Affinage

PYGL

Glycogen phosphorylase, liver form · UniProt P06737

Length
847 aa
Mass
97.1 kDa
Annotated
2026-04-28
19 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PYGL encodes the liver isoform of glycogen phosphorylase, a key enzyme that catalyzes glycogen breakdown to glucose-1-phosphate, coupling hepatic glycogen stores to glycolytic flux and downstream metabolic pathways. Its enzymatic activity is regulated post-translationally by O-GlcNAcylation at Ser430, which promotes and is mutually reinforcing with activating phosphorylation at Ser15 (PMID:34939084); transcriptionally, PYGL is induced by HIF1α under hypoxia (PMID:37063425, PMID:39525037, PMID:38545181), by FOXO3a (PMID:35439639), and by the P2Y12–AhR signaling axis (PMID:41974649), while its promoter is subject to DNA methylation-dependent silencing (PMID:34673295) and its mRNA is directly targeted by miR-155-5p (PMID:35611851). Loss-of-function mutations in PYGL cause glycogen storage disease type VI (Hers disease), characterized by impaired hepatic glycogenolysis (PMID:9529348). Beyond its canonical metabolic role, PYGL-driven glycogenolysis fuels glycolysis to promote epithelial–mesenchymal transition in pancreatic cancer (PMID:37063425), modulates apoptosis in glioma (PMID:39525037), contributes to drug resistance in renal cell carcinoma and breast cancer (PMID:38545181, PMID:41974649), and sustains NADPH oxidase–dependent inflammatory signaling (PMID:32126244).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 High

    Establishing that PYGL encodes the liver glycogen phosphorylase and that its loss of function causes glycogen storage disease type VI (Hers disease) defined the gene's essential enzymatic role in hepatic glycogenolysis.

    Evidence Mutation screening in GSD VI families identifying missense (N338S, N376K) and splice-site mutations at conserved residues

    PMID:9529348

    Open questions at the time
    • Crystal structure–activity relationships for the identified mutants not determined
    • Genotype–phenotype severity correlation not established
  2. 2020 Medium

    Demonstrating that PYGL activity fuels NADPH oxidase–dependent oxidative stress and NF-κB–driven inflammation in vivo revealed a non-canonical role for glycogenolysis in innate immune signaling.

    Evidence Pharmacological inhibition of Pygl in zebrafish skin inflammation models with measurement of neutrophil infiltration and NF-κB activity

    PMID:32126244

    Open questions at the time
    • Mechanism by which glycogen-derived metabolites specifically activate NADPH oxidase not defined
    • Not validated in mammalian immune cells
  3. 2021 Medium

    Showing that maternal diet causes Pygl promoter hypermethylation with consequent reduced expression and glycogen/lipid accumulation in offspring liver established epigenetic regulation as a major control layer for PYGL expression.

    Evidence Mouse maternal high-fat/high-sucrose diet model with bisulfite sequencing of Pygl promoter and rescue by uncarboxylated osteocalcin via CREBH/ATF4

    PMID:34673295

    Open questions at the time
    • Whether DNA methylation changes are reversible postnatally not tested
    • Direct binding of CREBH/ATF4 to Pygl promoter not shown by ChIP
  4. 2022 High

    Identifying O-GlcNAcylation at Ser430 as a post-translational activator of PYGL that cross-talks with Ser15 phosphorylation revealed a nutrient-sensing mechanism integrating hexosamine biosynthesis with glycogenolysis.

    Evidence O-GlcNAc mapping and Ser430 mutagenesis in HEK293T/HCT116 cells with enzymatic activity assays under glucose, insulin, glucagon, and hypoxia conditions

    PMID:34939084

    Open questions at the time
    • Kinase(s) mediating Ser15 phosphorylation downstream of Ser430 O-GlcNAcylation not identified
    • In vivo relevance of Ser430 modification not tested
  5. 2022 Medium

    Demonstrating that FOXO3a directly binds the PYGL promoter to upregulate expression linked glycogenolysis to the AKT1-FOXO3a signaling axis and downstream lipogenesis, identifying a transcriptional activator of PYGL beyond HIF1α.

    Evidence ChIP assay showing FOXO3a at PYGL promoter combined with SELENOF/PYGL RNAi and lipid accumulation readouts

    PMID:35439639

    Open questions at the time
    • Whether FOXO3a regulation of PYGL operates in hepatocytes in vivo not established
    • Precise FOXO3a binding element in PYGL promoter not mapped
  6. 2022 Medium

    Validation of miR-155-5p as a direct post-transcriptional repressor of PYGL established a microRNA-mediated regulatory layer controlling glycogenolysis in hypoxia-stimulated vascular smooth muscle cells.

    Evidence Dual-luciferase reporter assay confirming miR-155-5p targeting of PYGL 3′-UTR, with epistatic rescue by PYGL siRNA in PASMCs

    PMID:35611851

    Open questions at the time
    • Physiological relevance in pulmonary hypertension in vivo not demonstrated
    • Other miRNAs targeting PYGL not surveyed
  7. 2023 Medium

    Showing that HIF1α-induced PYGL drives glycogen mobilization to fuel glycolysis and EMT in pancreatic cancer established PYGL as a metabolic effector of hypoxia-driven tumor progression.

    Evidence HIF1α and PYGL knockdown/overexpression in PDAC cells with glycogen quantification, 2-DG rescue, and in vivo liver metastasis xenografts

    PMID:37063425

    Open questions at the time
    • Whether HIF1α binds PYGL promoter directly in PDAC cells not shown by ChIP in this study
    • Relative contribution of PYGL versus other glycogen-metabolizing enzymes to EMT unclear
  8. 2024 Medium

    ChIP-confirmed HIF1α binding at the PYGL locus in renal cell carcinoma and glioma, combined with evidence that PYGL knockdown impairs glycolysis and promotes apoptosis, consolidated HIF1α as a direct transcriptional activator of PYGL with functional consequences for cancer cell survival and drug resistance.

    Evidence ChIP for HIF1α at PYGL in ccRCC; PYGL KD with ECAR/ATP/lactate and apoptosis marker measurement in glioma; CP-91149 resensitization to sunitinib in ccRCC

    PMID:38545181 PMID:39525037

    Open questions at the time
    • HIF1α response element in PYGL promoter not precisely mapped
    • Whether PYGL inhibition affects normal tissue glycogenolysis and toxicity in vivo not assessed
  9. 2026 Medium

    Identification of the extracellular ATP–P2Y12–AhR axis as an inducer of PYGL expression revealed a purinergic signaling route to glycogenolysis that drives endocrine therapy resistance in ER-positive breast cancer.

    Evidence P2Y12/AhR manipulation, PYGL KD/OE, glycolysis assays, breast cancer organoids, and clinical specimen analysis

    PMID:41974649

    Open questions at the time
    • Whether AhR binds the PYGL promoter directly not shown
    • Generalizability to other endocrine-resistant cancer types unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural and regulatory model explaining how multiple transcriptional inputs (HIF1α, FOXO3a, AhR, CREBH/ATF4), post-translational modifications (O-GlcNAcylation, phosphorylation), and post-transcriptional repressors (miR-155-5p) are integrated at PYGL to fine-tune glycogenolysis in different tissues remains to be constructed.
  • No structural basis for how Ser430 O-GlcNAcylation allosterically affects Ser15 phosphorylation or catalytic activity
  • Relative hierarchy and tissue-specificity of transcriptional regulators not systematically compared
  • Role of PYGL in neuronal glycogen metabolism in mammals not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 8 R-HSA-1643685 Disease 5
Partners
FOXO3HIF1A

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PYGL encodes the liver isoform of glycogen phosphorylase; missense mutations N338S and N376K at absolutely conserved residues cause loss of function underlying glycogen storage disease type VI (Hers disease), demonstrating the enzymatic role of PYGL in hepatic glycogenolysis. Mutation identification, sequence conservation analysis, splice-site and missense mutation characterization in GSD VI patients American journal of human genetics High 9529348
2022 PYGL is O-GlcNAcylated at Ser430, and this modification promotes phosphorylation of Ser15 (the activating phosphorylation site); O-GlcNAcylation at Ser430 and pSer15 are mutually reinforcing, and Ser430 O-GlcNAcylation is required for full PYGL enzymatic activity. O-GlcNAc modification mapping in HEK293T and HCT116 cells, site-directed mutagenesis of Ser430, western blot under glucose/insulin/glucagon/hypoxia conditions, enzymatic activity assays Glycobiology High 34939084
2023 Hypoxia induces PYGL expression in a HIF1α-dependent manner, promoting glycogen mobilization via glycogen phosphorylase activity to fuel glycolysis, which in turn induces EMT in pancreatic cancer cells; this effect is suppressed by the glycolysis inhibitor 2-DG. HIF1α knockdown/overexpression, PYGL knockdown/overexpression in PDAC cells, glycogen quantification, 2-DG rescue, in vivo liver metastasis xenograft model International journal of biological sciences Medium 37063425
2022 SELENOF deficiency impairs AKT1-FOXO3a-PYGL signaling; FOXO3a binds directly to the PYGL promoter to increase PYGL expression, which drives glycogenolysis and thereby promotes lipogenesis and lipid accumulation in response to supranutritional selenium. RNAi knockdown of SELENOF and PYGL, chromatin immunoprecipitation (ChIP) assay for FOXO3a binding to PYGL promoter, transcriptomic and immunoblot analysis Biochimica et biophysica acta. Gene regulatory mechanisms Medium 35439639
2021 Maternal high-fat, high-sucrose diet causes hypermethylation of the Pygl gene promoter in offspring liver, reducing Pygl expression, impairing hepatic glycogenolysis, and causing glycogen and triglyceride accumulation; uncarboxylated osteocalcin administration during pregnancy upregulates Pygl via CREBH and ATF4 transcription factors and indirect epigenomic pathways, mitigating these metabolic defects. Mouse maternal diet model, bisulfite sequencing/methylation analysis of Pygl, RNA interference, immunoblotting, osteocalcin administration during pregnancy Molecular metabolism Medium 34673295
2020 PYGL (Pygl) and G6PD (G6pd), both vitamin B6-regulated enzymes, fuel NADPH oxidase activity to promote skin inflammation; inhibition of Pygl in zebrafish skin inflammation models alleviates oxidative-stress-induced inflammation. Zebrafish skin inflammation models, pharmacological inhibition of Pygl and G6pd, measurement of neutrophil infiltration, oxidative stress, and Nfkb activity Developmental and comparative immunology Medium 32126244
2022 miR-155-5p directly targets PYGL mRNA (validated by dual-luciferase reporter assay); in hypoxia-stimulated pulmonary artery smooth muscle cells (PASMCs), elevated miR-155-5p suppresses PYGL, and PYGL siRNA rescues the effect of miR-155-5p inhibitor on cell proliferation, migration, and cell cycle progression. Dual-luciferase reporter assay, qRT-PCR, western blot, siRNA knockdown, CCK-8 assay, transwell assay, flow cytometry Bioengineered Medium 35611851
2024 HIF1α directly regulates PYGL expression under hypoxic conditions in glioma cells; PYGL knockdown impairs glycolysis (reduced ECAR, ATP, lactate, PKM2, LDHA), increases glycogen accumulation, and enhances apoptosis via modulation of Bcl-2, caspase-3, and Bax. PYGL knockdown in glioma cell lines, HIF1α manipulation, extracellular acidification rate (ECAR) measurement, ATP and lactate assays, western blot for apoptosis markers, glycogen quantification Translational cancer research Medium 39525037
2024 HIF1α transcription factor induces PYGL upregulation in clear cell renal cell carcinoma (ccRCC), as demonstrated by chromatin immunoprecipitation; pharmacological targeting of PYGL with CP-91149 restores sunitinib sensitivity in resistant ccRCC cell lines. Chromatin immunoprecipitation (ChIP) for HIF1α at PYGL locus, PYGL knockdown, CP-91149 treatment in sunitinib-resistant ccRCC cell lines Heliyon Medium 38545181
2026 Extracellular ATP activates the P2Y12-AhR signaling axis to upregulate PYGL expression in ER-positive breast cancer cells, enhancing glycolytic activity and promoting endocrine therapy resistance. Extracellular ATP treatment, P2Y12 and AhR manipulation, PYGL knockdown/overexpression, glycolysis assays, breast cancer organoids, clinical specimen analysis Cell death & disease Medium 41974649
2025 PYGL-1, the C. elegans ortholog of human glycogen phosphorylase PYGL, is required in neurons for glycogen-dependent glycolytic plasticity (GDGP); GDGP is employed under mitochondrial dysfunction (transient hypoxia or mitochondrial mutants) and is necessary for sustaining the synaptic vesicle cycle. RNAi screen in C. elegans, glycolytic sensor HYlight in single neurons of living animals, hypoxia and mitochondrial dysfunction genetic models bioRxivpreprint Medium bio_10.1101_2025.04.10.648039

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI. American journal of human genetics 67 9529348
2023 PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer. International journal of biological sciences 36 37063425
2004 Intermittent and recurrent hepatomegaly due to glycogen storage in a patient with type 1 diabetes: genetic analysis of the liver glycogen phosphorylase gene (PYGL). Diabetes research and clinical practice 28 15223230
2020 The vitamin B6-regulated enzymes PYGL and G6PD fuel NADPH oxidases to promote skin inflammation. Developmental and comparative immunology 23 32126244
2023 Cellular hierarchy framework based on single-cell/multi-patient sample sequencing reveals metabolic biomarker PYGL as a therapeutic target for HNSCC. Journal of experimental & clinical cancer research : CR 17 37420300
2022 miR-155-5p regulates hypoxia-induced pulmonary artery smooth muscle cell function by targeting PYGL. Bioengineered 15 35611851
2022 O-GlcNAcylation increases PYGL activity by promoting phosphorylation. Glycobiology 14 34939084
2022 Selenoprotein F (SELENOF)-mediated AKT1-FOXO3a-PYGL axis contributes to selenium supranutrition-induced glycogenolysis and lipogenesis. Biochimica et biophysica acta. Gene regulatory mechanisms 13 35439639
2021 Long noncoding RNA KCNMB2-AS1 promotes the development of esophageal cancer by modulating the miR-3194-3p/PYGL axis. Bioengineered 13 34516362
2020 Novel PYGL mutations in Chinese children leading to glycogen storage disease type VI: two case reports. BMC medical genetics 13 32268899
2021 Glycogen storage disease type VI with a novel PYGL mutation: Two case reports and literature review. Medicine 12 33879691
2021 Hepatic glycogenolysis is determined by maternal high-calorie diet via methylation of Pygl and it is modified by oteocalcin administration in mice. Molecular metabolism 7 34673295
2020 A Novel, Recurrent, 3.6-kb Deletion in the PYGL Gene Contributes to Glycogen Storage Disease Type VI. The Journal of molecular diagnostics : JMD 5 32961316
2024 Integrated genomic and proteomic analyses identify PYGL as a novel experimental therapeutic target for clear cell renal cell carcinoma. Heliyon 3 38545181
2024 PYGL regulation of glycolysis and apoptosis in glioma cells under hypoxic conditions via HIF1α-dependent mechanisms. Translational cancer research 3 39525037
2017 Glycogen Storage Disease Type VI With a Novel Mutation in PYGL Gene. Indian pediatrics 3 28984260
2026 Sodium taurocholate cotransporter polypeptide deficiency combined with novel PYGL mutations in glycogen storage disease type VI: a rare case report. Clinics and research in hepatology and gastroenterology 0 41775331
2026 Extracellular ATP promotes endocrine resistance in ER+ breast cancer through upregulation of PYGL. Cell death & disease 0 41974649
2022 [Genetic analysis of PYGL gene variants for a child with Glycogen storage disease VI]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 35076922