GBE1

id: Q04446
gene_symbol: GBE1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: GBE1 is the human glycogen (1,4-alpha-glucan) branching enzyme (EC 2.4.1.18),
  a monomeric, cytosolic glycosyl hydrolase family 13 (GH13, GlgB subfamily) enzyme
  that acts in glycogen synthesis together with glycogenin and glycogen synthase.
  During glycogen biosynthesis it cleaves a segment of roughly six to seven glucose
  residues from the non-reducing end of a growing alpha-1,4-linked glucan chain and
  re-attaches it through an alpha-1,6-glucosidic linkage to an internal glucose, thereby
  introducing the branch points that define the compact, globular architecture of
  glycogen. Branching increases the solubility of the glycogen polymer and multiplies
  the number of non-reducing ends available to glycogen synthase and glycogen phosphorylase,
  regulating both the rate of synthesis and the accessibility of stored glucose. Loss
  of GBE1 activity causes the accumulation of a poorly branched, amylopectin-like polyglucosan.
  Recessive GBE1 deficiency causes glycogen storage disease type IV (GSD IV, Andersen
  disease), whose classic infantile hepatic form progresses to lethal cirrhosis, with
  additional neuromuscular subtypes; the milder late-onset adult polyglucosan body
  disease (APBD) presents after the fourth decade with neurogenic bladder, spastic
  paraparesis, and peripheral neuropathy.
existing_annotations:
- term:
    id: GO:0003844
    label: 1,4-alpha-glucan branching enzyme activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) annotation to the defining catalytic activity of GBE1,
      1,4-alpha-glucan branching enzyme activity (EC 2.4.1.18). This is the core molecular
      function of the gene and is independently supported by direct enzymatic and
      structural characterization of the human protein.
    action: ACCEPT
    reason: The branching-enzyme activity is the well-established, conserved core function
      of GBE1 orthologs across eukaryotes and is directly demonstrated for the human
      enzyme by X-ray crystallography and activity assays.
    supported_by:
    - reference_id: PMID:26199317
      supporting_text: Glycogen branching enzyme 1 (GBE1) plays an essential role
        in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked
        glucose chains, to increase solubility of the glycogen polymer.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) annotation placing GBE1 activity in the cytoplasm.
      GBE1 is a soluble cytosolic enzyme that acts on cytosolic glycogen granules.
      The more specific term cytosol (GO:0005829) is also annotated and is preferred
      for the core cellular location.
    action: MODIFY
    reason: The essence is correct (GBE1 is a cytoplasmic enzyme), but the general
      cytoplasm term should be refined to the more informative cytosol (GO:0005829),
      which is separately supported and captures the actual soluble cytosolic localization.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
    proposed_replacement_terms:
    - id: GO:0005829
      label: cytosol
    supported_by:
    - reference_id: Reactome:R-HSA-3878762
      supporting_text: cytosolic glycogen branching enzyme (GBE1) associated with
        glycogen granules
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) annotation to glycogen biosynthetic process, the core
      biological process in which GBE1 participates by introducing branch points during
      glycogen synthesis. Directly supported for the human enzyme.
    action: ACCEPT
    reason: GBE1 is one of the three enzymes (with glycogenin and glycogen synthase)
      that build glycogen; branch formation is an essential, conserved step of glycogen
      biosynthesis.
    supported_by:
    - reference_id: PMID:26199317
      supporting_text: In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis
        of the linear glucan chain (2), which is elongated by glycogen synthase (GYS,
        EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE,
        EC 2.4.1.18) to introduce side chains
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic annotation to the root-level term catalytic
      activity. GBE1 is a catalytic enzyme, so this is not wrong, but it is far less
      informative than the specific 1,4-alpha-glucan branching enzyme activity (GO:0003844)
      that is also annotated.
    action: MODIFY
    reason: Correct but uninformatively general; should be replaced by the specific
      catalytic activity term GO:0003844, which is directly supported experimentally.
    proposed_replacement_terms:
    - id: GO:0003844
      label: 1,4-alpha-glucan branching enzyme activity
    supported_by:
    - reference_id: PMID:26199317
      supporting_text: functioning in concert with glycogen branching enzyme (GBE,
        EC 2.4.1.18) to introduce side chains
- term:
    id: GO:0003844
    label: 1,4-alpha-glucan branching enzyme activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated (ARBA/UniRule + InterPro + EC 2.4.1.18) electronic annotation
      to the defining branching enzyme molecular function. Concordant with the experimental
      IDA/EXP and phylogenetic IBA annotations for the same term.
    action: ACCEPT
    reason: This electronic annotation correctly captures the core catalytic activity
      of GBE1 and is fully consistent with direct experimental characterization.
    supported_by:
    - reference_id: PMID:26199317
      supporting_text: Glycogen branching enzyme 1 (GBE1) plays an essential role
        in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked
        glucose chains
- term:
    id: GO:0004553
    label: hydrolase activity, hydrolyzing O-glycosyl compounds
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic annotation (Glyco_hydro_13_N domain, IPR004193)
      to O-glycosyl hydrolase activity. GBE1 belongs to the GH13 glycosyl hydrolase
      family and its reaction begins with an amylase-type hydrolytic cleavage of an
      alpha-1,4 glucan chain, but the biologically meaningful function is the coupled
      branching (transglucosylation) reaction, captured by GO:0003844. Standalone
      hydrolase annotation over-represents a partial mechanistic step.
    action: MARK_AS_OVER_ANNOTATED
    reason: The GH13 domain match legitimately confers a hydrolase-family signature,
      and GBE1 does perform an amylase-type hydrolytic cleavage as the first half-reaction;
      however, GBE1 is not a hydrolase in its physiological role (it transfers, rather
      than releases, the cleaved segment), so this domain-derived term over-annotates
      a mechanistic detail rather than the true molecular function.
    supported_by:
    - reference_id: PMID:26199317
      supporting_text: In the first reaction (amylase-type hydrolysis), GBE cleaves
        every 8–14 glucose residues of a glucan chain, an α-1,4-linked segment of
        more than six glucose units from the non-reducing end. In the second reaction
        (transglucosylation), it transfers the cleaved oligosaccharide (‘donor’),
        via an α-1,6-glucosidic linkage, to the C6 hydroxyl group of a glucose unit
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic annotation to the broad process carbohydrate
      metabolic process. Correct but general; GBE1's specific process is glycogen
      biosynthetic process (GO:0005978), which is separately annotated with experimental
      support.
    action: MODIFY
    reason: The term is correct in essence but too general. It should be refined to
      the specific glycogen biosynthetic process (GO:0005978), which is directly supported.
    proposed_replacement_terms:
    - id: GO:0005978
      label: glycogen biosynthetic process
    supported_by:
    - reference_id: PMID:26199317
      supporting_text: Glycogen branching enzyme 1 (GBE1) plays an essential role
        in glycogen biosynthesis
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Automated (ARBA/UniRule + UniPathway UPA00164) electronic annotation
      to glycogen biosynthetic process, concordant with the experimental IDA and phylogenetic
      IBA annotations for the same term.
    action: ACCEPT
    reason: Correctly captures the core biological process of GBE1 and agrees with
      the direct experimental evidence.
    supported_by:
    - reference_id: PMID:26199317
      supporting_text: GBE1) plays an essential role in glycogen biosynthesis
- term:
    id: GO:0043169
    label: cation binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic annotation (alpha-amylase/branching_C domain,
      IPR006048) to cation binding. This is a generic prediction inherited from the
      broader alpha-amylase family, many members of which bind Ca2+/Cl-. There is
      no evidence that human GBE1 requires or binds a catalytic cation; the crystal
      structures and UniProt record describe no bound metal or cation-binding site,
      and the catalytic mechanism uses the conserved Asp357-Glu412-Asp481 triad without
      a metal cofactor.
    action: REMOVE
    reason: The cation binding term is an over-propagated electronic inference from
      the alpha-amylase family signature. Human GBE1 has three high-resolution structures
      (PDB 4BZY, 5CLT, 5CLW) and detailed mechanistic analysis with no cation-binding
      site or metal-dependent activity reported, and UniProt annotates no cofactor;
      the term is therefore likely incorrect for this protein.
    supported_by:
    - reference_id: PMID:26199317
      supporting_text: this constellation of three acidic residues functions as the
        nucleophile (Asp357, hGBE1 numbering hereinafter), proton donor (Glu412) and
        transition state stabilizer (Asp481) in the active site
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36217029
  qualifier: enables
  review:
    summary: IPI annotation from a proteome-scale SARS-CoV-2 host contactome, recording
      a binary interaction between GBE1 and the SARS-CoV-2 replicase polyprotein cleavage
      product (WITH/FROM UniProtKB:P0DTD1-PRO_0000449633, viral 'rep'). This is a
      generic protein binding term supported only by a high-throughput viral-host
      interaction screen and is uninformative about GBE1's native molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The bare protein binding term is uninformative and derives from a xenobiotic
      viral-host interaction screen rather than a physiological binding partner; per
      curation guidelines this generic IPI is marked as over-annotated rather than
      retained as a core function. It is not removed because the interaction datum
      itself is a validly recorded experimental observation.
    supported_by:
    - reference_id: PMID:36217029
      supporting_text: A proteome-scale map of the SARS-CoV-2-human contactome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: is_active_in
  review:
    summary: Automated (ARBA/UniRule) electronic annotation placing GBE1 activity
      in the cytosol. This agrees with the Reactome TAS cytosol annotations and with
      GBE1's biology as a soluble cytosolic enzyme acting on cytosolic glycogen granules.
    action: ACCEPT
    reason: Correctly captures the core subcellular location of the active enzyme;
      concordant with independent Reactome and structural evidence that GBE1 is a
      soluble cytosolic protein.
    supported_by:
    - reference_id: Reactome:R-HSA-3878762
      supporting_text: cytosolic glycogen branching enzyme (GBE1) associated with
        glycogen granules transfers terminal alpha(1,4) glucose blocks to form alpha(1,6)
        branches
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322077
  qualifier: involved_in
  review:
    summary: Reactome TAS annotation (Glycogen synthesis pathway) to glycogen biosynthetic
      process. GBE1 catalyzes the branch-formation reaction that is one of the three
      reactions unique to glycogen synthesis, making this a well-supported core process
      annotation.
    action: ACCEPT
    reason: Authoritative pathway-based (TAS) support for GBE1's core role in glycogen
      biosynthesis; concordant with experimental IDA and IBA annotations.
    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:0003844
    label: 1,4-alpha-glucan branching enzyme activity
  evidence_type: EXP
  original_reference_id: PMID:8613547
  qualifier: enables
  review:
    summary: Experimental (EXP) annotation to the defining branching enzyme molecular
      function, based on transient-expression GBE activity assays of wild-type and
      disease-mutant human GBE cDNA. GSD IV mutations (R515C, F257L, L224P) inactivated
      GBE activity while Y329S retained ~50%, directly linking this protein to branching
      enzyme activity.
    action: ACCEPT
    reason: Direct experimental demonstration that the human GBE gene product possesses,
      and disease mutations abolish, 1,4-alpha-glucan branching enzyme activity; this
      is a core function annotation.
    supported_by:
    - reference_id: PMID:8613547
      supporting_text: Transient expression experiments showed that these mutations
        inactivated GBE activity.
- term:
    id: GO:0003844
    label: 1,4-alpha-glucan branching enzyme activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3878762
  qualifier: enables
  review:
    summary: Reactome TAS annotation (from the GSD IV disease reaction, in which defective
      GBE1 fails to catalyze branch formation) to 1,4-alpha-glucan branching enzyme
      activity. Reinforces the core catalytic function via pathway knowledge.
    action: ACCEPT
    reason: Authoritative pathway-based support for the branching enzyme activity as
      GBE1's core molecular function; consistent with experimental evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-3878762
      supporting_text: cytosolic glycogen branching enzyme (GBE1) associated with
        glycogen granules transfers terminal alpha(1,4) glucose blocks to form alpha(1,6)
        branches on growing glycogen molecules
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS annotation (by sequence similarity to UniProtKB:P32775, yeast GLC3
      branching enzyme) placing GBE1 in the cytoplasm. Correct in essence, but the
      more specific and separately supported cytosol (GO:0005829) is the preferred
      core location term.
    action: MODIFY
    reason: GBE1 is indeed cytoplasmic, but the annotation should be refined to the
      more informative cytosol (GO:0005829), consistent with Reactome and the soluble
      nature of the enzyme.
    proposed_replacement_terms:
    - id: GO:0005829
      label: cytosol
    supported_by:
    - reference_id: Reactome:R-HSA-3878762
      supporting_text: cytosolic glycogen branching enzyme (GBE1)
- term:
    id: GO:0003844
    label: 1,4-alpha-glucan branching enzyme activity
  evidence_type: IDA
  original_reference_id: PMID:26199317
  qualifier: enables
  review:
    summary: Direct assay (IDA) annotation to 1,4-alpha-glucan branching enzyme activity,
      from structural and biochemical characterization of recombinant human GBE1 (PDB
      4BZY/5CLT/5CLW) including activity measurements on wild-type and Y329S protein.
      This is the strongest evidence for the core molecular function.
    action: ACCEPT
    reason: Definitive experimental demonstration of the branching enzyme activity
      of the human protein, with an X-ray structure of the catalytic core and quantitative
      activity assays; core function.
    supported_by:
    - reference_id: PMID:26199317
      supporting_text: The GBE1 structure reveals a conserved amylase core that houses
        the active centre for the branching reaction
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:26199317
  qualifier: involved_in
  review:
    summary: Direct assay (IDA) annotation to glycogen biosynthetic process, from
      the structural/biochemical study establishing GBE1's essential branching role
      in glycogen biosynthesis. Core process annotation.
    action: ACCEPT
    reason: Experimentally grounded assignment of GBE1 to its core biological process;
      consistent with pathway and phylogenetic annotations.
    supported_by:
    - reference_id: PMID:26199317
      supporting_text: Glycogen branching enzyme 1 (GBE1) plays an essential role
        in glycogen biosynthesis
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24837458
  qualifier: enables
  review:
    summary: IPI annotation (WITH/FROM UniProtKB:O95210, STBD1) recording that GBE1
      co-immunoprecipitates with STBD1, a glycogen-associated carbohydrate-binding
      protein, in a study of STBD1's protein interactions. This is a physiologically
      plausible glycogen-hub interaction, but the bare protein binding term is uninformative
      about GBE1's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term does not convey GBE1's function and is
      supported only by a co-immunoprecipitation in a study focused on STBD1; per
      curation guidelines the bare IPI is marked as over-annotated rather than removed,
      since the underlying interaction with a glycogen-associated protein is a validly
      recorded observation.
    supported_by:
    - reference_id: PMID:24837458
      supporting_text: co-immunoprecipitation experiments demonstrated that HA–STBD1
        could bind to FLAG-tagged Laforin, GBE1 and GDE
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: High-throughput mass-spectrometry (HDA) detection of GBE1 in exosomes
      isolated from expressed prostatic secretions in urine. GBE1 is a soluble cytosolic
      glycogen-metabolizing enzyme; its detection in a large proteomic catalog of
      exosomes reflects the well-known tendency of abundant cytosolic proteins to
      appear in exosome/EV proteomes and does not indicate a functional extracellular
      localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is a bulk-proteomics localization that conflicts with the strong,
      consistent cytosolic assignment of GBE1 from structure, Reactome, and orthology.
      It is retained as an over-annotation (common contaminant signal in exosome proteomes)
      rather than a core or functional cellular component.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: In-depth proteomic analyses of exosomes isolated from expressed
        prostatic secretions in urine.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput mass-spectrometry (HDA) detection of GBE1 among 1132
      proteins profiled in the human urinary exosome proteome. As above, this reflects
      the recurrent appearance of abundant cytosolic enzymes in exosome proteomes
      rather than a functional extracellular localization of the cytosolic branching
      enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bulk exosome-proteomics detection that contradicts the well-established
      cytosolic localization of GBE1; retained as an over-annotation rather than a
      core cellular component.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: we used LC-MS/MS to profile the proteome of human urinary exosomes
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322005
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol, from a reaction modeling GBE1 branch
      formation on polyGlc-GYG1 complexed with GYS1-a. Consistent with the soluble
      cytosolic localization of GBE1 acting on cytosolic glycogen granules.
    action: ACCEPT
    reason: Authoritative pathway-based support for the core cytosolic localization;
      concordant with structural and orthology evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-3878762
      supporting_text: cytosolic glycogen branching enzyme (GBE1) associated with
        glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322016
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol, from a reaction modeling GBE1 branch
      formation on polyGlc-GYG2 complexed with GYS2-a (liver isozyme context). Consistent
      with GBE1's cytosolic localization.
    action: ACCEPT
    reason: Authoritative pathway-based support for the core cytosolic localization
      of GBE1.
    supported_by:
    - reference_id: Reactome:R-HSA-3878762
      supporting_text: cytosolic glycogen branching enzyme (GBE1) associated with
        glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322057
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol, from a reaction modeling GBE1 branch
      formation on polyGlc-GYG1 complexed with GYS1-b. Consistent with GBE1's cytosolic
      localization.
    action: ACCEPT
    reason: Authoritative pathway-based support for the core cytosolic localization
      of GBE1.
    supported_by:
    - reference_id: Reactome:R-HSA-3878762
      supporting_text: cytosolic glycogen branching enzyme (GBE1) associated with
        glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3878762
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol, from the GSD IV disease reaction
      in which defective GBE1 fails to catalyze branch formation. Confirms the core
      cytosolic localization of the enzyme.
    action: ACCEPT
    reason: Authoritative pathway-based support for the core cytosolic localization
      of GBE1.
    supported_by:
    - reference_id: Reactome:R-HSA-3878762
      supporting_text: Normally, cytosolic glycogen branching enzyme (GBE1) associated
        with glycogen granules transfers terminal alpha(1,4) glucose blocks
- term:
    id: GO:0003844
    label: 1,4-alpha-glucan branching enzyme activity
  evidence_type: TAS
  original_reference_id: PMID:8613547
  qualifier: enables
  review:
    summary: Traceable author statement (TAS) annotation to 1,4-alpha-glucan branching
      enzyme activity, from the study characterizing GSD IV disease mutations by expression
      and GBE activity assays. Reinforces the core catalytic function.
    action: ACCEPT
    reason: Well-supported statement of GBE1's core molecular function; the same paper
      provides direct experimental (EXP) evidence via activity assays.
    supported_by:
    - reference_id: PMID:8613547
      supporting_text: Glycogen storage disease type IV (GSD-IV) is an autosomal recessive
        disease resulting from deficient glycogen-branching enzyme (GBE) activity.
- term:
    id: GO:0005977
    label: glycogen metabolic process
  evidence_type: TAS
  original_reference_id: PMID:8613547
  qualifier: involved_in
  review:
    summary: Traceable author statement (TAS) annotation to the parent process glycogen
      metabolic process. Correct but more general than the specific glycogen biosynthetic
      process (GO:0005978) that GBE1 directly participates in, which is separately
      annotated with experimental support.
    action: MODIFY
    reason: The term is correct in essence but too general; GBE1 acts specifically
      in glycogen biosynthesis (branch formation during synthesis), so the annotation
      should be refined to glycogen biosynthetic process (GO:0005978).
    proposed_replacement_terms:
    - id: GO:0005978
      label: glycogen biosynthetic process
    supported_by:
    - reference_id: PMID:8613547
      supporting_text: resulting from deficient glycogen-branching enzyme (GBE) activity
- term:
    id: GO:0006091
    label: generation of precursor metabolites and energy
  evidence_type: TAS
  original_reference_id: PMID:8613547
  qualifier: involved_in
  review:
    summary: Traceable author statement (TAS) annotation to the very broad process
      generation of precursor metabolites and energy. This reflects glycogen's general
      role as an energy store, but the term is too general and not specific to GBE1's
      molecular contribution (branch formation during glycogen biosynthesis).
    action: MODIFY
    reason: Over-general process term. GBE1's role is in building the glycogen store
      (a biosynthetic/anabolic step), not directly in energy generation; the annotation
      is better represented by glycogen biosynthetic process (GO:0005978).
    proposed_replacement_terms:
    - id: GO:0005978
      label: glycogen biosynthetic process
    supported_by:
    - reference_id: PMID:8613547
      supporting_text: Glycogen storage disease type IV (GSD-IV) is an autosomal recessive
        disease resulting from deficient glycogen-branching enzyme (GBE) activity.
core_functions:
- description: Catalyzes the formation of alpha-1,6-glucosidic branch points during
    glycogen biosynthesis by cleaving a segment from the non-reducing end of an alpha-1,4-linked
    glucan chain and transferring it to an internal glucose, increasing glycogen solubility
    and the number of non-reducing ends.
  molecular_function:
    id: GO:0003844
    label: 1,4-alpha-glucan branching enzyme activity
  directly_involved_in:
  - id: GO:0005978
    label: glycogen biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:26199317
    supporting_text: Glycogen branching enzyme 1 (GBE1) plays an essential role in
      glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked
      glucose chains, to increase solubility of the glycogen polymer.
  - reference_id: Reactome:R-HSA-3878762
    supporting_text: cytosolic glycogen branching enzyme (GBE1) associated with glycogen
      granules transfers terminal alpha(1,4) glucose blocks to form alpha(1,6) branches
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- 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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Bulk urinary-exosome proteomics catalog; GBE1 appears among 1132
      identified proteins. Supports only the (over-annotated) exosome localization,
      not GBE1 function.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Bulk exosome proteomics from prostatic-secretion urine; supports
      only the over-annotated extracellular exosome localization.
- id: PMID:24837458
  title: The carbohydrate-binding domain of overexpressed STBD1 is important for its
    stability and protein-protein interactions.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Study of STBD1; GBE1 co-immunoprecipitates with STBD1 (Fig. 4A),
      a glycogen-associated protein. Supports a plausible glycogen-hub interaction
      but only the generic protein binding term.
- id: PMID:26199317
  title: Structural basis of glycogen branching enzyme deficiency and pharmacologic
    rescue by rational peptide design.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Crystal structures of human GBE1 (PDB 4BZY/5CLT/5CLW) with mechanistic
      and activity analysis; the definitive primary source for GBE1's branching enzyme
      activity, monomeric state, catalytic triad, and disease mutations.
- id: PMID:36217029
  title: A proteome-scale map of the SARS-CoV-2-human contactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput viral-host interaction screen; records a GBE1-SARS-CoV-2
      rep binary interaction. Supports only the generic (over-annotated) protein binding
      term, not native function.
- id: PMID:8613547
  title: Hepatic and neuromuscular forms of glycogen storage disease type IV caused
    by mutations in the same glycogen-branching enzyme gene.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary human GBE1 genetics/biochemistry paper; expression assays
      show GSD IV mutations inactivate GBE activity. Supports core branching enzyme
      activity and the GSD IV disease association.
- id: Reactome:R-HSA-3322005
  title: GBE1 catalyzes branch formation in polyGlc-GYG1 complexed with GYS1-a
  findings: []
- id: Reactome:R-HSA-3322016
  title: GBE1 catalyzes branch formation in polyGlc-GYG2 complexed with GYS2-a
  findings: []
- id: Reactome:R-HSA-3322057
  title: GBE1 catalyzes branch formation in polyGlc-GYG1 complexed with GYS1-b
  findings: []
- id: Reactome:R-HSA-3322077
  title: Glycogen synthesis
  findings: []
- id: Reactome:R-HSA-3878762
  title: Defective GBE1 does not catalyze branch formation in growing glycogen chains
    (liver)
  findings: []