UniProt: P06737 (PYGL_HUMAN), 847 aa, HGNC:9725, chromosome 14. EC 2.4.1.1.
Core biology (from UniProt P06737 + literature)
- PYGL is the liver isoform of glycogen phosphorylase, the rate-limiting enzyme
of glycogenolysis. Homodimer; uses a pyridoxal-5'-phosphate (PLP) cofactor
covalently bound at Lys681 (FT MOD_RES 681 N6-(pyridoxal phosphate)lysine).
- Reaction (RHEA:41732, EC 2.4.1.1):
\[(1->4)-alpha-D-glucosyl](n) + phosphate =
\[(1->4)-alpha-D-glucosyl](n-1) + alpha-D-glucose 1-phosphate. Phosphorolyses
alpha-1,4 glycosidic bonds at glycogen non-reducing ends, releasing
glucose-1-phosphate; stops ~4 residues short of alpha-1,6 branch points (then AGL
debranches). PMID:22225877
- Allosterically activated by AMP (BINDING 43-45, 76, 310) and inhibited by ATP,
ADP and glucose-6-phosphate (UniProt ACTIVITY REGULATION). Covalent activation:
phosphorylase kinase (PHK) phosphorylates Ser15, converting inactive b form to
active a form; PP1 dephosphorylation inactivates it. [PMID:10949035; PMID:22225877]
- PMID:22225877 (Zhang 2012, full text): acetylation at K470/K796 negatively regulates
GP by recruiting PP1 via PPP1R3B/G_L; measured catalytic activity of purified human
GP; establishes EC 2.4.1.1 catalytic activity and PPP1R3B interaction. This is the
experimental basis for the EXP/IDA glycogen phosphorylase activity and
1,4-alpha-oligoglucan phosphorylase activity annotations.
- Subcellular location: Cytoplasm, cytosol (UniProt; ECO:0000305|PubMed:22225877).
Disease
- Glycogen storage disease type VI (GSD6 / Hers disease; MIM:232700): liver GP
deficiency → mild-to-moderate fasting hypoglycemia, mild ketosis, growth retardation,
prominent hepatomegaly; heart and skeletal muscle spared. Predominantly missense
mutations affecting enzyme activity. [PMID:9529348; PMID:17705025]
Annotation review reasoning
- Core MF: GO:0008184 glycogen phosphorylase activity (IBA/IDA/IMP/EXP all
converge). GO:0004645 (1,4-alpha-oligoglucan phosphorylase activity) is the
parent/EC-mapped term; ACCEPT (EXP-backed by PMID:22225877; IEA is EC/InterPro).
- Core BP: GO:0005980 glycogen catabolic process (IBA) — the precise process;
GO:0005977 glycogen metabolic process and GO:0005975 carbohydrate metabolic process
are correct-but-general parents (KEEP_AS_NON_CORE / accept as broad IEA).
- Core CC: GO:0005829 cytosol (IBA + IEA + Reactome TAS).
- Cofactor: GO:0030170 pyridoxal phosphate binding (IEA/InterPro) — ACCEPT; PLP is
the essential covalent cofactor (Lys681).
- Ligand-binding IDA terms (D-glucose, AMP, ATP, purine nucleobase, vitamin, bile acid
binding) come from crystallography of allosteric/inhibitor sites (PMID:10980448,
PMID:12204691, PMID:10949035; all abstract-only in cache). These are structurally
real but represent binding at allosteric/drug-discovery sites rather than the core
catalytic function; AMP binding is the physiological allosteric activator (core-ish),
while vitamin binding, bile acid binding, purine nucleobase binding are generic/
drug-screen-derived → MARK_AS_OVER_ANNOTATED. Defer to curator on full text (can't
REMOVE experimental annotations without reading full text).
protein binding (GO:0005515) IPIs (PMID:25416956, 25910212, 32296183, 33961781):
large-scale interactome maps; with/from = PYGB (P11216), PYGM (P11217) — glycogen
phosphorylase isoform homo/hetero association. Per policy: bare protein binding →
MARK_AS_OVER_ANNOTATED (uninformative), not REMOVE.identical protein binding (GO:0042802, IPI, PMID:10980448, with/from P06737):
homodimer — biologically real (UniProt SUBUNIT: Homodimer). ACCEPT.- Extracellular / secretory granule / ficolin granule / exosome localizations
(GO:0005576, GO:0034774, GO:1904813, GO:0070062): from Reactome neutrophil
degranulation module (TAS) and a prostate-exosome proteomics screen (HDA,
PMID:23533145). PYGL is a cytosolic enzyme; these are bystander/secretome-catalog
localizations, not sites of function → MARK_AS_OVER_ANNOTATED.
glucose homeostasis (GO:0042593, IMP, PMID:17705025): GSD6 phenotype (fasting
hypoglycemia) supports an organismal glucose-homeostasis role; KEEP_AS_NON_CORE
(systemic/physiological, downstream of the core enzymatic function).