PYGM

UniProt ID: P11217
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

Muscle isoform of glycogen phosphorylase (myophosphorylase; EC 2.4.1.1), the rate-limiting enzyme of muscle glycogenolysis. As a pyridoxal-5'-phosphate-dependent homodimer it catalyzes the phosphorolytic cleavage of alpha-1,4-glycosidic bonds at the non-reducing ends of glycogen, releasing alpha-D-glucose-1-phosphate, and stops approximately four residues short of alpha-1,6 branch points. This provides the glucose-1-phosphate (feeding glycolysis via glucose-6-phosphate) that supports rapid ATP generation in skeletal muscle during exercise. Activity is allosterically activated by AMP and inhibited by ATP, ADP and glucose-6-phosphate, and is controlled covalently through reversible phosphorylation of Ser-15 by phosphorylase kinase, interconverting the less-active phosphorylase b and the active phosphorylase a. The enzyme is cytosolic and highly enriched in skeletal muscle. Loss-of-function variants cause glycogen storage disease type V (McArdle disease), a myopathy of exercise intolerance, cramps, muscle weakness and recurrent myoglobinuria, characteristically with a "second-wind" phenomenon.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005829 cytosol
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetically inferred cytosolic localization. Muscle glycogen phosphorylase is a soluble cytosolic enzyme that acts on cytoplasmic glycogen particles, consistent with the TAS/Reactome cytosol annotations below.
Reason: Correct subcellular localization for a cytosolic glycogenolytic enzyme; the IBA call is concordant with independent Reactome TAS annotations to the same term.
GO:0005980 glycogen catabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetically inferred role in glycogen catabolism. This is the central biological process of muscle glycogen phosphorylase, which performs the rate-limiting phosphorolytic step of glycogen breakdown.
Reason: Core biological process, well supported by experimental IDA/IMP annotations on this gene and by the enzyme's defined catalytic activity.
GO:0008184 glycogen phosphorylase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetically inferred glycogen phosphorylase activity, the defining molecular function of PYGM (EC 2.4.1.1).
Reason: Core molecular function; concordant with experimental IDA/IMP annotations and UniProt's experimentally supported catalytic activity.
GO:0004645 1,4-alpha-oligoglucan phosphorylase activity
IEA
GO_REF:0000120 		MODIFY
Summary: Electronically inferred alpha-1,4-glucan phosphorylase activity (the parent EC 2.4.1.1 activity encompassing glycogen phosphorylase). Correct in essence; the more specific and experimentally supported term for this enzyme is GO:0008184 glycogen phosphorylase activity.
Reason: The activity is real but GO:0008184 glycogen phosphorylase activity is the more precise term for the muscle isoform acting physiologically on glycogen; both terms map to the same EC 2.4.1.1 reaction. Retain the specific term as the core molecular function.
Proposed replacements: glycogen phosphorylase activity
GO:0005975 carbohydrate metabolic process
IEA
GO_REF:0000002 		MODIFY
Summary: Broad InterPro-derived carbohydrate metabolism term. Not incorrect, but far less informative than the specific glycogen catabolic process annotation.
Reason: Over-general parent term; the specific process for this enzyme is GO:0005980 glycogen catabolic process, which is already annotated experimentally.
Proposed replacements: glycogen catabolic process
GO:0008184 glycogen phosphorylase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronically inferred glycogen phosphorylase activity, matching the experimentally established core molecular function.
Reason: Correct core molecular function; consistent with IBA, IDA, IMP and TAS annotations to the same term.
GO:0030170 pyridoxal phosphate binding
IEA
GO_REF:0000002 		ACCEPT
Summary: Pyridoxal-5'-phosphate (PLP) is the essential cofactor of glycogen phosphorylase, covalently attached via a Schiff base to Lys-681, where it participates in the phosphorolysis catalytic mechanism.
Reason: Well supported by UniProt (COFACTOR pyridoxal 5'-phosphate; MOD_RES 681 N6-(pyridoxal phosphate)lysine) and by the conserved PLP-binding site of the glycogen phosphorylase family. Retained as a core cofactor-binding function.
Supporting Evidence:
file:human/PYGM/PYGM-uniprot.txt
Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326;
GO:0005515 protein binding
IPI
PMID:24722188
Protein interaction network of alternatively spliced isoform... 		MARK AS OVER ANNOTATED
Summary: Interaction detected in a high-throughput isoform interactome screen (interactor PRKAB2, an AMPK regulatory subunit). "Protein binding" is an uninformative molecular function that does not describe the catalytic role of PYGM.
Reason: Bare GO:0005515 protein binding conveys no specific functional information and derives from a large-scale interactome dataset. The AMPK-subunit interaction may be biologically relevant to metabolic regulation but is better captured by a specific term than by "protein binding". Retained but flagged as over-annotated per curation guidelines discouraging bare protein binding.
Supporting Evidence:
PMID:24722188
Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		MARK AS OVER ANNOTATED
Summary: Interactions (PRKAB2, NTAQ1) detected in a proteome-scale human interactome map. Bare "protein binding" is uninformative for this enzyme's function.
Reason: Derived from a systematic proteome-scale interactome screen; GO:0005515 does not describe a specific molecular function. Retained but flagged as over-annotated.
Supporting Evidence:
PMID:25416956
A proteome-scale map of the human interactome network.
GO:0005515 protein binding
IPI
PMID:31515488
Extensive disruption of protein interactions by genetic vari... 		MARK AS OVER ANNOTATED
Summary: Interaction (NTAQ1) reported in a systematic study of interaction disruption by genetic variants. Bare "protein binding" is uninformative.
Reason: High-throughput binary interaction data; GO:0005515 conveys no specific function. Retained but flagged as over-annotated.
Supporting Evidence:
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		MARK AS OVER ANNOTATED
Summary: Interactions (PRKAB2, and the phosphorylase paralogs PYGL and PYGB) detected in the HuRI binary interactome map. Bare "protein binding" is uninformative.
Reason: Systematic binary interactome dataset; several partners are paralogous phosphorylases (isoenzyme cross-detection). GO:0005515 conveys no specific molecular function. Retained but flagged as over-annotated.
Supporting Evidence:
PMID:32296183
A reference map of the human binary protein interactome.
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: Interaction (PYGB, brain phosphorylase paralog) detected in a proteome-scale cell-specific interactome study. Bare "protein binding" is uninformative.
Reason: High-throughput affinity-purification interactome data; GO:0005515 conveys no specific function. Retained but flagged as over-annotated.
Supporting Evidence:
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding
IPI
PMID:36217029
A proteome-scale map of the SARS-CoV-2-human contactome. 		MARK AS OVER ANNOTATED
Summary: Interaction with a SARS-CoV-2 viral protein (rep/nsp12) reported in a virus-host contactome screen. Bare "protein binding", involving a xeno (viral) partner, is uninformative for PYGM's physiological function.
Reason: Viral-host high-throughput interaction dataset; not indicative of a native molecular function of PYGM and captured only as bare protein binding. Retained but flagged as over-annotated.
Supporting Evidence:
PMID:36217029
A proteome-scale map of the SARS-CoV-2-human contactome.
GO:0004645 1,4-alpha-oligoglucan phosphorylase activity
EXP
PMID:1150650
Regulation of glycogen phosphorylase. Role of the peptide re... 		MODIFY
Summary: Experimental characterization of skeletal muscle glycogen phosphorylase catalytic and regulatory properties (AMP activation, glucose-6-P inhibition, phosphorylase b to a interconversion). This is the EC 2.4.1.1 alpha-1,4-glucan phosphorylase activity of the enzyme.
Reason: Experimentally supported activity, but GO:0008184 glycogen phosphorylase activity is the more precise term for the physiological substrate (glycogen) of the muscle isoform. Both correspond to EC 2.4.1.1. Do not remove an experimental annotation; refine to the specific term.
Proposed replacements: glycogen phosphorylase activity
Supporting Evidence:
PMID:1150650
derived from the NH2-terminal region of skeletal muscle glycogen phosphorylase
GO:0004645 1,4-alpha-oligoglucan phosphorylase activity
EXP
PMID:8316268
Molecular genetic heterogeneity of myophosphorylase deficien... 		MODIFY
Summary: Functional/catalytic-activity evidence associated with molecular-genetic characterization of myophosphorylase (McArdle disease). Represents the EC 2.4.1.1 alpha-1,4-glucan phosphorylase activity of PYGM.
Reason: Correct activity but better represented by the specific term GO:0008184 glycogen phosphorylase activity for this muscle isoform. Experimental annotation refined, not removed.
Proposed replacements: glycogen phosphorylase activity
Supporting Evidence:
PMID:8316268
The myophosphorylase gene has been sequenced and assigned to chromosome 11
GO:0005980 glycogen catabolic process
IDA
PMID:1150650
Regulation of glycogen phosphorylase. Role of the peptide re... 		ACCEPT
Summary: Direct experimental evidence for the role of skeletal muscle glycogen phosphorylase in glycogen breakdown, via characterization of its catalytic and allosteric properties.
Reason: Core biological process supported by direct assay of the muscle enzyme's phosphorolytic activity and its regulation.
Supporting Evidence:
PMID:1150650
induce the enzymic properties of phosphorylase a
GO:0005980 glycogen catabolic process
IMP
PMID:8316268
Molecular genetic heterogeneity of myophosphorylase deficien... 		ACCEPT
Summary: Mutational (McArdle disease) evidence linking loss of myophosphorylase function to impaired muscle glycogen catabolism. Loss-of-function PYGM variants cause a block in glycogenolysis (GSD5).
Reason: Core biological process; disease-causing loss-of-function variants demonstrate the enzyme's requirement for muscle glycogen breakdown.
Supporting Evidence:
PMID:8316268
exercise intolerance, muscle cramps, and recurrent
GO:0008184 glycogen phosphorylase activity
IDA
PMID:1150650
Regulation of glycogen phosphorylase. Role of the peptide re... 		ACCEPT
Summary: Direct assay of skeletal muscle glycogen phosphorylase activity, including its allosteric regulation (AMP activation, cooperative binding, glucose-6-P inhibition) and phosphorylase b to a interconversion.
Reason: Core molecular function with direct experimental support in the muscle enzyme.
Supporting Evidence:
PMID:1150650
the enzyme, normally present as a dimer, associates to a
GO:0008184 glycogen phosphorylase activity
IMP
PMID:8316268
Molecular genetic heterogeneity of myophosphorylase deficien... 		ACCEPT
Summary: Loss of glycogen phosphorylase activity resulting from disease-causing PYGM mutations (McArdle disease) demonstrates that this gene enables glycogen phosphorylase activity in muscle.
Reason: Core molecular function; genotype-phenotype evidence supports the enzymatic role of PYGM.
Supporting Evidence:
PMID:8316268
The myophosphorylase gene has been sequenced and assigned to chromosome 11
GO:0070062 extracellular exosome
HDA
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expres... 		MARK AS OVER ANNOTATED
Summary: PYGM was detected by shotgun mass spectrometry among ~900 proteins in exosomes purified from expressed prostatic secretions in urine. This is a high-throughput proteomic co-detection, not evidence of a functional extracellular/exosomal role for this cytosolic muscle enzyme.
Reason: Common high-throughput exosome-proteomics detection of an abundant cytosolic protein; it does not reflect the site where PYGM performs its function (cytosolic glycogenolysis). Flagged as over-annotated rather than removed, per policy for experimental (HDA) detection.
Supporting Evidence:
PMID:23533145
exosome preparations were characterized by a shotgun proteomics procedure
GO:0005829 cytosol
TAS
Reactome:R-HSA-453338 		ACCEPT
Summary: Reactome-curated cytosolic localization of the PYGM b dimer (AMP-complex reaction). Correct localization for this soluble glycogenolytic enzyme.
Reason: Correct core localization; concordant with the IBA cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-453342 		ACCEPT
Summary: Reactome-curated cytosolic localization of the PYGM b dimer (AMP-binding reaction). Correct localization.
Reason: Correct core localization; concordant with the IBA and other TAS cytosol annotations.
GO:0005829 cytosol
TAS
Reactome:R-HSA-71541 		ACCEPT
Summary: Reactome-curated cytosolic localization of PYGM associated with its phosphorylation (b to a conversion) by the cytosolic phosphorylase kinase complex.
Reason: Correct core localization; the enzyme and its activating kinase act in the cytosol.
GO:0005977 glycogen metabolic process
TAS
PMID:9633816
Molecular diagnosis of McArdle disease: revised genomic stru... 		MODIFY
Summary: Traceable author statement placing myophosphorylase in glycogen metabolism. Correct but general; the specific role of PYGM is in the catabolic branch (glycogen breakdown).
Reason: The broad glycogen metabolic process is a parent of the more precise GO:0005980 glycogen catabolic process, which is already experimentally annotated and better reflects PYGM's directional (glycogenolytic) role.
Proposed replacements: glycogen catabolic process
Supporting Evidence:
PMID:9633816
caused by mutations in the muscle glycogen phosphorylase gene
GO:0008184 glycogen phosphorylase activity
TAS
PMID:9633816
Molecular diagnosis of McArdle disease: revised genomic stru... 		ACCEPT
Summary: Traceable author statement supporting the glycogen phosphorylase activity of myophosphorylase, in the context of McArdle disease molecular diagnosis.
Reason: Core molecular function; concordant with the experimental IDA/IMP and IBA/IEA annotations to the same term.
Supporting Evidence:
PMID:9633816
caused by mutations in the muscle glycogen phosphorylase gene

Core Functions

Muscle glycogen phosphorylase catalyzes the rate-limiting phosphorolytic cleavage of alpha-1,4-glycosidic bonds at glycogen non-reducing ends, releasing glucose-1-phosphate, using a covalently bound pyridoxal-5'-phosphate cofactor.

Molecular Function:
glycogen phosphorylase activity
Supporting Evidence:
  • PMID:1150650
    induce the enzymic properties of phosphorylase a
  • file:human/PYGM/PYGM-uniprot.txt
    EC=2.4.1.1 {ECO:0000269|PubMed:1150650, ECO:0000269|PubMed:8316268}

The enzyme performs the committed, rate-limiting step of muscle glycogenolysis, mobilizing stored glycogen to supply glucose-1-phosphate for glycolytic ATP production during exercise; its loss causes McArdle disease.

Molecular Function:
glycogen phosphorylase activity
Directly Involved In:
glycogen catabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:8316268
    exercise intolerance, muscle cramps, and recurrent
  • file:human/PYGM/PYGM-uniprot.txt
    catalyzes the rate-limiting step in

Glycogen phosphorylase requires pyridoxal-5'-phosphate as an essential cofactor, covalently bound via a Schiff base to an active-site lysine (Lys-681), for catalysis.

Molecular Function:
pyridoxal phosphate binding
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/PYGM/PYGM-uniprot.txt
    Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326;

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:1150650
Regulation of glycogen phosphorylase. Role of the peptide region surrounding the phosphoserine residue in determining enzyme properties.
  • Skeletal muscle glycogen phosphorylase is regulated through phosphorylation of its N-terminal region (phosphorylase b to a), AMP allosteric activation, glucose-6-P inhibition, and dimer-to-tetramer association.
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
  • PYGM was among ~900 proteins detected by shotgun proteomics in urinary prostatic-secretion exosomes; a high-throughput co-detection, not a functional localization.
PMID:24722188
Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:36217029
A proteome-scale map of the SARS-CoV-2-human contactome.
PMID:8316268
Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's disease).
  • Loss-of-function mutations in the muscle glycogen phosphorylase gene cause McArdle disease, a common cause of exercise intolerance, muscle cramps, and recurrent myoglobinuria.
PMID:9633816
Molecular diagnosis of McArdle disease: revised genomic structure of the myophosphorylase gene and identification of a novel mutation.
  • McArdle disease is an autosomal recessive disorder of muscle glycogen metabolism caused by mutations in the muscle glycogen phosphorylase gene.
Reactome:R-HSA-453338
PYGM b dimer:AMP complex => PYGM dimer, b form + 2 AMP
Reactome:R-HSA-453342
PYGM dimer, b form + 2 AMP => PYGM b dimer:AMP complex
Reactome:R-HSA-71541
glycogen phosphorylase (PYGM) dimer b + 2 ATP => glycogen phosphorylase (PYGM) dimer a + 2 ADP

📚 Additional Documentation

Notes

(PYGM-notes.md)

PYGM (muscle glycogen phosphorylase) — review notes

UniProtKB:P11217, HGNC:9726, EC 2.4.1.1, 842 aa.

Core biology (from UniProt P11217 + task brief)

  • Muscle isoform of glycogen phosphorylase; rate-limiting enzyme of muscle glycogenolysis.
  • Catalyzes phosphorolytic cleavage of alpha-1,4 glycosidic bonds at glycogen non-reducing
    ends, releasing alpha-D-glucose-1-phosphate (Rhea:RHEA:41732, EC 2.4.1.1). Stops ~4 residues
    from alpha-1,6 branch points.
    [file:UniProt CATALYTIC ACTIVITY, "Reaction=(1->4)-alpha-D-glucosyl + phosphate = (1->4)-alpha-D-glucosyl + alpha-D-glucose 1-phosphate"]
  • Cofactor: pyridoxal 5'-phosphate (PLP) covalently attached at Lys-681
    [file:UniProt COFACTOR "Name=pyridoxal 5'-phosphate"; MOD_RES 681 "N6-(pyridoxal phosphate)lysine"].
  • Homodimer (phosphorylase b); homotetramer for active phosphorylase A
    [file:UniProt SUBUNIT "Homodimer ... Homotetramer; to form the enzymatically active phosphorylase A"].
  • Allosteric enzyme: activated by AMP; inhibited by ATP, ADP, glucose-6-phosphate
    [file:UniProt ACTIVITY REGULATION "activated by AMP and inhibited by ATP, ADP, and glucose-6-phosphate"].
  • Covalent regulation: phosphorylation of Ser-15 by phosphorylase kinase (PHK) converts
    phosphorylase b (inactive) → phosphorylase a (active)
    [file:UniProt PTM "Phosphorylation of Ser-15 converts phosphorylase B (unphosphorylated) to phosphorylase A"].
  • Cytosolic. Expressed skeletal-muscle-enriched (HPA: skeletal muscle, tongue).

Disease

  • GSD5 / McArdle disease [MIM:232600]: exercise intolerance, cramps, muscle weakness,
    recurrent myoglobinuria (rhabdomyolysis), "second wind" phenomenon.
    [file:UniProt DISEASE "myopathy characterized by exercise intolerance, cramps, muscle weakness and recurrent myoglobinuria"]

Key experimental refs (cached)

  • PMID:1150650 (Carty, Tu, Graves 1975): CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBUNIT,
    phosphorylation at Ser-15. Abstract confirms phosphorylase b/a interconversion, AMP
    regulation, dimer→tetramer association, glucose-6-P inhibition. Abstract-only. Basis of
    UniProt EC=2.4.1.1 experimental evidence and the IDA glycogen phosphorylase activity /
    glycogen catabolic process annotations.
  • PMID:8316268 (Tsujino, Shanske, DiMauro 1993 NEJM): McArdle disease molecular genetics;
    UniProt tags this as FUNCTION + CATALYTIC ACTIVITY + GSD5 variants (R50X truncation, G205S,
    K543T). IMP for glycogen phosphorylase activity / glycogen catabolic process. Abstract-only.
  • PMID:9633816 (Kubisch 1998): revised genomic structure of myophosphorylase gene, McArdle
    diagnosis. TAS source (ProtInc/PINC) for glycogen phosphorylase activity + glycogen
    metabolic process. Abstract is about genomic structure/mutation but paper concerns the
    muscle glycogen phosphorylase gene — TAS annotation to the enzyme's activity/process is
    appropriate.

Localization annotations

  • GO:0005829 cytosol — IBA + 3x TAS(Reactome). Correct; cytosolic enzyme.
  • GO:0070062 extracellular exosome — HDA, PMID:23533145 (prostatic-secretion exosome
    proteomics). High-throughput MS detection in secreted vesicles; not the site of catalytic
    function. MARK_AS_OVER_ANNOTATED (per policy, not REMOVE for HDA MS detection).

Protein binding IPIs (all GO:0005515, IPI, IntAct)

Large-scale interactome / IntAct screens. Bare "protein binding" is uninformative per
curation guidelines → MARK_AS_OVER_ANNOTATED (not REMOVE, per policy).
- PMID:24722188 O43741 (PRKAB2, AMPK beta2 subunit)
- PMID:25416956 O43741 (PRKAB2), Q96HA8 (NTAQ1)
- PMID:31515488 Q96HA8 (NTAQ1)
- PMID:32296183 O43741 (PRKAB2), P06737 (PYGL, liver phosphorylase), P11216 (PYGB, brain phosphorylase)
- PMID:33961781 P11216 (PYGB)
- PMID:36217029 P0DTD1-PRO_0000449633 (SARS-CoV-2 nsp12/rep; xeno)
UniProt INTERACTION lists PRKAB2, NTAQ1, PYGB, PYGL, and SARS-CoV-2 rep as interactors.
PRKAB2 (AMPK) interaction is biologically plausible (glycogen metabolism regulation); PYGB/PYGL
are paralogs (isoenzyme heterodimer detection in HT screens). None are informative MF terms.

Core functions (author-supplied, strictly validated)

  • MF: GO:0008184 glycogen phosphorylase activity
  • BP (directly_involved_in): GO:0005980 glycogen catabolic process
  • CC (locations): GO:0005829 cytosol
  • cofactor / MF: GO:0030170 pyridoxal phosphate binding

📄 View Raw YAML

 
id: P11217
gene_symbol: PYGM
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Muscle isoform of glycogen phosphorylase (myophosphorylase; EC 2.4.1.1),
  the rate-limiting enzyme of muscle glycogenolysis. As a pyridoxal-5'-phosphate-dependent
  homodimer it catalyzes the phosphorolytic cleavage of alpha-1,4-glycosidic bonds at
  the non-reducing ends of glycogen, releasing alpha-D-glucose-1-phosphate, and stops
  approximately four residues short of alpha-1,6 branch points. This provides the
  glucose-1-phosphate (feeding glycolysis via glucose-6-phosphate) that supports rapid
  ATP generation in skeletal muscle during exercise. Activity is allosterically activated
  by AMP and inhibited by ATP, ADP and glucose-6-phosphate, and is controlled covalently
  through reversible phosphorylation of Ser-15 by phosphorylase kinase, interconverting
  the less-active phosphorylase b and the active phosphorylase a. The enzyme is cytosolic
  and highly enriched in skeletal muscle. Loss-of-function variants cause glycogen storage
  disease type V (McArdle disease), a myopathy of exercise intolerance, cramps, muscle
  weakness and recurrent myoglobinuria, characteristically with a "second-wind" phenomenon.
alternative_products:
- name: '1'
  id: P11217-1
- name: '2'
  id: P11217-2
  sequence_note: VSP_043047
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetically inferred cytosolic localization. Muscle glycogen phosphorylase
      is a soluble cytosolic enzyme that acts on cytoplasmic glycogen particles, consistent
      with the TAS/Reactome cytosol annotations below.
    action: ACCEPT
    reason: Correct subcellular localization for a cytosolic glycogenolytic enzyme; the
      IBA call is concordant with independent Reactome TAS annotations to the same term.
- term:
    id: GO:0005980
    label: glycogen catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetically inferred role in glycogen catabolism. This is the central
      biological process of muscle glycogen phosphorylase, which performs the rate-limiting
      phosphorolytic step of glycogen breakdown.
    action: ACCEPT
    reason: Core biological process, well supported by experimental IDA/IMP annotations
      on this gene and by the enzyme's defined catalytic activity.
- term:
    id: GO:0008184
    label: glycogen phosphorylase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically inferred glycogen phosphorylase activity, the defining
      molecular function of PYGM (EC 2.4.1.1).
    action: ACCEPT
    reason: Core molecular function; concordant with experimental IDA/IMP annotations
      and UniProt's experimentally supported catalytic activity.
- term:
    id: GO:0004645
    label: 1,4-alpha-oligoglucan phosphorylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronically inferred alpha-1,4-glucan phosphorylase activity (the parent
      EC 2.4.1.1 activity encompassing glycogen phosphorylase). Correct in essence; the
      more specific and experimentally supported term for this enzyme is GO:0008184
      glycogen phosphorylase activity.
    action: MODIFY
    reason: The activity is real but GO:0008184 glycogen phosphorylase activity is the
      more precise term for the muscle isoform acting physiologically on glycogen; both
      terms map to the same EC 2.4.1.1 reaction. Retain the specific term as the core
      molecular function.
    proposed_replacement_terms:
    - id: GO:0008184
      label: glycogen phosphorylase activity
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Broad InterPro-derived carbohydrate metabolism term. Not incorrect, but
      far less informative than the specific glycogen catabolic process annotation.
    action: MODIFY
    reason: Over-general parent term; the specific process for this enzyme is
      GO:0005980 glycogen catabolic process, which is already annotated experimentally.
    proposed_replacement_terms:
    - id: GO:0005980
      label: glycogen catabolic process
- term:
    id: GO:0008184
    label: glycogen phosphorylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronically inferred glycogen phosphorylase activity, matching the
      experimentally established core molecular function.
    action: ACCEPT
    reason: Correct core molecular function; consistent with IBA, IDA, IMP and TAS
      annotations to the same term.
- term:
    id: GO:0030170
    label: pyridoxal phosphate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Pyridoxal-5'-phosphate (PLP) is the essential cofactor of glycogen
      phosphorylase, covalently attached via a Schiff base to Lys-681, where it
      participates in the phosphorolysis catalytic mechanism.
    action: ACCEPT
    reason: Well supported by UniProt (COFACTOR pyridoxal 5'-phosphate; MOD_RES 681
      N6-(pyridoxal phosphate)lysine) and by the conserved PLP-binding site of the
      glycogen phosphorylase family. Retained as a core cofactor-binding function.
    supported_by:
    - reference_id: file:human/PYGM/PYGM-uniprot.txt
      supporting_text: "Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326;"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24722188
  qualifier: enables
  review:
    summary: Interaction detected in a high-throughput isoform interactome screen
      (interactor PRKAB2, an AMPK regulatory subunit). "Protein binding" is an
      uninformative molecular function that does not describe the catalytic role of PYGM.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare GO:0005515 protein binding conveys no specific functional information
      and derives from a large-scale interactome dataset. The AMPK-subunit interaction may
      be biologically relevant to metabolic regulation but is better captured by a specific
      term than by "protein binding". Retained but flagged as over-annotated per curation
      guidelines discouraging bare protein binding.
    supported_by:
    - reference_id: PMID:24722188
      supporting_text: Protein interaction network of alternatively spliced isoforms from
        brain links genetic risk factors for autism.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Interactions (PRKAB2, NTAQ1) detected in a proteome-scale human interactome
      map. Bare "protein binding" is uninformative for this enzyme's function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Derived from a systematic proteome-scale interactome screen; GO:0005515 does
      not describe a specific molecular function. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Interaction (NTAQ1) reported in a systematic study of interaction disruption
      by genetic variants. Bare "protein binding" is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput binary interaction data; GO:0005515 conveys no specific
      function. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants
        across the allele frequency spectrum in human populations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Interactions (PRKAB2, and the phosphorylase paralogs PYGL and PYGB) detected
      in the HuRI binary interactome map. Bare "protein binding" is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Systematic binary interactome dataset; several partners are paralogous
      phosphorylases (isoenzyme cross-detection). GO:0005515 conveys no specific molecular
      function. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Interaction (PYGB, brain phosphorylase paralog) detected in a proteome-scale
      cell-specific interactome study. Bare "protein binding" is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput affinity-purification interactome data; GO:0005515 conveys no
      specific function. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the
        human interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36217029
  qualifier: enables
  review:
    summary: Interaction with a SARS-CoV-2 viral protein (rep/nsp12) reported in a
      virus-host contactome screen. Bare "protein binding", involving a xeno (viral)
      partner, is uninformative for PYGM's physiological function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Viral-host high-throughput interaction dataset; not indicative of a native
      molecular function of PYGM and captured only as bare protein binding. Retained but
      flagged as over-annotated.
    supported_by:
    - reference_id: PMID:36217029
      supporting_text: A proteome-scale map of the SARS-CoV-2-human contactome.
- term:
    id: GO:0004645
    label: 1,4-alpha-oligoglucan phosphorylase activity
  evidence_type: EXP
  original_reference_id: PMID:1150650
  qualifier: enables
  review:
    summary: Experimental characterization of skeletal muscle glycogen phosphorylase
      catalytic and regulatory properties (AMP activation, glucose-6-P inhibition,
      phosphorylase b to a interconversion). This is the EC 2.4.1.1 alpha-1,4-glucan
      phosphorylase activity of the enzyme.
    action: MODIFY
    reason: Experimentally supported activity, but GO:0008184 glycogen phosphorylase
      activity is the more precise term for the physiological substrate (glycogen) of the
      muscle isoform. Both correspond to EC 2.4.1.1. Do not remove an experimental
      annotation; refine to the specific term.
    proposed_replacement_terms:
    - id: GO:0008184
      label: glycogen phosphorylase activity
    supported_by:
    - reference_id: PMID:1150650
      supporting_text: derived from the NH2-terminal region of skeletal muscle glycogen
        phosphorylase
- term:
    id: GO:0004645
    label: 1,4-alpha-oligoglucan phosphorylase activity
  evidence_type: EXP
  original_reference_id: PMID:8316268
  qualifier: enables
  review:
    summary: Functional/catalytic-activity evidence associated with molecular-genetic
      characterization of myophosphorylase (McArdle disease). Represents the EC 2.4.1.1
      alpha-1,4-glucan phosphorylase activity of PYGM.
    action: MODIFY
    reason: Correct activity but better represented by the specific term GO:0008184
      glycogen phosphorylase activity for this muscle isoform. Experimental annotation
      refined, not removed.
    proposed_replacement_terms:
    - id: GO:0008184
      label: glycogen phosphorylase activity
    supported_by:
    - reference_id: PMID:8316268
      supporting_text: The myophosphorylase gene has been sequenced and assigned to
        chromosome 11
- term:
    id: GO:0005980
    label: glycogen catabolic process
  evidence_type: IDA
  original_reference_id: PMID:1150650
  qualifier: involved_in
  review:
    summary: Direct experimental evidence for the role of skeletal muscle glycogen
      phosphorylase in glycogen breakdown, via characterization of its catalytic and
      allosteric properties.
    action: ACCEPT
    reason: Core biological process supported by direct assay of the muscle enzyme's
      phosphorolytic activity and its regulation.
    supported_by:
    - reference_id: PMID:1150650
      supporting_text: induce the enzymic properties of phosphorylase a
- term:
    id: GO:0005980
    label: glycogen catabolic process
  evidence_type: IMP
  original_reference_id: PMID:8316268
  qualifier: involved_in
  review:
    summary: Mutational (McArdle disease) evidence linking loss of myophosphorylase
      function to impaired muscle glycogen catabolism. Loss-of-function PYGM variants
      cause a block in glycogenolysis (GSD5).
    action: ACCEPT
    reason: Core biological process; disease-causing loss-of-function variants demonstrate
      the enzyme's requirement for muscle glycogen breakdown.
    supported_by:
    - reference_id: PMID:8316268
      supporting_text: exercise intolerance, muscle cramps, and recurrent
- term:
    id: GO:0008184
    label: glycogen phosphorylase activity
  evidence_type: IDA
  original_reference_id: PMID:1150650
  qualifier: enables
  review:
    summary: Direct assay of skeletal muscle glycogen phosphorylase activity, including
      its allosteric regulation (AMP activation, cooperative binding, glucose-6-P
      inhibition) and phosphorylase b to a interconversion.
    action: ACCEPT
    reason: Core molecular function with direct experimental support in the muscle enzyme.
    supported_by:
    - reference_id: PMID:1150650
      supporting_text: the enzyme, normally present as a dimer, associates to a
- term:
    id: GO:0008184
    label: glycogen phosphorylase activity
  evidence_type: IMP
  original_reference_id: PMID:8316268
  qualifier: enables
  review:
    summary: Loss of glycogen phosphorylase activity resulting from disease-causing PYGM
      mutations (McArdle disease) demonstrates that this gene enables glycogen
      phosphorylase activity in muscle.
    action: ACCEPT
    reason: Core molecular function; genotype-phenotype evidence supports the enzymatic
      role of PYGM.
    supported_by:
    - reference_id: PMID:8316268
      supporting_text: The myophosphorylase gene has been sequenced and assigned to
        chromosome 11
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: PYGM was detected by shotgun mass spectrometry among ~900 proteins in
      exosomes purified from expressed prostatic secretions in urine. This is a
      high-throughput proteomic co-detection, not evidence of a functional
      extracellular/exosomal role for this cytosolic muscle enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: Common high-throughput exosome-proteomics detection of an abundant cytosolic
      protein; it does not reflect the site where PYGM performs its function (cytosolic
      glycogenolysis). Flagged as over-annotated rather than removed, per policy for
      experimental (HDA) detection.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: exosome preparations were characterized by a shotgun proteomics
        procedure
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-453338
  qualifier: located_in
  review:
    summary: Reactome-curated cytosolic localization of the PYGM b dimer (AMP-complex
      reaction). Correct localization for this soluble glycogenolytic enzyme.
    action: ACCEPT
    reason: Correct core localization; concordant with the IBA cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-453342
  qualifier: located_in
  review:
    summary: Reactome-curated cytosolic localization of the PYGM b dimer (AMP-binding
      reaction). Correct localization.
    action: ACCEPT
    reason: Correct core localization; concordant with the IBA and other TAS cytosol
      annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71541
  qualifier: located_in
  review:
    summary: Reactome-curated cytosolic localization of PYGM associated with its
      phosphorylation (b to a conversion) by the cytosolic phosphorylase kinase complex.
    action: ACCEPT
    reason: Correct core localization; the enzyme and its activating kinase act in the
      cytosol.
- term:
    id: GO:0005977
    label: glycogen metabolic process
  evidence_type: TAS
  original_reference_id: PMID:9633816
  qualifier: involved_in
  review:
    summary: Traceable author statement placing myophosphorylase in glycogen metabolism.
      Correct but general; the specific role of PYGM is in the catabolic branch (glycogen
      breakdown).
    action: MODIFY
    reason: The broad glycogen metabolic process is a parent of the more precise
      GO:0005980 glycogen catabolic process, which is already experimentally annotated and
      better reflects PYGM's directional (glycogenolytic) role.
    proposed_replacement_terms:
    - id: GO:0005980
      label: glycogen catabolic process
    supported_by:
    - reference_id: PMID:9633816
      supporting_text: caused by mutations in the muscle glycogen phosphorylase gene
- term:
    id: GO:0008184
    label: glycogen phosphorylase activity
  evidence_type: TAS
  original_reference_id: PMID:9633816
  qualifier: enables
  review:
    summary: Traceable author statement supporting the glycogen phosphorylase activity of
      myophosphorylase, in the context of McArdle disease molecular diagnosis.
    action: ACCEPT
    reason: Core molecular function; concordant with the experimental IDA/IMP and IBA/IEA
      annotations to the same term.
    supported_by:
    - reference_id: PMID:9633816
      supporting_text: caused by mutations in the muscle glycogen phosphorylase gene
core_functions:
- description: Muscle glycogen phosphorylase catalyzes the rate-limiting phosphorolytic
    cleavage of alpha-1,4-glycosidic bonds at glycogen non-reducing ends, releasing
    glucose-1-phosphate, using a covalently bound pyridoxal-5'-phosphate cofactor.
  molecular_function:
    id: GO:0008184
    label: glycogen phosphorylase activity
  supported_by:
  - reference_id: PMID:1150650
    supporting_text: induce the enzymic properties of phosphorylase a
  - reference_id: file:human/PYGM/PYGM-uniprot.txt
    supporting_text: "EC=2.4.1.1 {ECO:0000269|PubMed:1150650, ECO:0000269|PubMed:8316268}"
- description: The enzyme performs the committed, rate-limiting step of muscle
    glycogenolysis, mobilizing stored glycogen to supply glucose-1-phosphate for
    glycolytic ATP production during exercise; its loss causes McArdle disease.
  molecular_function:
    id: GO:0008184
    label: glycogen phosphorylase activity
  directly_involved_in:
  - id: GO:0005980
    label: glycogen catabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:8316268
    supporting_text: exercise intolerance, muscle cramps, and recurrent
  - reference_id: file:human/PYGM/PYGM-uniprot.txt
    supporting_text: catalyzes the rate-limiting step in
- description: Glycogen phosphorylase requires pyridoxal-5'-phosphate as an essential
    cofactor, covalently bound via a Schiff base to an active-site lysine (Lys-681),
    for catalysis.
  molecular_function:
    id: GO:0030170
    label: pyridoxal phosphate binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/PYGM/PYGM-uniprot.txt
    supporting_text: "Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326;"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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:1150650
  title: Regulation of glycogen phosphorylase. Role of the peptide region surrounding
    the phosphoserine residue in determining enzyme properties.
  findings:
  - statement: Skeletal muscle glycogen phosphorylase is regulated through phosphorylation
      of its N-terminal region (phosphorylase b to a), AMP allosteric activation,
      glucose-6-P inhibition, and dimer-to-tetramer association.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; abstract-only. Supports catalytic activity, allosteric
      regulation, and the homodimer subunit structure of the muscle enzyme (UniProt cites
      it for CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBUNIT, and Ser-15 phosphorylation).
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings:
  - statement: PYGM was among ~900 proteins detected by shotgun proteomics in urinary
      prostatic-secretion exosomes; a high-throughput co-detection, not a functional
      localization.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. High-throughput exosome proteomics; supports only
      the (over-annotated) extracellular exosome detection, not a functional role.
- id: PMID:24722188
  title: Protein interaction network of alternatively spliced isoforms from brain
    links genetic risk factors for autism.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Large-scale isoform interactome; source of an
      uninformative bare protein binding IPI (PRKAB2).
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Proteome-scale interactome screen; source of bare
      protein binding IPIs (PRKAB2, NTAQ1).
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Systematic interaction-perturbation study; source of
      a bare protein binding IPI (NTAQ1).
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (HuRI). Binary interactome map; source of bare protein
      binding IPIs, several with paralogous phosphorylases (PYGL, PYGB).
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Proteome-scale interactome study; source of a bare
      protein binding IPI (PYGB paralog).
- id: PMID:36217029
  title: A proteome-scale map of the SARS-CoV-2-human contactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Virus-host contactome; source of a bare (xeno) protein
      binding IPI with SARS-CoV-2 rep, not a native function.
- id: PMID:8316268
  title: Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's
    disease).
  findings:
  - statement: Loss-of-function mutations in the muscle glycogen phosphorylase gene cause
      McArdle disease, a common cause of exercise intolerance, muscle cramps, and recurrent
      myoglobinuria.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; abstract-only. Establishes PYGM loss-of-function as the
      cause of McArdle disease (GSD5) and underpins the FUNCTION/CATALYTIC ACTIVITY and
      IMP glycogen-catabolism annotations.
- id: PMID:9633816
  title: 'Molecular diagnosis of McArdle disease: revised genomic structure of the
    myophosphorylase gene and identification of a novel mutation.'
  findings:
  - statement: McArdle disease is an autosomal recessive disorder of muscle glycogen
      metabolism caused by mutations in the muscle glycogen phosphorylase gene.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; abstract-only. Focused on genomic structure and mutation
      detection; TAS source for glycogen phosphorylase activity and glycogen metabolic
      process.
- id: Reactome:R-HSA-453338
  title: PYGM b dimer:AMP complex => PYGM dimer, b form + 2 AMP
  findings: []
- id: Reactome:R-HSA-453342
  title: PYGM dimer, b form + 2 AMP => PYGM b dimer:AMP complex
  findings: []
- id: Reactome:R-HSA-71541
  title: glycogen phosphorylase (PYGM) dimer b + 2 ATP => glycogen phosphorylase (PYGM)
    dimer a + 2 ADP
  findings: []