id: Q9BUM1
gene_symbol: G6PC3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      IBA localization of G6PC3 to the endoplasmic reticulum. Correct but a
      generic parent of the more precise ER membrane assignment.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:25492228
      supporting_text: >-
        G6Pase-β is an enzyme embedded in the endoplasmic reticulum membrane
        that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose
        and phosphate.
- term:
    id: GO:0006094
    label: gluconeogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      IBA involvement in gluconeogenesis, inherited from the glucose-6-phosphatase
      family (including hepatic orthologs).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:25492228
      supporting_text: >-
        the ubiquitous G6Pase-β/G6PT complex maintains energy homeostasis and
        functionality in neutrophils and macrophages
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      IBA glucose-6-phosphatase activity, the core molecular function of G6PC3,
      concordant with experimental evidence.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:14718531
      supporting_text: >-
        Glc-6-Pase-beta is also a nine-transmembrane domain protein that forms a
        covalently bound phosphoryl enzyme intermediate during Glc-6-P hydrolysis.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      IBA generic membrane localization. Correct but uninformative given the
      well-established ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    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
    supported_by:
    - reference_id: file:human/G6PC3/G6PC3-uniprot.txt
      supporting_text: 'Multi-pass membrane protein'
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (ARBA/InterPro/RHEA/EC) assignment of glucose-6-phosphatase
      activity, matching the experimentally established function.
    action: ACCEPT
    reason: >-
      The IEA mapping (EC 3.1.3.9, RHEA:16689, InterPro glucose-6-phosphatase
      family) agrees with the direct experimental molecular function. Correct.
    supported_by:
    - reference_id: file:human/G6PC3/G6PC3-uniprot.txt
      supporting_text: >-
        Reaction=D-glucose 6-phosphate + H2O = D-glucose + phosphate;
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt subcellular-location keyword mapping to ER membrane, the precise
      localization of G6PC3.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/G6PC3/G6PC3-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
    - reference_id: PMID:25492228
      supporting_text: >-
        G6Pase-β is an enzyme embedded in the endoplasmic reticulum membrane
        that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose
        and phosphate.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Ensembl orthology-based transfer of ER localization. Correct but a generic
      parent of ER membrane.
    action: ACCEPT
    reason: >-
      ER localization is well established for G6PC3. Correct, though the specific
      ER membrane term is more informative and captured elsewhere.
    supported_by:
    - reference_id: PMID:25492228
      supporting_text: >-
        G6Pase-β is an enzyme embedded in the endoplasmic reticulum membrane
        that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose
        and phosphate.
- term:
    id: GO:0006094
    label: gluconeogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic (UniPathway/ortholog) assignment of gluconeogenesis, a
      family/pathway-level process.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/G6PC3/G6PC3-uniprot.txt
      supporting_text: 'Carbohydrate biosynthesis; gluconeogenesis.'
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-based assignment of glucose 6-phosphate metabolic process, the
      direct metabolic process performed by G6PC3.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:25492228
      supporting_text: >-
        Both phosphatases catalyze the hydrolysis of glucose-6-phosphate (G6P)
        to glucose and phosphate and both are key enzymes for intracellular
        glucose production.
- term:
    id: GO:0006094
    label: gluconeogenesis
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70263
  qualifier: involved_in
  review:
    summary: >-
      Reactome pathway (Gluconeogenesis) traceable assignment placing G6PC3 in
      the gluconeogenesis pathway.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/G6PC3/G6PC3-uniprot.txt
      supporting_text: 'Carbohydrate biosynthesis; gluconeogenesis.'
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:14718531
  qualifier: enables
  review:
    summary: >-
      Experimental demonstration of glucose-6-phosphatase (G6P hydrolase)
      activity, with identification of His167 as the catalytic phosphate acceptor.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:14718531
      supporting_text: >-
        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).
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3282876
  qualifier: enables
  review:
    summary: >-
      Reactome traceable assignment of glucose-6-phosphatase activity (context:
      defective G6PC3 does not hydrolyze G6P), consistent with the core function.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:25492228
      supporting_text: >-
        Fourteen missense mutations completely abolish G6Pase-β enzymatic activity
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Human Protein Atlas immunofluorescence (IDA) localizing G6PC3 to the
      endoplasmic reticulum.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:25492228
      supporting_text: >-
        G6Pase-β is an enzyme embedded in the endoplasmic reticulum membrane
        that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose
        and phosphate.
- term:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  evidence_type: IMP
  original_reference_id: PMID:25492228
  qualifier: enables
  review:
    summary: >-
      IMP for glucose-6-phosphatase activity: functional analysis of SCN4
      disease mutations shows they abolish or reduce G6P hydrolase activity.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:25492228
      supporting_text: >-
        Fourteen missense mutations completely abolish G6Pase-β enzymatic activity
        while the p.S139I and p.R189Q mutations retain 49% and 45%, respectively of
        wild type G6Pase-β activity.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput MS membrane-proteome survey of an NK-like cell line
      (PMID:19946888) detecting G6PC3 among membrane proteins.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        spectrometric analysis identified 1843 proteins with high confidence
        scores.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3282876
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assignment of ER membrane localization for G6PC3.
    action: ACCEPT
    reason: >-
      ER membrane is the precise, well-supported localization of the multi-pass
      G6PC3 protein. Core cellular component.
    supported_by:
    - reference_id: file:human/G6PC3/G6PC3-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3262512
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assignment of ER membrane localization (reaction:
      G6PC3 hydrolyzes G6P to form Glc and Pi, ubiquitous).
    action: ACCEPT
    reason: >-
      Duplicate ER membrane localization from a second Reactome reaction; correct
      and consistent with the multi-pass ER membrane residence of G6PC3.
    supported_by:
    - reference_id: file:human/G6PC3/G6PC3-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
core_functions:
- description: >-
    Glucose-6-phosphatase activity: hydrolysis of glucose-6-phosphate to glucose
    and inorganic phosphate at the luminal face of the endoplasmic reticulum
    membrane, via a covalent phosphohistidine (His167) intermediate, contributing
    to glucose 6-phosphate metabolism and intracellular glucose production in
    concert with the ER G6P transporter SLC37A4.
  molecular_function:
    id: GO:0004346
    label: glucose-6-phosphatase activity
  directly_involved_in:
  - id: GO:0051156
    label: glucose 6-phosphate metabolic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:14718531
    supporting_text: >-
      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).
  - reference_id: PMID:25492228
    supporting_text: >-
      Both phosphatases catalyze the hydrolysis of glucose-6-phosphate (G6P)
      to glucose and phosphate and both are key enzymes for intracellular
      glucose production.
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:14718531
  title: Histidine 167 is the phosphate acceptor in glucose-6-phosphatase-beta forming
    a phosphohistidine enzyme intermediate during catalysis.
  findings:
  - statement: >-
      G6Pase-beta is a nine-transmembrane ER protein that forms a covalent
      phosphoryl enzyme intermediate during G6P hydrolysis; the phosphate
      acceptor is His167, lying in the ER lumen with active-site residues Arg79
      and His114.
    supporting_text: >-
      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).
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache but directly establishes the catalytic mechanism
      and active-site residues of G6PC3 (G6Pase-beta); supports the core MF.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings:
  - statement: >-
      Large-scale membrane-proteome MS survey of an NK-like cell line that
      identified G6PC3 among 1843 high-confidence proteins; the source of the
      generic HDA "membrane" annotation.
    supporting_text: >-
      spectrometric analysis identified 1843 proteins with high confidence
      scores.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Generic high-throughput membrane proteomics; supports only a non-specific
      membrane localization, superseded by ER membrane. Not G6PC3-specific.
- id: PMID:25492228
  title: Functional analysis of mutations in a severe congenital neutropenia syndrome
    caused by glucose-6-phosphatase-β deficiency.
  findings:
  - statement: >-
      G6PC3 (G6Pase-beta) is an ER-membrane enzyme that hydrolyses G6P to glucose
      and phosphate; functional analysis of SCN4 missense mutations shows 14 of 16
      completely abolish enzymatic activity, establishing the core function and
      disease mechanism.
    supporting_text: >-
      Fourteen missense mutations completely abolish G6Pase-β enzymatic activity
      while the p.S139I and p.R189Q mutations retain 49% and 45%, respectively of
      wild type G6Pase-β activity.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available (PMC4794745). Directly supports G6PC3 catalytic
      activity, ER-membrane localization, SLC37A4/G6PT partnership, and the SCN4
      disease mechanism. Basis of the IMP GO:0004346 annotation.
- id: Reactome:R-HSA-3262512
  title: G6PC3 hydrolyzes G6P to form Glc and Pi (ubiquitous)
  findings: []
- id: Reactome:R-HSA-3282876
  title: Defective G6PC3 does not hydrolyze glucose 6-phosphate
  findings: []
- id: Reactome:R-HSA-70263
  title: Gluconeogenesis
  findings: []