GBE1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003844 1,4-alpha-glucan branching enzyme activity	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:26199317 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.
GO:0005737 cytoplasm	IBA GO_REF:0000033	MODIFY	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. 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 replacements: cytosol Supporting Evidence: Reactome:R-HSA-3878762 cytosolic glycogen branching enzyme (GBE1) associated with glycogen granules
GO:0005978 glycogen biosynthetic process	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:26199317 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
GO:0003824 catalytic activity	IEA GO_REF:0000002	MODIFY	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. Reason: Correct but uninformatively general; should be replaced by the specific catalytic activity term GO:0003844, which is directly supported experimentally. Proposed replacements: 1,4-alpha-glucan branching enzyme activity Supporting Evidence: PMID:26199317 functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains
GO:0003844 1,4-alpha-glucan branching enzyme activity	IEA GO_REF:0000120	ACCEPT	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. Reason: This electronic annotation correctly captures the core catalytic activity of GBE1 and is fully consistent with direct experimental characterization. Supporting Evidence: PMID:26199317 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
GO:0004553 hydrolase activity, hydrolyzing O-glycosyl compounds	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:26199317 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
GO:0005975 carbohydrate metabolic process	IEA GO_REF:0000002	MODIFY	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. 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 replacements: glycogen biosynthetic process Supporting Evidence: PMID:26199317 Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis
GO:0005978 glycogen biosynthetic process	IEA GO_REF:0000120	ACCEPT	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. Reason: Correctly captures the core biological process of GBE1 and agrees with the direct experimental evidence. Supporting Evidence: PMID:26199317 GBE1) plays an essential role in glycogen biosynthesis
GO:0043169 cation binding	IEA GO_REF:0000002	REMOVE	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. 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. Supporting Evidence: PMID:26199317 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
GO:0005515 protein binding	IPI PMID:36217029 A proteome-scale map of the SARS-CoV-2-human contactome.	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:36217029 A proteome-scale map of the SARS-CoV-2-human contactome
GO:0005829 cytosol	IEA GO_REF:0000120	ACCEPT	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. 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. Supporting Evidence: Reactome:R-HSA-3878762 cytosolic glycogen branching enzyme (GBE1) associated with glycogen granules transfers terminal alpha(1,4) glucose blocks to form alpha(1,6) branches
GO:0005978 glycogen biosynthetic process	TAS Reactome:R-HSA-3322077	ACCEPT	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. Reason: Authoritative pathway-based (TAS) support for GBE1's core role in glycogen biosynthesis; concordant with experimental IDA and IBA annotations. Supporting Evidence: Reactome:R-HSA-3322077 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
GO:0003844 1,4-alpha-glucan branching enzyme activity	EXP PMID:8613547 Hepatic and neuromuscular forms of glycogen storage disease ...	ACCEPT	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. 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. Supporting Evidence: PMID:8613547 Transient expression experiments showed that these mutations inactivated GBE activity.
GO:0003844 1,4-alpha-glucan branching enzyme activity	TAS Reactome:R-HSA-3878762	ACCEPT	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. Reason: Authoritative pathway-based support for the branching enzyme activity as GBE1's core molecular function; consistent with experimental evidence. Supporting Evidence: Reactome:R-HSA-3878762 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
GO:0005737 cytoplasm	ISS GO_REF:0000024	MODIFY	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. 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 replacements: cytosol Supporting Evidence: Reactome:R-HSA-3878762 cytosolic glycogen branching enzyme (GBE1)
GO:0003844 1,4-alpha-glucan branching enzyme activity	IDA PMID:26199317 Structural basis of glycogen branching enzyme deficiency and...	ACCEPT	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. 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. Supporting Evidence: PMID:26199317 The GBE1 structure reveals a conserved amylase core that houses the active centre for the branching reaction
GO:0005978 glycogen biosynthetic process	IDA PMID:26199317 Structural basis of glycogen branching enzyme deficiency and...	ACCEPT	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. Reason: Experimentally grounded assignment of GBE1 to its core biological process; consistent with pathway and phylogenetic annotations. Supporting Evidence: PMID:26199317 Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis
GO:0005515 protein binding	IPI PMID:24837458 The carbohydrate-binding domain of overexpressed STBD1 is im...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:24837458 co-immunoprecipitation experiments demonstrated that HA–STBD1 could bind to FLAG-tagged Laforin, GBE1 and GDE
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:23533145 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:19056867 we used LC-MS/MS to profile the proteome of human urinary exosomes
GO:0005829 cytosol	TAS Reactome:R-HSA-3322005	ACCEPT	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. Reason: Authoritative pathway-based support for the core cytosolic localization; concordant with structural and orthology evidence. Supporting Evidence: Reactome:R-HSA-3878762 cytosolic glycogen branching enzyme (GBE1) associated with glycogen granules
GO:0005829 cytosol	TAS Reactome:R-HSA-3322016	ACCEPT	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. Reason: Authoritative pathway-based support for the core cytosolic localization of GBE1. Supporting Evidence: Reactome:R-HSA-3878762 cytosolic glycogen branching enzyme (GBE1) associated with glycogen granules
GO:0005829 cytosol	TAS Reactome:R-HSA-3322057	ACCEPT	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. Reason: Authoritative pathway-based support for the core cytosolic localization of GBE1. Supporting Evidence: Reactome:R-HSA-3878762 cytosolic glycogen branching enzyme (GBE1) associated with glycogen granules
GO:0005829 cytosol	TAS Reactome:R-HSA-3878762	ACCEPT	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. Reason: Authoritative pathway-based support for the core cytosolic localization of GBE1. Supporting Evidence: Reactome:R-HSA-3878762 Normally, cytosolic glycogen branching enzyme (GBE1) associated with glycogen granules transfers terminal alpha(1,4) glucose blocks
GO:0003844 1,4-alpha-glucan branching enzyme activity	TAS PMID:8613547 Hepatic and neuromuscular forms of glycogen storage disease ...	ACCEPT	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. Reason: Well-supported statement of GBE1's core molecular function; the same paper provides direct experimental (EXP) evidence via activity assays. Supporting Evidence: PMID:8613547 Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease resulting from deficient glycogen-branching enzyme (GBE) activity.
GO:0005977 glycogen metabolic process	TAS PMID:8613547 Hepatic and neuromuscular forms of glycogen storage disease ...	MODIFY	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. 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 replacements: glycogen biosynthetic process Supporting Evidence: PMID:8613547 resulting from deficient glycogen-branching enzyme (GBE) activity
GO:0006091 generation of precursor metabolites and energy	TAS PMID:8613547 Hepatic and neuromuscular forms of glycogen storage disease ...	MODIFY	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). 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 replacements: glycogen biosynthetic process Supporting Evidence: PMID:8613547 Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease resulting from deficient glycogen-branching enzyme (GBE) activity.

Gene Description

Existing Annotations Review

Core Functions

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.

References

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