id: P54840
gene_symbol: GYS2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GYS2 is the liver isoform of glycogen synthase (EC 2.4.1.11), the committed and
  rate-limiting enzyme of hepatic glycogen chain elongation. Using UDP-glucose as the
  glucosyl donor, it transfers glucose residues in alpha-1,4-glycosidic linkage to the
  non-reducing ends of a growing glycogen chain that has been primed by glycogenin; the
  branching enzyme GBE1 subsequently introduces the alpha-1,6 branch points. GYS2 is a
  soluble cytosolic enzyme that assembles with glycogenin into a glycogen synthase-glycogenin
  complex. Its activity is tightly regulated: it is allosterically activated by
  glucose-6-phosphate and inhibited by multisite phosphorylation (by kinases including GSK3
  and casein kinase 2), with dephosphorylation by protein phosphatase 1 restoring activity.
  Expression is essentially liver-specific. Biallelic loss-of-function mutations in GYS2
  cause glycogen storage disease type 0, liver form (GSD 0a), characterized by fasting
  ketotic hypoglycemia with low blood lactate and alanine, postprandial hyperglycemia and
  hyperlactatemia, and deficient hepatic glycogen.
existing_annotations:
- term:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred glycogen synthase catalytic activity (EC 2.4.1.11); this is
      the core molecular function of GYS2 and is well supported by direct enzyme
      characterization of the human liver enzyme.
    action: ACCEPT
    reason: >-
      The IBA transfer across the glycogen synthase orthologue set correctly assigns the
      committed catalytic step of glycogen elongation, adding UDP-glucose-derived glucosyl
      units in alpha-1,4 linkage to a growing chain. Directly supported by the UniProt
      functional and catalytic-activity annotation and by enzyme characterization of the
      purified human liver enzyme.
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: transfers the glycosyl residue from UDP-Glc to the non-reducing end of
    - reference_id: PMID:1731614
      supporting_text: >-
        the rat and human liver glycogen synthases were similar in their pH profile, in their
        kinetic constants for the substrate UDP-glucose and the activator glucose 6-phosphate
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      GYS2 is a central enzyme of the glycogen biosynthetic process, extending glycogen
      chains during hepatic glycogen storage.
    action: ACCEPT
    reason: >-
      Correct core biological process. GYS2 acts within glycogen synthesis together with
      glycogenin and the branching enzyme; the UniProt pathway annotation places it in
      glycogen biosynthesis, and loss of GYS2 causes deficient hepatic glycogen (GSD 0a).
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: 'PATHWAY: Glycan biosynthesis; glycogen biosynthesis.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Cytoplasmic localization inferred phylogenetically; consistent with the known cytosolic
      activity of glycogen synthase.
    action: ACCEPT
    reason: >-
      Glycogen synthase is a soluble cytosolic enzyme active in the cytoplasm as part of the
      glycogen synthase-glycogenin complex. Cytoplasm is a correct (if broad) location; the
      more specific cytosol annotations are also present.
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: heterooctamer composed of a tetramer of GS and 2 dimers of glycogenin,
- term:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of the core UDP-glucose:glycogen glucosyltransferase activity
      (EC 2.4.1.11, RHEA:18549) via combined IEA methods.
    action: ACCEPT
    reason: >-
      Redundant with, and consistent with, the experimentally supported core catalytic
      function. The EC/RHEA mapping matches the UniProt catalytic activity.
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: transfers the glycosyl residue from UDP-Glc to the non-reducing end of
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assignment of glycogen biosynthetic process, consistent with the core role
      of GYS2.
    action: ACCEPT
    reason: >-
      Redundant with the IBA/IDA/IMP glycogen biosynthesis annotations and correct for GYS2.
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: 'PATHWAY: Glycan biosynthesis; glycogen biosynthesis.'
- term:
    id: GO:0061547
    label: glycogen synthase activity, transferring glucose-1-phosphate
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      Captures the minor phosphoglucose-incorporation side reaction of glycogen synthase, in
      which a glucose-phosphate is occasionally transferred, introducing phosphomonoesters
      into glycogen.
    action: ACCEPT
    reason: >-
      This is a genuine, documented low-frequency capability of glycogen synthase (GYS1/GYS2):
      roughly one phosphorylated glucose is incorporated per ten thousand glucose units, and
      laforin (EPM2A) normally removes these phosphate groups. The ARBA electronic assignment
      of this specific activity is biologically appropriate for GYS2, so it is kept rather
      than removed; it is a minor side activity relative to the core UDP-glucose donor
      elongation.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        Glycogen synthase 2 (GYS2) catalyzes the incorporation of phosphoglucose into the
        glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen granule.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: >-
      Cytosolic localization transferred electronically from the mouse orthologue; consistent
      with the soluble cytosolic nature of glycogen synthase.
    action: ACCEPT
    reason: >-
      GYS2 is a soluble cytosolic enzyme. Cytosol is the correct, specific compartment and is
      corroborated by multiple TAS (Reactome) and ISS annotations.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        Glycogen synthase 2 (GYS2) catalyzes the incorporation of phosphoglucose into the
        glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen granule.
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322077
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable assignment placing GYS2 in the glycogen synthesis pathway, where it
      catalyzes the linear alpha-1,4 extension of the glucose oligomer.
    action: ACCEPT
    reason: >-
      Correct core biological process, curated from the Reactome "Glycogen synthesis" pathway,
      which explicitly identifies glycogen synthase as the enzyme catalyzing linear chain
      extension.
    supported_by:
    - reference_id: Reactome:R-HSA-3322077
      supporting_text: >-
        the linear extension of the glucose oligomer catalyzed by glycogen synthase, and the
        formation of branches catalyzed by glycogen branching enzyme, are unique to glycogen
        synthesis
- term:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  evidence_type: EXP
  original_reference_id: PMID:9691087
  qualifier: enables
  review:
    summary: >-
      Experimental support for glycogen synthase catalytic activity of GYS2: GSD-0 disease
      variants expressed in COS7 cells showed severely impaired activity, establishing GYS2 as
      the catalytic liver glycogen synthase.
    action: ACCEPT
    reason: >-
      The disease-mutation study functionally demonstrates that GYS2 encodes an active liver
      glycogen synthase whose activity is abolished/severely reduced by loss-of-function
      variants. Core catalytic function.
    supported_by:
    - reference_id: PMID:9691087
      supporting_text: >-
        Expression of the mutated enzymes in COS7 cells indicated severely impaired GS
        activity. In conclusion, the results demonstrate that GSD-0 is caused by different
        mutations in the GYS2 gene.
- term:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  evidence_type: IMP
  original_reference_id: PMID:9691087
  qualifier: enables
  review:
    summary: >-
      Mutational (IMP) evidence that GYS2 confers glycogen synthase activity: loss-of-function
      variants abolish enzyme activity in patients and in a heterologous expression assay.
    action: ACCEPT
    reason: >-
      Consistent with the EXP annotation from the same study; the impaired activity of GYS2
      mutants supports the core catalytic function assignment.
    supported_by:
    - reference_id: PMID:9691087
      supporting_text: >-
        GS activity in the liver of the affected children was extremely low or nil, resulting
        in subnormal glycogen content.
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:9691087
  qualifier: involved_in
  review:
    summary: >-
      Mutational evidence that GYS2 is required for hepatic glycogen biosynthesis: GYS2
      deficiency causes subnormal liver glycogen content (GSD type 0).
    action: ACCEPT
    reason: >-
      Loss of GYS2 function reduces hepatic glycogen synthesis, directly implicating the gene
      in the glycogen biosynthetic process. Core biological process.
    supported_by:
    - reference_id: PMID:9691087
      supporting_text: >-
        GS activity in the liver of the affected children was extremely low or nil, resulting
        in subnormal glycogen content.
- term:
    id: GO:0061547
    label: glycogen synthase activity, transferring glucose-1-phosphate
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3780994
  qualifier: enables
  review:
    summary: >-
      Reactome-curated minor activity in which GYS2 incorporates phosphoglucose into glycogen,
      the origin of glycogen phosphomonoesters.
    action: ACCEPT
    reason: >-
      Curated from the Reactome reaction describing GYS2-catalyzed incorporation of
      phosphoglucose into glycogen. This is a real, well-documented low-rate side activity of
      glycogen synthase; kept as a genuine molecular capability, minor relative to the core
      UDP-glucose donor elongation.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        Glycogen synthase 2 (GYS2) catalyzes the incorporation of phosphoglucose into the
        glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen granule.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3858506
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of cytosolic localization for GYS2.
    action: ACCEPT
    reason: >-
      GYS2 is a soluble cytosolic enzyme; cytosol is the correct compartment. This Reactome
      annotation derives from the GSD-0 (defective GYS2) reaction context.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322019
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of cytosolic localization for GYS2.
    action: ACCEPT
    reason: >-
      Duplicate cytosol assignment from a Reactome glycogen-synthesis reaction; correct
      compartment for this soluble enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322009
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of cytosolic localization for GYS2.
    action: ACCEPT
    reason: >-
      Duplicate cytosol assignment from a Reactome glycogen-synthesis reaction; correct
      compartment for this soluble enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322014
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of cytosolic localization for GYS2.
    action: ACCEPT
    reason: >-
      Duplicate cytosol assignment from a Reactome glycogen-synthesis reaction; correct
      compartment for this soluble enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322016
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of cytosolic localization for GYS2.
    action: ACCEPT
    reason: >-
      Duplicate cytosol assignment from a Reactome glycogen-synthesis reaction; correct
      compartment for this soluble enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3780994
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of cytosolic localization for GYS2.
    action: ACCEPT
    reason: >-
      Cytosol assignment from the Reactome GYS2 phosphoglucose-incorporation reaction, which
      explicitly places GYS2 in a cytosolic glycogen granule.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3780995
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of cytosolic localization for GYS2.
    action: ACCEPT
    reason: >-
      Duplicate cytosol assignment from a Reactome glycogen-metabolism reaction; correct
      compartment for this soluble enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3780997
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of cytosolic localization for GYS2.
    action: ACCEPT
    reason: >-
      Duplicate cytosol assignment from a Reactome glycogen-metabolism reaction; correct
      compartment for this soluble enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781011
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of cytosolic localization for GYS2.
    action: ACCEPT
    reason: >-
      Duplicate cytosol assignment from a Reactome glycogen-metabolism reaction; correct
      compartment for this soluble enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781021
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of cytosolic localization for GYS2.
    action: ACCEPT
    reason: >-
      Duplicate cytosol assignment from a Reactome glycogen-metabolism reaction; correct
      compartment for this soluble enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3878762
  qualifier: located_in
  review:
    summary: Reactome traceable assignment of cytosolic localization for GYS2.
    action: ACCEPT
    reason: >-
      Duplicate cytosol assignment from a Reactome glycogen-metabolism reaction; correct
      compartment for this soluble enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0009749
    label: response to glucose
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Response to glucose transferred by sequence similarity from the yeast glycogen synthase
      orthologue (Saccharomyces cerevisiae Gsy2, UniProtKB:P17625). Plausible for a
      glucose-storage enzyme but peripheral to the core catalytic role and not experimentally
      verified in human GYS2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Glycogen synthase activity is downstream of glucose availability and glucose-6-phosphate
      (its allosteric activator), so a role in the cellular response to glucose is biologically
      plausible. However, this is an ISS transfer from a distant fungal orthologue rather than a
      direct human observation, and it describes a regulatory/physiological context rather than
      the committed catalytic function; retained as a non-core annotation.
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: 'ACTIVITY REGULATION: Allosteric activation by glucose-6-phosphate'
- term:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Core glycogen synthase catalytic activity transferred by sequence similarity from the
      yeast orthologue; concordant with the human enzyme's characterized activity.
    action: ACCEPT
    reason: >-
      Consistent with the experimental, IBA, and IEA assignments of the core UDP-glucose:glycogen
      glucosyltransferase activity.
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: transfers the glycosyl residue from UDP-Glc to the non-reducing end of
- term:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  evidence_type: IDA
  original_reference_id: PMID:1731614
  qualifier: enables
  review:
    summary: >-
      Direct enzyme characterization of purified human liver glycogen synthase, establishing
      its UDP-glucose-dependent, glucose-6-phosphate-activated glycogen synthase activity.
    action: ACCEPT
    reason: >-
      Westphal and Nuttall purified human liver glycogen synthase to near homogeneity and
      characterized its kinetics for UDP-glucose and its activation by glucose-6-phosphate.
      This is direct experimental evidence for the core catalytic function of GYS2.
    supported_by:
    - reference_id: PMID:1731614
      supporting_text: >-
        The human enzyme, purified to near homogeneity, had a specific activity of 40 U/mg
        protein compared with 20 U/mg protein for the rat enzyme.
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: transfers the glycosyl residue from UDP-Glc to the non-reducing end of
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization transferred by sequence similarity from the yeast orthologue;
      correct broad compartment for this soluble enzyme.
    action: ACCEPT
    reason: >-
      Glycogen synthase is a soluble cytoplasmic/cytosolic enzyme. Cytoplasm is a correct,
      broader location; the more specific cytosol annotations are also retained.
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: heterooctamer composed of a tetramer of GS and 2 dimers of glycogenin,
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Cytosolic localization transferred by sequence similarity from the yeast orthologue;
      correct specific compartment.
    action: ACCEPT
    reason: >-
      Cytosol is the correct, specific compartment for GYS2 and is corroborated by TAS
      (Reactome), IEA, and the IBA cytoplasm annotations.
    supported_by:
    - reference_id: Reactome:R-HSA-3780994
      supporting_text: >-
        the glycogen-GYG1 molecules with which it is associated in a cytosolic glycogen
        granule
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Cytoskeleton localization transferred by sequence similarity from Saccharomyces cerevisiae
      glycogen synthase (Gsy2, UniProtKB:P17625). This reflects the fungal enzyme's association
      with cortical structures and is not supported for human liver GYS2.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is an ISS transfer from a distant fungal orthologue. Human liver GYS2 is a soluble
      cytosolic enzyme that assembles with glycogenin into the glycogen synthase-glycogenin
      complex; there is no experimental evidence that it is a cytoskeletal protein. The
      localization appears over-propagated from the yeast source rather than reflecting human
      biology.
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: heterooctamer composed of a tetramer of GS and 2 dimers of glycogenin,
- term:
    id: GO:0005938
    label: cell cortex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Cell cortex localization transferred by sequence similarity from yeast glycogen synthase
      (UniProtKB:P17625); not supported for human liver GYS2.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      As with the cytoskeleton and cortical actin cytoskeleton annotations, this is an ISS
      transfer from the fungal orthologue reflecting yeast-specific cortical association.
      Human GYS2 is a soluble cytosolic component of the glycogen synthase-glycogenin complex,
      with no evidence of cell cortex localization; over-annotation.
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: heterooctamer composed of a tetramer of GS and 2 dimers of glycogenin,
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Glycogen biosynthetic process transferred by sequence similarity from the yeast
      orthologue; correct core process for GYS2.
    action: ACCEPT
    reason: >-
      Redundant with the IBA/IDA/IMP/TAS glycogen biosynthesis annotations and correct for the
      committed glycogen elongation enzyme.
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: 'PATHWAY: Glycan biosynthesis; glycogen biosynthesis.'
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:1731614
  qualifier: involved_in
  review:
    summary: >-
      Direct characterization of purified human liver glycogen synthase supports its role in
      hepatic glycogen synthesis.
    action: ACCEPT
    reason: >-
      Westphal and Nuttall characterized the human liver enzyme and framed it as an important
      enzyme in liver glycogen synthesis, providing direct experimental support for
      involvement in the glycogen biosynthetic process.
    supported_by:
    - reference_id: PMID:1731614
      supporting_text: >-
        Since glycogen synthase is an important enzyme in liver glycogen synthesis, the
        characterization of this enzyme in the human will help provide insight regarding human
        liver glycogen synthesis.
- term:
    id: GO:0030864
    label: cortical actin cytoskeleton
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Cortical actin cytoskeleton localization transferred by sequence similarity from yeast
      glycogen synthase (UniProtKB:P17625); not supported for human liver GYS2.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This ISS transfer from the fungal orthologue reflects the yeast enzyme's association with
      cortical actin patches and does not represent human GYS2 biology. Human liver GYS2 is a
      soluble cytosolic enzyme; there is no evidence for cortical actin cytoskeleton
      localization. Over-propagated annotation from a distant orthologue.
    supported_by:
    - reference_id: file:human/GYS2/GYS2-uniprot.txt
      supporting_text: heterooctamer composed of a tetramer of GS and 2 dimers of glycogenin,
core_functions:
- description: >-
    Liver glycogen synthase: transfers glucose from UDP-glucose to the non-reducing end of a
    growing glycogen chain, forming alpha-1,4-glycosidic linkages, thereby elongating glycogen
    during hepatic glycogen storage.
  molecular_function:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  directly_involved_in:
  - id: GO:0005978
    label: glycogen biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:1731614
    supporting_text: >-
      the rat and human liver glycogen synthases were similar in their pH profile, in their
      kinetic constants for the substrate UDP-glucose and the activator glucose 6-phosphate
  - reference_id: file:human/GYS2/GYS2-uniprot.txt
    supporting_text: transfers the glycosyl residue from UDP-Glc to the non-reducing end of
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  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:1731614
  title: Comparative characterization of human and rat liver glycogen synthase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; abstract characterizes purified human liver glycogen synthase kinetics
      for UDP-glucose and glucose-6-phosphate activation. Supports the core catalytic MF and
      liver-specific expression. Full text not cached (abstract-only).
- id: PMID:9691087
  title: Mutations in the liver glycogen synthase gene in children with hypoglycemia
    due to glycogen storage disease type 0.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; identifies GYS2 mutations causing GSD type 0 and shows severely impaired
      GS activity of variants in COS7 cells, supporting the catalytic MF and glycogen
      biosynthetic process. Full text not cached (abstract-only).
- id: file:human/GYS2/GYS2-uniprot.txt
  title: UniProtKB entry P54840 (GYS2_HUMAN), Glycogen [starch] synthase, liver
  findings: []
- id: Reactome:R-HSA-3322009
  title: GYS2 catalyzes the polyglucosylation of oligoGlc-GYG2
  findings: []
- id: Reactome:R-HSA-3322014
  title: Autoglucosylation of GYG2 complexed with GYS2-a
  findings: []
- id: Reactome:R-HSA-3322016
  title: GBE1 catalyzes branch formation in polyGlc-GYG2 complexed with GYS2-a
  findings: []
- id: Reactome:R-HSA-3322019
  title: Autoglucosylation of GYG2 complexed with GYS2-b
  findings: []
- id: Reactome:R-HSA-3322077
  title: Glycogen synthesis
  findings: []
- id: Reactome:R-HSA-3780994
  title: GYS2 catalyzes the incorporation of phosphoglucose into glycogen-GYG2
  findings: []
- id: Reactome:R-HSA-3780995
  title: NHLRC1 mediated ubiquitination of EPM2A (laforin) and PPP1RC3 (PTG) associated
    with glycogen-GYG2
  findings: []
- id: Reactome:R-HSA-3780997
  title: PPP1R3C binds to glycogen:GYG2:GYS2
  findings: []
- id: Reactome:R-HSA-3781011
  title: EPM2A dimer dephosphorylates phosphoglycogen-GYG2
  findings: []
- id: Reactome:R-HSA-3781021
  title: EPM2A dimer binds PPP1R3C:phosphoglycogen-GYG2 complex
  findings: []
- id: Reactome:R-HSA-3858506
  title: Defective GYS2 does not transfer glucose to growing glycogen chains
  findings: []
- id: Reactome:R-HSA-3878762
  title: Defective GBE1 does not catalyze branch formation in growing glycogen chains
    (liver)
  findings: []