (odd number of
    TM helices). Active-site residues Arg-83, His-119, His-176 reside on the luminal side.
  • His-176 is the nucleophile that forms the phosphohistidine-enzyme intermediate;
    His-119 is the proton donor (ACT_SITE 119 proton donor, 176 nucleophile in UniProt FT).
  • PAP2 phosphatase superfamily fold (InterPro IPR016275 Glucose-6-phosphatase;
    IPR000326 PAP2/HPO). N-glycosylated at Asn-96 (PMID:9705299, 19159218).

Disease: Glycogen storage disease type Ia (GSD1A / von Gierke disease, MIM:232200)

Autosomal recessive; deficiency of G6Pase impairs the terminal steps of glycogenolysis
and gluconeogenesis. Fasting hypoglycemia, severe hepatomegaly (glycogen accumulation),
kidney enlargement, growth retardation, lactic acidemia, hyperlipidemia, hyperuricemia.
Dozens of loss-of-function missense variants characterized (e.g. R83C prevalent in
Ashkenazi Jews; V166G, T16R, Y209C, G188R, K76N, R170Q — several show complete loss of
enzyme activity in expression assays). GSD1b (a distinct entity) is caused by SLC37A4/G6PT
transporter defects, not G6PC1.

Existing-annotation notes / provenance issues

  • PMID:10318794 ("Transmembrane topology of human glucose 6-phosphate transporter")
    is primarily about the G6P transporter (SLC37A4/G6PT). GOA carries three P35575
    annotations citing it (GO:0004346 IDA, GO:0016020 IDA, GO:0005789 TAS). Per curation
    policy I do NOT REMOVE experimental annotations on the basis of the abstract
    foregrounding the transporter; the MF/location are correct for G6PC1. Marked
    MF-IDA as ACCEPT; the generic GO:0016020 membrane IDA marked as over-annotated in favor
    of the specific ER membrane term.
  • PMID:15661744 ("Brain contains a functional glucose-6-phosphatase complex...") abstract
    foregrounds glucose-6-phosphatase-beta (G6PC3), but MGI assigned an IDA GO:0004346 to
    P35575. Function is correct for the gene; ACCEPT (defer to curator; do not REMOVE on
    abstract alone).
  • GO:0042301 phosphate ion binding (IMP, PMID:12093795): the paper shows His-176 is the
    covalent phosphate acceptor (phosphohistidine intermediate) and Arg-83 positions the
    phosphate; "phosphate ion binding" is a mechanistic sub-aspect of catalysis rather than
    a standalone core MF. Kept as non-core.
  • IEA GO:1904638 response to resveratrol, GO:0032094 response to food, GO:0009743 response
    to carbohydrate, GO:0032868/GO:0032869 response to insulin, GO:0031667 response to
    nutrient levels: all Ensembl-projected from rat P43428. These reflect transcriptional
    regulation of the gene (G6PC1 is a canonical insulin/gluconeogenic transcriptional
    target), not molecular functions of the protein; kept as non-core.
  • GO:0005515 protein binding (IPI, PMID:32814053; partners WFS1/O76024 and RNF11/Q9Y3C5
    via IntAct Y2H): uninformative bare protein-binding; MARK_AS_OVER_ANNOTATED per policy.

Core functions

  • MF: GO:0004346 glucose-6-phosphatase activity (EC 3.1.3.9)
  • BP: GO:0006094 gluconeogenesis; GO:0042593 glucose homeostasis
  • CC: GO:0005789 endoplasmic reticulum membrane (active site luminal)

📄 View Raw YAML

 
id: P35575
gene_symbol: G6PC1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Glucose-6-phosphatase catalytic subunit 1 (G6PC1; EC 3.1.3.9) is the
  liver/kidney/intestine catalytic subunit of the glucose-6-phosphatase system. It
  is a multi-pass integral endoplasmic reticulum membrane protein (nine transmembrane
  helices) whose catalytic active site faces the ER lumen. G6PC1 hydrolyzes
  D-glucose-6-phosphate to D-glucose and inorganic phosphate, the terminal, committed
  step shared by both gluconeogenesis and glycogenolysis, enabling hepatic and renal
  glucose output into the blood. It acts together with the ER glucose-6-phosphate
  transporter SLC37A4/G6PT, which supplies luminal glucose-6-phosphate to the active
  site. Catalysis proceeds via a phosphohistidine-enzyme intermediate in which His-176
  is the nucleophile and His-119 the proton donor. Loss-of-function variants in G6PC1
  cause glycogen storage disease type Ia (von Gierke disease), characterized by fasting
  hypoglycemia, hepatomegaly, nephromegaly, lactic acidemia, hyperlipidemia, and
  hyperuricemia.
alternative_products:
- name: '1'
  id: P35575-1
- name: '2'
  id: P35575-2
  sequence_note: VSP_047558, VSP_047559
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:12093795
      supporting_text: is anchored
    - reference_id: PMID:9497333
      supporting_text: termini facing the endoplasmic reticulum lumen and the cytoplasm
- term:
    id: GO:0006094
    label: gluconeogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetically inferred involvement in gluconeogenesis. G6PC1 catalyzes
      the terminal, committed step of gluconeogenesis, so this is a core biological
      process.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9332655
      supporting_text: the final common step of glycogenolysis and gluconeogenesis
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically inferred glucose-6-phosphatase activity, the core
      molecular function of G6PC1.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:12093795
      supporting_text: a key enzyme in glucose homeostasis
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Generic membrane localization inferred phylogenetically. G6PC1 is a
      multi-pass membrane protein, but the informative location is the ER membrane.
    action: MARK_AS_OVER_ANNOTATED
    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
    supported_by:
    - reference_id: PMID:9497333
      supporting_text: an odd number of transmembrane helices
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of glucose-6-phosphatase activity (EC 3.1.3.9 /
      RHEA:16689). Consistent with the experimentally established core function.
    action: ACCEPT
    reason: Automated EC/RHEA-based inference matches the experimentally validated
      catalytic activity of G6PC1.
    supported_by:
    - reference_id: PMID:12093795
      supporting_text: a key enzyme in glucose homeostasis
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic assignment (UniProt subcellular-location mapping) of
      localization to the endoplasmic reticulum membrane, the correct and core
      location of G6PC1.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9497333
      supporting_text: termini facing the endoplasmic reticulum lumen and the cytoplasm
- term:
    id: GO:0048878
    label: chemical homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific and experimentally supported role is glucose homeostasis
      (GO:0042593), retained as a core function; chemical homeostasis is an
      uninformative parent term.
    supported_by:
    - reference_id: PMID:9497333
      supporting_text: the key enzyme in
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: systematic yeast two-hybrid interaction screening
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl-projected localization to the endoplasmic reticulum from a
      rodent ortholog. Correct but non-core relative to the specific ER membrane term.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:9497333
      supporting_text: termini facing the endoplasmic reticulum lumen and the cytoplasm
- term:
    id: GO:0006094
    label: gluconeogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic (UniPathway/ARBA) assignment of involvement in gluconeogenesis,
      consistent with the enzyme's terminal role in the pathway.
    action: ACCEPT
    reason: G6PC1 catalyzes the last step of gluconeogenesis; automated pathway
      inference agrees with experimental evidence.
    supported_by:
    - reference_id: PMID:9332655
      supporting_text: the final common step of glycogenolysis and gluconeogenesis
- term:
    id: GO:0009743
    label: response to carbohydrate
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-projected from rat ortholog. Reflects nutritional/transcriptional
      regulation of the gene rather than a molecular function of the protein.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:8211187
      supporting_text: the key enzyme in glucose homeostasis
- term:
    id: GO:0016773
    label: phosphotransferase activity, alcohol group as acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ensembl-projected molecular function term. G6PC1 is a phosphohydrolase
      (phosphatase), not a phosphotransferase; this branch is incorrect for the
      enzyme's mechanism.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:12093795
      supporting_text: His(176) is the phosphate acceptor in G6Pase
- term:
    id: GO:0031667
    label: response to nutrient levels
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-projected from rat ortholog. Reflects nutrient-dependent
      transcriptional regulation of G6PC1 rather than the protein's molecular function.
    action: KEEP_AS_NON_CORE
    reason: G6PC1 expression responds to fasting/feeding and nutrient status; this is
      a physiological-regulation context, not the enzyme's core function.
    supported_by:
    - reference_id: PMID:8211187
      supporting_text: the key enzyme in glucose homeostasis
- term:
    id: GO:0032094
    label: response to food
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-projected from rat ortholog. Feeding-state regulatory context
      of gene expression, not a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: Reflects nutritional regulation of G6PC1 expression rather than the
      enzyme's catalytic role; retained as non-core.
    supported_by:
    - reference_id: PMID:8211187
      supporting_text: the key enzyme in glucose homeostasis
- term:
    id: GO:0032868
    label: response to insulin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-projected from rat ortholog. G6PC1 is a canonical insulin-repressed
      gluconeogenic gene, but this reflects transcriptional regulation, not a core
      molecular function.
    action: KEEP_AS_NON_CORE
    reason: Insulin suppresses G6PC1 transcription; this regulatory-response annotation
      is physiologically real but peripheral to the enzyme's core catalytic function.
    supported_by:
    - reference_id: PMID:8211187
      supporting_text: the key enzyme in glucose homeostasis
- term:
    id: GO:0032869
    label: cellular response to insulin stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Reflects insulin-signaling regulation of G6PC1 expression; retained as
      non-core context.
    supported_by:
    - reference_id: PMID:8211187
      supporting_text: the key enzyme in glucose homeostasis
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:9332655
      supporting_text: the final common step of glycogenolysis and gluconeogenesis
- term:
    id: GO:0055088
    label: lipid homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-projected from rat ortholog. G6PC1 deficiency causes hyperlipidemia
      secondarily, but a direct role of the enzyme in lipid homeostasis is not
      established.
    action: KEEP_AS_NON_CORE
    reason: Hyperlipidemia is a downstream metabolic consequence of GSD1a rather than
      a direct function of G6PC1; kept as non-core physiological context.
    supported_by:
    - reference_id: PMID:8211187
      supporting_text: the key enzyme in glucose homeostasis
- term:
    id: GO:1904638
    label: response to resveratrol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:8211187
      supporting_text: the key enzyme in glucose homeostasis
- term:
    id: GO:0006094
    label: gluconeogenesis
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70263
  qualifier: involved_in
  review:
    summary: Reactome traceable assignment placing G6PC1 in gluconeogenesis, where it
      catalyzes the terminal hydrolysis of glucose-6-phosphate to glucose. Core.
    action: ACCEPT
    reason: Reactome curates G6PC1 as the enzyme performing the final step of
      gluconeogenesis, consistent with all biochemical evidence.
    supported_by:
    - reference_id: PMID:9332655
      supporting_text: the final common step of glycogenolysis and gluconeogenesis
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:12093795
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: This study biochemically dissects the G6Pase catalytic mechanism (His-176
      nucleophile, His-119 proton donor), directly supporting the enzyme's core
      molecular function.
    supported_by:
    - reference_id: PMID:12093795
      supporting_text: His(176) is the phosphate acceptor in G6Pase
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3274540
  qualifier: enables
  review:
    summary: Reactome traceable assignment of glucose-6-phosphatase activity (in the
      context of loss-of-function disease variants). Consistent with the core function.
    action: ACCEPT
    reason: Reactome curates G6PC1 as glucose-6-phosphatase; the disease-variant model
      documents the same catalytic activity. Core function.
    supported_by:
    - reference_id: PMID:12093795
      supporting_text: a key enzyme in glucose homeostasis
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:10960498
  qualifier: enables
  review:
    summary: Experimental study of the G188R variant establishing G6Pase catalytic
      deficiency, supporting the enzyme's glucose-6-phosphatase activity. Core.
    action: ACCEPT
    reason: Characterization of a loss-of-function G6PC1 variant confirms the enzyme's
      glucose-6-phosphatase catalytic activity.
    supported_by:
    - reference_id: PMID:10960498
      supporting_text: a deficiency in
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:15542400
  qualifier: enables
  review:
    summary: Site-directed mutagenesis and expression assays of T16R and Y209C variants
      show abolished enzymatic activity, directly demonstrating G6Pase catalytic
      function. Core.
    action: ACCEPT
    reason: Expression assays of disease variants that abolish activity provide direct
      evidence for G6PC1 glucose-6-phosphatase activity.
    supported_by:
    - reference_id: PMID:15542400
      supporting_text: mutations abolished enzymatic activity
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:9332655
  qualifier: enables
  review:
    summary: Expression of the V166G variant in COS-1 cells caused complete
      inactivation of G6Pase, demonstrating the enzyme's glucose-6-phosphatase
      activity. Core.
    action: ACCEPT
    reason: Site-directed mutagenesis abolishing catalytic activity directly supports
      G6PC1 glucose-6-phosphatase function.
    supported_by:
    - reference_id: PMID:9332655
      supporting_text: complete inactivation of the G6Pase
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:9497333
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: This study maps the G6Pase active site and catalytic residues, directly
      supporting the enzyme's core molecular function.
    supported_by:
    - reference_id: PMID:9497333
      supporting_text: the key enzyme in
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:9497333
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9497333
      supporting_text: termini facing the endoplasmic reticulum lumen and the cytoplasm
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3274540
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of ER membrane localization. Consistent
      with the experimentally established core location.
    action: ACCEPT
    reason: Reactome curates G6PC1 as associated with the ER membrane; this matches
      the topology data and is a core location.
    supported_by:
    - reference_id: PMID:9497333
      supporting_text: an odd number of transmembrane helices
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71825
  qualifier: located_in
  review:
    summary: Reactome traceable assignment (liver G6P hydrolysis reaction) placing
      G6PC1 at the ER membrane. Core location.
    action: ACCEPT
    reason: Reactome curates G6PC1 associated with the inner face of the ER membrane
      catalyzing G6P hydrolysis; consistent with the core location.
    supported_by:
    - reference_id: PMID:9497333
      supporting_text: an odd number of transmembrane helices
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9944724
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: The encoded G6PC1 protein localizes to the ER membrane; the localization
      is accurate regardless of the transcriptional-regulation context of the model.
    supported_by:
    - reference_id: PMID:9497333
      supporting_text: an odd number of transmembrane helices
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:10318794
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10318794
      supporting_text: the active site of glucose
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:8211187
  qualifier: enables
  review:
    summary: Direct assay of the expressed human G6Pase protein (indistinguishable
      from microsomal G6Pase), with disease mutations that completely inactivate the
      enzyme. Core function.
    action: ACCEPT
    reason: The expressed protein was shown to have glucose-6-phosphatase activity and
      disease mutations abolish it, directly supporting the core molecular function.
    supported_by:
    - reference_id: PMID:8211187
      supporting_text: completely inactivate the enzyme
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: PMID:10318794
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: G6PC1 is an integral ER membrane protein with its active site facing the
      ER lumen; the ER membrane localization is correct and core.
    supported_by:
    - reference_id: PMID:10318794
      supporting_text: the active site of glucose
- term:
    id: GO:0006094
    label: gluconeogenesis
  evidence_type: IMP
  original_reference_id: PMID:8211187
  qualifier: involved_in
  review:
    summary: Mutational (IMP) evidence in which inactivating G6PC1 mutations cause
      GSD1a and impair the terminal step of gluconeogenesis. Core biological process.
    action: ACCEPT
    reason: Loss-of-function mutations that inactivate the enzyme establish G6PC1's
      involvement in gluconeogenesis via the GSD1a phenotype.
    supported_by:
    - reference_id: PMID:8211187
      supporting_text: completely inactivate the enzyme
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:10318794
  qualifier: located_in
  review:
    summary: IDA for the generic membrane term. G6PC1 is an integral membrane protein,
      but the specific ER membrane term is the informative location.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:9497333
      supporting_text: an odd number of transmembrane helices
- term:
    id: GO:0042301
    label: phosphate ion binding
  evidence_type: IMP
  original_reference_id: PMID:12093795
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:12093795
      supporting_text: His(176) is the phosphate acceptor in G6Pase
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: IMP
  original_reference_id: PMID:8211187
  qualifier: involved_in
  review:
    summary: IMP evidence that inactivating G6PC1 mutations disrupt glucose homeostasis
      (GSD1a with fasting hypoglycemia). G6PC1 is the key enzyme for blood glucose
      homeostasis. Core.
    action: ACCEPT
    reason: G6PC1 is described as the key enzyme in glucose homeostasis; loss-of-function
      mutations cause hypoglycemia, directly supporting this process. Core function.
    supported_by:
    - reference_id: PMID:8211187
      supporting_text: the key enzyme in glucose homeostasis
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:15661744
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:15661744
      supporting_text: hydrolysis of glucose-6-phosphate
- term:
    id: GO:0005977
    label: glycogen metabolic process
  evidence_type: TAS
  original_reference_id: PMID:8211187
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:9332655
      supporting_text: the final common step of glycogenolysis and gluconeogenesis
core_functions:
- description: 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.
  molecular_function:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  directly_involved_in:
  - id: GO:0006094
    label: gluconeogenesis
  - id: GO:0042593
    label: glucose homeostasis
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:12093795
    supporting_text: a key enzyme in glucose homeostasis
  - reference_id: PMID:9332655
    supporting_text: the final common step of glycogenolysis and gluconeogenesis
references:
- 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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10318794
  title: Transmembrane topology of human glucose 6-phosphate transporter.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Primarily about the G6P transporter (SLC37A4/G6PT); establishes that
      the glucose-6-phosphatase active site is situated in the ER lumen. Supports the
      luminal-active-site location of the G6PC1 system.
- id: PMID:10960498
  title: Glucose-6-phosphatase mutation G188R confers an atypical glycogen storage
    disease type 1b phenotype.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: G188R loss-of-function G6PC1 variant; supports glucose-6-phosphatase
      catalytic activity and the GSD1a disease association.
- id: PMID:12093795
  title: The catalytic center of glucose-6-phosphatase. HIS176 is the nucleophile
    forming the phosphohistidine-enzyme intermediate during catalysis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines the catalytic mechanism (His-176 nucleophile, His-119 proton
      donor); primary support for glucose-6-phosphatase activity.
- id: PMID:15542400
  title: 'Glycogen storage disease type Ia in Argentina: two novel glucose-6-phosphatase
    mutations affecting protein stability.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: T16R and Y209C variants abolish enzymatic activity in expression
      assays; supports glucose-6-phosphatase activity and GSD1a.
- id: PMID:15661744
  title: Brain contains a functional glucose-6-phosphatase complex capable of endogenous
    glucose production.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract foregrounds glucose-6-phosphatase-beta (G6PC3) in astrocytes;
      cited by MGI for a G6PC1 IDA of glucose-6-phosphatase activity. Function is
      correct for G6PC1, but the abstract does not directly assay G6PC1.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput Y2H interactome screen; source of bare protein-binding
      IPI annotations (WFS1, RNF11). No functional consequence established for G6PC1.
- id: PMID:8211187
  title: Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease
    type 1a.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cloning and expression of human G6Pase; inactivating GSD1a mutations.
      Primary support for glucose-6-phosphatase activity, gluconeogenesis, and glucose
      homeostasis.
- id: PMID:9332655
  title: 'Glycogen storage disease type 1a in Israel: biochemical, clinical, and mutational
    studies.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: States G6Pase catalyzes the final common step of glycogenolysis and
      gluconeogenesis; V166G variant causes complete inactivation.
- id: PMID:9497333
  title: Transmembrane topology of glucose-6-phosphatase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes nine-TM ER membrane topology with luminal active site and
      His-176 as catalytic phosphoryl acceptor; primary support for ER membrane location.
- id: Reactome:R-HSA-3274540
  title: Defective G6PC does not hydrolyze glucose 6-phosphate
  findings: []
- id: Reactome:R-HSA-70263
  title: Gluconeogenesis
  findings: []
- id: Reactome:R-HSA-71825
  title: G6PC hydrolyzes G6P to Glc and Pi (liver)
  findings: []
- id: Reactome:R-HSA-9944724
  title: TCF19:NuRD represses G6PC gene expression
  findings: []