{"gene":"PYGL","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1998,"finding":"Mutations in PYGL (encoding liver glycogen phosphorylase) cause glycogen storage disease type VI (Hers disease). Two missense mutations, N338S and N376K, replace absolutely conserved amino acids in the phosphorylase active site; two splice-site mutations cause intron retention/exon skipping, demonstrating that PYGL loss-of-function underlies hepatic glycogen accumulation.","method":"Mutation identification by sequencing, splice-site analysis, conservation analysis across species","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct sequencing of patients with defined disease, functional inference from conserved catalytic residues, replicated across multiple patients and independently confirmed in subsequent GSD VI case reports","pmids":["9529348"],"is_preprint":false},{"year":2022,"finding":"PYGL is O-GlcNAcylated on Ser430, and this modification positively regulates PYGL enzymatic activity. O-GlcNAcylation at Ser430 mutually reinforces phosphorylation of the activating residue Ser15 (pSer15), and both modifications are decreased under glucose/insulin conditions and increased under glucagon or hypoxia (Na2S2O4) conditions.","method":"Site-directed mutagenesis of Ser430, immunoprecipitation, phosphorylation assays, OGT/OGA manipulation in HEK293T and HCT116 cells, glycogen phosphorylase activity assays","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific O-GlcNAcylation site combined with enzymatic activity assays and phosphorylation analysis, single lab with multiple orthogonal methods","pmids":["34939084"],"is_preprint":false},{"year":2023,"finding":"Hypoxia induces PYGL expression in a HIF1α-dependent manner in pancreatic cancer cells, promoting glycogen mobilization via glycogen phosphorylase activity to fuel glycolysis, which in turn drives EMT and metastasis. The glycolysis inhibitor 2-DG suppresses this PYGL-driven EMT.","method":"HIF1α knockdown/overexpression, PYGL knockdown/overexpression, glycogen measurement, glycolysis assays, 2-DG rescue, in vivo liver metastasis models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis (HIF1α→PYGL→glycolysis→EMT) with pathway rescue by 2-DG, in vitro and in vivo, single lab","pmids":["37063425"],"is_preprint":false},{"year":2022,"finding":"FOXO3a directly binds the PYGL promoter to upregulate its transcription. In the context of selenium supranutrition, SELENOF modulates the AKT1-FOXO3a-PYGL axis: increased FOXO3a DNA-binding capacity upregulates PYGL expression, increasing glycogenolysis and promoting lipogenesis. PYGL knockdown abrogated Se-induced lipid accumulation.","method":"ChIP assay (FOXO3a binding to PYGL promoter), RNA interference knockdown of SELENOF and PYGL, immunoblotting, transcriptomic analysis, enzymatic activity measurements","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct FOXO3a binding to PYGL promoter, RNAi epistasis confirms pathway order, single lab","pmids":["35439639"],"is_preprint":false},{"year":2021,"finding":"Maternal high-fat, high-sucrose diet causes hypermethylation of the Pygl gene promoter in offspring liver, reducing PYGL/glycogen phosphorylase L expression, impairing hepatic glycogenolysis, and causing hepatic glycogen and triglyceride accumulation. Administration of uncarboxylated osteocalcin during pregnancy upregulates Pygl expression via CREBH and ATF4 transcription factors and epigenomic pathways, reversing these metabolic defects.","method":"Mouse dietary model, bisulfite sequencing/methylation analysis of Pygl promoter, gene expression analysis, osteocalcin administration, metabolic phenotyping","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct epigenetic (methylation) mechanism linking maternal diet to Pygl expression with functional metabolic readout, multiple methods, single lab","pmids":["34673295"],"is_preprint":false},{"year":2020,"finding":"In zebrafish skin inflammation models, inhibition of glycogen phosphorylase L (Pygl) alleviates oxidative-stress-induced skin inflammation by reducing NADPH oxidase-fueled oxidative stress and Nfkb activity, demonstrating that glycogen stores processed by Pygl provide substrates that fuel NADPH oxidase activity and promote neutrophil infiltration.","method":"Pharmacological inhibition of Pygl in zebrafish skin inflammation models, measurement of neutrophil infiltration, oxidative stress, and Nfkb activity; vitamin B6 vitamer treatment","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional inhibition studies in live zebrafish model with defined cellular readouts (neutrophil infiltration, ROS, Nfkb), single lab","pmids":["32126244"],"is_preprint":false},{"year":2024,"finding":"HIF1α directly regulates PYGL expression under hypoxia in glioma cells. PYGL knockdown impairs glycolysis (reduced ECAR, ATP, lactate, PKM2, and LDHA expression), increases glycogen accumulation, inhibits proliferation/invasion/migration, and enhances apoptosis via modulation of Bcl-2, caspase-3, and Bax. PYGL overexpression-driven glycolysis promotion is counteracted by 2-DG.","method":"PYGL knockdown/overexpression, Seahorse extracellular flux assay, glycogen measurement, flow cytometry for apoptosis, 2-DG rescue, HIF1α manipulation","journal":"Translational cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple functional assays in vitro with rescue experiment, single lab, no structural or reconstitution data","pmids":["39525037"],"is_preprint":false},{"year":2024,"finding":"HIF1α (transcription factor) binds to the PYGL promoter and upregulates PYGL expression in ccRCC, as demonstrated by chromatin immunoprecipitation. PYGL knockdown inhibited ccRCC cell proliferation, migration, invasion, and tumorigenesis; CP-91149 (PYGL inhibitor) restored sunitinib sensitivity in resistant ccRCC cell lines.","method":"Chromatin immunoprecipitation (ChIP) for HIF1α at PYGL promoter, PYGL knockdown, pharmacological PYGL inhibition with CP-91149, cell proliferation/invasion assays, drug resistance assays","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct HIF1α binding to PYGL promoter, functional loss-of-function with defined readouts, single lab","pmids":["38545181"],"is_preprint":false},{"year":2026,"finding":"Chicoric acid (CA) allosterically inhibits PYGL by binding to specific residues (Glu162, Arg247, Glu273), inducing conformational changes that suppress glycogenolysis. CA also disrupts the interaction between PYGL and lactate dehydrogenase A (LDHA), accelerating proteasomal degradation of LDHA and reducing glycolytic flux in NSCLC cells.","method":"Molecular docking, cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), site-directed mutagenesis of PYGL binding residues, co-immunoprecipitation for PYGL-LDHA interaction, proteasome inhibitor rescue, Seahorse glycolysis assay, xenograft models","journal":"Cellular & molecular biology letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding confirmed by SPR and CETSA, allosteric binding site validated by site-directed mutagenesis, PYGL-LDHA interaction by Co-IP, multiple orthogonal methods in single study","pmids":["42056865"],"is_preprint":false},{"year":2026,"finding":"Extracellular ATP activates the P2Y12-AhR signaling axis in ER+ breast cancer cells, leading to upregulation of PYGL expression, enhanced glycolytic activity, and endocrine therapy resistance. PYGL knockdown reversed ATP-mediated endocrine resistance.","method":"P2Y12 receptor and AhR inhibition/knockdown, PYGL knockdown, glycolysis measurement, endocrine resistance assays in cell lines and breast cancer organoids","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis (P2Y12→AhR→PYGL→glycolysis→resistance) with pathway rescue, organoid validation, single lab","pmids":["41974649"],"is_preprint":false},{"year":2025,"finding":"In C. elegans, PYGL-1 (ortholog of human PYGL/glycogen phosphorylase) is required in neurons for glycogen-dependent glycolytic plasticity (GDGP) in response to mitochondrial dysfunction or transient hypoxia. Loss of PYGL-1 impairs the ability of neurons to upregulate glycolysis under these conditions and disrupts the synaptic vesicle cycle, demonstrating a cell-autonomous role for neuronal glycogenolysis in sustaining synaptic function.","method":"RNAi screen in C. elegans, glycolytic sensor (HYlight) imaging in single neurons, genetic epistasis with mitochondrial function mutants, synaptic vesicle cycle assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo RNAi with live glycolytic sensor imaging and functional synaptic readout; C. elegans ortholog study; preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.04.10.648039"],"is_preprint":true}],"current_model":"PYGL encodes liver glycogen phosphorylase, an enzyme that catalyzes glycogenolysis by releasing glucose-1-phosphate from glycogen; its activity is positively regulated by phosphorylation of Ser15 and O-GlcNAcylation of Ser430 (which mutually reinforce each other), its transcription is induced by HIF1α under hypoxia and by FOXO3a, it interacts with LDHA to channel glycolytic flux, and loss-of-function mutations cause glycogen storage disease type VI, while its aberrant upregulation in cancer fuels glycolysis to drive EMT, metastasis, and therapy resistance."},"narrative":{"mechanistic_narrative":"PYGL encodes liver glycogen phosphorylase, the enzyme that mobilizes hepatic glycogen by liberating glucose-1-phosphate, and loss-of-function mutations in its conserved catalytic residues cause glycogen storage disease type VI (Hers disease) with hepatic glycogen accumulation [PMID:9529348]. Its activity is positively controlled by reciprocal covalent modification: O-GlcNAcylation at Ser430 and phosphorylation at the activating Ser15 mutually reinforce one another, with both modifications rising under glucagon or hypoxic conditions and falling under glucose/insulin [PMID:34939084]. Beyond hormonal control, PYGL transcription is driven by HIF1α under hypoxia [PMID:37063425, PMID:38545181] and by FOXO3a binding directly to its promoter [PMID:35439639], and is repressed by promoter hypermethylation in a model of maternal diet-induced metabolic dysfunction [PMID:34673295]. By processing glycogen stores to feed glycolysis, PYGL couples glycogenolysis to downstream cellular programs: it fuels NADPH oxidase-driven oxidative stress and neutrophil-mediated inflammation [PMID:32126244], sustains neuronal glycolytic plasticity and the synaptic vesicle cycle [PMID:bio_10.1101_2025.04.10.648039], and in multiple cancers drives glycolytic flux that promotes EMT, metastasis, proliferation, and therapy resistance [PMID:37063425, PMID:39525037, PMID:38545181, PMID:41974649]. PYGL physically interacts with lactate dehydrogenase A (LDHA), an interaction that can be disrupted pharmacologically to accelerate LDHA degradation and reduce glycolytic flux [PMID:42056865].","teleology":[{"year":1998,"claim":"Establishing that PYGL is a disease gene answered whether hepatic glycogen accumulation could arise from a defect in the glycogen-degrading enzyme itself, linking PYGL catalytic function to human metabolic disease.","evidence":"Sequencing of GSD VI patients identifying active-site missense mutations (N338S, N376K) at absolutely conserved residues and splice-site mutations","pmids":["9529348"],"confidence":"High","gaps":["Does not resolve the enzyme's regulatory inputs","No structural mechanism for how each mutation impairs catalysis"]},{"year":2022,"claim":"Identification of Ser430 O-GlcNAcylation answered how nutrient signaling tunes PYGL activity, revealing a post-translational layer beyond classical Ser15 phosphorylation.","evidence":"Site-directed mutagenesis of Ser430, OGT/OGA manipulation, phosphorylation and phosphorylase activity assays in HEK293T and HCT116 cells","pmids":["34939084"],"confidence":"High","gaps":["Mechanism of mutual reinforcement between O-GlcNAcylation and pSer15 not structurally defined","Physiological significance in liver not tested"]},{"year":2022,"claim":"Demonstrating direct FOXO3a binding to the PYGL promoter answered how transcriptional inputs couple glycogenolysis to lipogenic metabolism under selenium supranutrition.","evidence":"ChIP of FOXO3a at the PYGL promoter and SELENOF/PYGL RNAi epistasis with lipid accumulation readouts","pmids":["35439639"],"confidence":"Medium","gaps":["Generality of the SELENOF-AKT1-FOXO3a-PYGL axis beyond selenium context unknown","Direct enzymatic contribution to lipogenesis not isolated"]},{"year":2021,"claim":"Linking Pygl promoter methylation to maternal diet answered how environmental/epigenetic programming can suppress hepatic glycogenolysis and produce offspring metabolic defects.","evidence":"Mouse maternal high-fat/high-sucrose dietary model with bisulfite methylation analysis, expression profiling, and osteocalcin rescue via CREBH/ATF4","pmids":["34673295"],"confidence":"Medium","gaps":["Causal contribution of Pygl downregulation vs other genes to phenotype not isolated","Human relevance of the methylation event unestablished"]},{"year":2020,"claim":"Inhibiting Pygl in zebrafish answered whether glycogen processed by phosphorylase functions as a substrate source for inflammatory oxidative stress, connecting glycogenolysis to NADPH oxidase and NF-kB.","evidence":"Pharmacological Pygl inhibition in zebrafish skin inflammation models with neutrophil, ROS, and Nfkb readouts","pmids":["32126244"],"confidence":"Medium","gaps":["Mechanistic link from glucose-1-phosphate to NADPH oxidase substrate supply not biochemically traced","Mammalian inflammation relevance untested"]},{"year":2023,"claim":"Placing PYGL downstream of HIF1α answered how hypoxic tumor cells mobilize glycogen to feed glycolysis and drive EMT and metastasis.","evidence":"HIF1α and PYGL gain/loss-of-function, glycogen and glycolysis assays, 2-DG rescue, and in vivo liver metastasis models in pancreatic cancer","pmids":["37063425"],"confidence":"Medium","gaps":["Single cancer type","Whether glycogenolysis is rate-limiting for metastasis in vivo not quantified"]},{"year":2024,"claim":"Confirming HIF1α-driven PYGL transcription across glioma and ccRCC established the hypoxia-PYGL-glycolysis axis as a recurrent oncogenic dependency and a therapeutic target for restoring drug sensitivity.","evidence":"ChIP of HIF1α at PYGL promoter, PYGL knockdown with Seahorse/apoptosis assays, and CP-91149 inhibition restoring sunitinib sensitivity","pmids":["39525037","38545181"],"confidence":"Medium","gaps":["No structural model of HIF1α occupancy at the PYGL locus","Resistance-reversal mechanism beyond glycolytic suppression not defined"]},{"year":2026,"claim":"Identifying PYGL's allosteric inhibitor binding site and its physical interaction with LDHA answered how PYGL is coupled to glycolytic flux at the protein level, defining a druggable PYGL-LDHA node.","evidence":"Molecular docking, SPR, CETSA, mutagenesis of Glu162/Arg247/Glu273, Co-IP of PYGL-LDHA, proteasome rescue, and xenografts in NSCLC","pmids":["42056865"],"confidence":"High","gaps":["Reciprocal validation and stoichiometry of the PYGL-LDHA complex not fully resolved","Whether the interaction is direct or scaffold-mediated unclear"]},{"year":2026,"claim":"Placing PYGL downstream of extracellular ATP-P2Y12-AhR signaling answered how a receptor-driven pathway converges on glycogenolysis to confer endocrine therapy resistance.","evidence":"P2Y12/AhR inhibition, PYGL knockdown, glycolysis and endocrine resistance assays in ER+ breast cancer cells and organoids","pmids":["41974649"],"confidence":"Medium","gaps":["Direct transcriptional vs indirect control of PYGL by AhR not distinguished","Mechanism of glycolysis-to-resistance coupling not defined"]},{"year":2025,"claim":"Demonstrating a cell-autonomous neuronal requirement for the PYGL ortholog answered whether neuronal glycogenolysis sustains glycolytic plasticity and synaptic function under metabolic stress.","evidence":"RNAi screen in C. elegans with single-neuron HYlight glycolytic sensor imaging, mitochondrial epistasis, and synaptic vesicle cycle assays (preprint)","pmids":["bio_10.1101_2025.04.10.648039"],"confidence":"Medium","gaps":["Ortholog study not yet peer-reviewed","Conservation of neuronal glycogenolytic plasticity in mammals untested"]},{"year":null,"claim":"How the multiple transcriptional, epigenetic, and post-translational inputs are integrated to set PYGL activity in a tissue- and context-specific manner, and the structural basis of its LDHA interaction, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating Ser15/Ser430 modifications with catalysis","Direct vs indirect nature and stoichiometry of PYGL-LDHA complex unresolved","Tissue-specific hierarchy of HIF1α, FOXO3a, and methylation control unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,7]}],"complexes":[],"partners":["LDHA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06737","full_name":"Glycogen phosphorylase, liver form","aliases":[],"length_aa":847,"mass_kda":97.1,"function":"Allosteric enzyme that catalyzes the rate-limiting step in glycogen catabolism, the phosphorolytic cleavage of glycogen to produce glucose-1-phosphate, and plays a central role in maintaining cellular and organismal glucose homeostasis","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/P06737/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PYGL","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2},{"gene":"PSMC4","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2},{"gene":"SAR1B","stoichiometry":0.2},{"gene":"TRAPPC11","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PYGL","total_profiled":1310},"omim":[{"mim_id":"613741","title":"GLYCOGEN PHOSPHORYLASE, LIVER; PYGL","url":"https://www.omim.org/entry/613741"},{"mim_id":"610541","title":"PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 3B; PPP1R3B","url":"https://www.omim.org/entry/610541"},{"mim_id":"608455","title":"GLYCOGEN PHOSPHORYLASE, MUSCLE; PYGM","url":"https://www.omim.org/entry/608455"},{"mim_id":"606664","title":"GLYCINE N-METHYLTRANSFERASE DEFICIENCY","url":"https://www.omim.org/entry/606664"},{"mim_id":"606628","title":"GLYCINE N-METHYLTRANSFERASE; GNMT","url":"https://www.omim.org/entry/606628"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":136.2}],"url":"https://www.proteinatlas.org/search/PYGL"},"hgnc":{"alias_symbol":["GSD6"],"prev_symbol":[]},"alphafold":{"accession":"P06737","domains":[{"cath_id":"-","chopping":"19-78_100-125","consensus_level":"medium","plddt":91.6251,"start":19,"end":125},{"cath_id":"3.40.50.2000","chopping":"79-94_129-225_240-481","consensus_level":"high","plddt":92.1915,"start":79,"end":481},{"cath_id":"3.40.50.2000","chopping":"497-714_772-810","consensus_level":"high","plddt":96.4004,"start":497,"end":810}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06737","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06737-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06737-F1-predicted_aligned_error_v6.png","plddt_mean":92.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PYGL","jax_strain_url":"https://www.jax.org/strain/search?query=PYGL"},"sequence":{"accession":"P06737","fasta_url":"https://rest.uniprot.org/uniprotkb/P06737.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06737/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06737"}},"corpus_meta":[{"pmid":"9529348","id":"PMC_9529348","title":"Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI.","date":"1998","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9529348","citation_count":68,"is_preprint":false},{"pmid":"37063425","id":"PMC_37063425","title":"PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37063425","citation_count":42,"is_preprint":false},{"pmid":"15223230","id":"PMC_15223230","title":"Intermittent and recurrent hepatomegaly due to glycogen storage in a patient with type 1 diabetes: genetic analysis of the liver glycogen phosphorylase gene (PYGL).","date":"2004","source":"Diabetes research and clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/15223230","citation_count":28,"is_preprint":false},{"pmid":"32126244","id":"PMC_32126244","title":"The vitamin B6-regulated enzymes PYGL and G6PD fuel NADPH oxidases to promote skin inflammation.","date":"2020","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32126244","citation_count":24,"is_preprint":false},{"pmid":"37420300","id":"PMC_37420300","title":"Cellular hierarchy framework based on single-cell/multi-patient sample sequencing reveals metabolic biomarker PYGL as a therapeutic target for HNSCC.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37420300","citation_count":19,"is_preprint":false},{"pmid":"35611851","id":"PMC_35611851","title":"miR-155-5p regulates hypoxia-induced pulmonary artery smooth muscle cell function by targeting PYGL.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35611851","citation_count":15,"is_preprint":false},{"pmid":"34939084","id":"PMC_34939084","title":"O-GlcNAcylation increases PYGL activity by promoting phosphorylation.","date":"2022","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/34939084","citation_count":14,"is_preprint":false},{"pmid":"35439639","id":"PMC_35439639","title":"Selenoprotein F (SELENOF)-mediated AKT1-FOXO3a-PYGL axis contributes to selenium supranutrition-induced glycogenolysis and lipogenesis.","date":"2022","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/35439639","citation_count":14,"is_preprint":false},{"pmid":"33879691","id":"PMC_33879691","title":"Glycogen storage disease type VI with a novel PYGL mutation: Two case reports and literature review.","date":"2021","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33879691","citation_count":13,"is_preprint":false},{"pmid":"34516362","id":"PMC_34516362","title":"Long noncoding RNA KCNMB2-AS1 promotes the development of esophageal cancer by modulating the miR-3194-3p/PYGL axis.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34516362","citation_count":13,"is_preprint":false},{"pmid":"32268899","id":"PMC_32268899","title":"Novel PYGL mutations in Chinese children leading to glycogen storage disease type VI: two case reports.","date":"2020","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32268899","citation_count":13,"is_preprint":false},{"pmid":"34673295","id":"PMC_34673295","title":"Hepatic glycogenolysis is determined by maternal high-calorie diet via methylation of Pygl and it is modified by oteocalcin administration in mice.","date":"2021","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34673295","citation_count":7,"is_preprint":false},{"pmid":"39525037","id":"PMC_39525037","title":"PYGL regulation of glycolysis and apoptosis in glioma cells under hypoxic conditions via HIF1α-dependent mechanisms.","date":"2024","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39525037","citation_count":6,"is_preprint":false},{"pmid":"32961316","id":"PMC_32961316","title":"A Novel, Recurrent, 3.6-kb Deletion in the PYGL Gene Contributes to Glycogen Storage Disease Type VI.","date":"2020","source":"The Journal of molecular diagnostics : JMD","url":"https://pubmed.ncbi.nlm.nih.gov/32961316","citation_count":5,"is_preprint":false},{"pmid":"38545181","id":"PMC_38545181","title":"Integrated genomic and proteomic analyses identify PYGL as a novel experimental therapeutic target for clear cell renal cell carcinoma.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38545181","citation_count":4,"is_preprint":false},{"pmid":"28984260","id":"PMC_28984260","title":"Glycogen Storage Disease Type VI With a Novel Mutation in PYGL Gene.","date":"2017","source":"Indian pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/28984260","citation_count":3,"is_preprint":false},{"pmid":"35076922","id":"PMC_35076922","title":"[Genetic analysis of PYGL gene variants for a child with Glycogen storage disease VI].","date":"2022","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35076922","citation_count":0,"is_preprint":false},{"pmid":"42056865","id":"PMC_42056865","title":"Chicoric acid targets PYGL to normalize glycogenolysis-driven glycolysis to suppress non-small cell lung cancer.","date":"2026","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/42056865","citation_count":0,"is_preprint":false},{"pmid":"41974649","id":"PMC_41974649","title":"Extracellular ATP promotes endocrine resistance in ER+ breast cancer through upregulation of PYGL.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41974649","citation_count":0,"is_preprint":false},{"pmid":"41775331","id":"PMC_41775331","title":"Sodium taurocholate cotransporter polypeptide deficiency combined with novel PYGL mutations in glycogen storage disease type VI: a rare case report.","date":"2026","source":"Clinics and research in hepatology and gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/41775331","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.11.25333473","title":"Exploring the Potential of Antidepressants in Treating Coronary Artery Disease","date":"2025-08-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.11.25333473","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.10.648039","title":"Glycogen metabolism acts in neurons to support glycolytic plasticity","date":"2025-04-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.10.648039","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12461,"output_tokens":3095,"usd":0.041904,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10709,"output_tokens":3608,"usd":0.071873,"stage2_stop_reason":"end_turn"},"total_usd":0.113777,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Mutations in PYGL (encoding liver glycogen phosphorylase) cause glycogen storage disease type VI (Hers disease). Two missense mutations, N338S and N376K, replace absolutely conserved amino acids in the phosphorylase active site; two splice-site mutations cause intron retention/exon skipping, demonstrating that PYGL loss-of-function underlies hepatic glycogen accumulation.\",\n      \"method\": \"Mutation identification by sequencing, splice-site analysis, conservation analysis across species\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct sequencing of patients with defined disease, functional inference from conserved catalytic residues, replicated across multiple patients and independently confirmed in subsequent GSD VI case reports\",\n      \"pmids\": [\"9529348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PYGL is O-GlcNAcylated on Ser430, and this modification positively regulates PYGL enzymatic activity. O-GlcNAcylation at Ser430 mutually reinforces phosphorylation of the activating residue Ser15 (pSer15), and both modifications are decreased under glucose/insulin conditions and increased under glucagon or hypoxia (Na2S2O4) conditions.\",\n      \"method\": \"Site-directed mutagenesis of Ser430, immunoprecipitation, phosphorylation assays, OGT/OGA manipulation in HEK293T and HCT116 cells, glycogen phosphorylase activity assays\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific O-GlcNAcylation site combined with enzymatic activity assays and phosphorylation analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34939084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hypoxia induces PYGL expression in a HIF1α-dependent manner in pancreatic cancer cells, promoting glycogen mobilization via glycogen phosphorylase activity to fuel glycolysis, which in turn drives EMT and metastasis. The glycolysis inhibitor 2-DG suppresses this PYGL-driven EMT.\",\n      \"method\": \"HIF1α knockdown/overexpression, PYGL knockdown/overexpression, glycogen measurement, glycolysis assays, 2-DG rescue, in vivo liver metastasis models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis (HIF1α→PYGL→glycolysis→EMT) with pathway rescue by 2-DG, in vitro and in vivo, single lab\",\n      \"pmids\": [\"37063425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXO3a directly binds the PYGL promoter to upregulate its transcription. In the context of selenium supranutrition, SELENOF modulates the AKT1-FOXO3a-PYGL axis: increased FOXO3a DNA-binding capacity upregulates PYGL expression, increasing glycogenolysis and promoting lipogenesis. PYGL knockdown abrogated Se-induced lipid accumulation.\",\n      \"method\": \"ChIP assay (FOXO3a binding to PYGL promoter), RNA interference knockdown of SELENOF and PYGL, immunoblotting, transcriptomic analysis, enzymatic activity measurements\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct FOXO3a binding to PYGL promoter, RNAi epistasis confirms pathway order, single lab\",\n      \"pmids\": [\"35439639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Maternal high-fat, high-sucrose diet causes hypermethylation of the Pygl gene promoter in offspring liver, reducing PYGL/glycogen phosphorylase L expression, impairing hepatic glycogenolysis, and causing hepatic glycogen and triglyceride accumulation. Administration of uncarboxylated osteocalcin during pregnancy upregulates Pygl expression via CREBH and ATF4 transcription factors and epigenomic pathways, reversing these metabolic defects.\",\n      \"method\": \"Mouse dietary model, bisulfite sequencing/methylation analysis of Pygl promoter, gene expression analysis, osteocalcin administration, metabolic phenotyping\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct epigenetic (methylation) mechanism linking maternal diet to Pygl expression with functional metabolic readout, multiple methods, single lab\",\n      \"pmids\": [\"34673295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In zebrafish skin inflammation models, inhibition of glycogen phosphorylase L (Pygl) alleviates oxidative-stress-induced skin inflammation by reducing NADPH oxidase-fueled oxidative stress and Nfkb activity, demonstrating that glycogen stores processed by Pygl provide substrates that fuel NADPH oxidase activity and promote neutrophil infiltration.\",\n      \"method\": \"Pharmacological inhibition of Pygl in zebrafish skin inflammation models, measurement of neutrophil infiltration, oxidative stress, and Nfkb activity; vitamin B6 vitamer treatment\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional inhibition studies in live zebrafish model with defined cellular readouts (neutrophil infiltration, ROS, Nfkb), single lab\",\n      \"pmids\": [\"32126244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIF1α directly regulates PYGL expression under hypoxia in glioma cells. PYGL knockdown impairs glycolysis (reduced ECAR, ATP, lactate, PKM2, and LDHA expression), increases glycogen accumulation, inhibits proliferation/invasion/migration, and enhances apoptosis via modulation of Bcl-2, caspase-3, and Bax. PYGL overexpression-driven glycolysis promotion is counteracted by 2-DG.\",\n      \"method\": \"PYGL knockdown/overexpression, Seahorse extracellular flux assay, glycogen measurement, flow cytometry for apoptosis, 2-DG rescue, HIF1α manipulation\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple functional assays in vitro with rescue experiment, single lab, no structural or reconstitution data\",\n      \"pmids\": [\"39525037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIF1α (transcription factor) binds to the PYGL promoter and upregulates PYGL expression in ccRCC, as demonstrated by chromatin immunoprecipitation. PYGL knockdown inhibited ccRCC cell proliferation, migration, invasion, and tumorigenesis; CP-91149 (PYGL inhibitor) restored sunitinib sensitivity in resistant ccRCC cell lines.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for HIF1α at PYGL promoter, PYGL knockdown, pharmacological PYGL inhibition with CP-91149, cell proliferation/invasion assays, drug resistance assays\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct HIF1α binding to PYGL promoter, functional loss-of-function with defined readouts, single lab\",\n      \"pmids\": [\"38545181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Chicoric acid (CA) allosterically inhibits PYGL by binding to specific residues (Glu162, Arg247, Glu273), inducing conformational changes that suppress glycogenolysis. CA also disrupts the interaction between PYGL and lactate dehydrogenase A (LDHA), accelerating proteasomal degradation of LDHA and reducing glycolytic flux in NSCLC cells.\",\n      \"method\": \"Molecular docking, cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), site-directed mutagenesis of PYGL binding residues, co-immunoprecipitation for PYGL-LDHA interaction, proteasome inhibitor rescue, Seahorse glycolysis assay, xenograft models\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding confirmed by SPR and CETSA, allosteric binding site validated by site-directed mutagenesis, PYGL-LDHA interaction by Co-IP, multiple orthogonal methods in single study\",\n      \"pmids\": [\"42056865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Extracellular ATP activates the P2Y12-AhR signaling axis in ER+ breast cancer cells, leading to upregulation of PYGL expression, enhanced glycolytic activity, and endocrine therapy resistance. PYGL knockdown reversed ATP-mediated endocrine resistance.\",\n      \"method\": \"P2Y12 receptor and AhR inhibition/knockdown, PYGL knockdown, glycolysis measurement, endocrine resistance assays in cell lines and breast cancer organoids\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis (P2Y12→AhR→PYGL→glycolysis→resistance) with pathway rescue, organoid validation, single lab\",\n      \"pmids\": [\"41974649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, PYGL-1 (ortholog of human PYGL/glycogen phosphorylase) is required in neurons for glycogen-dependent glycolytic plasticity (GDGP) in response to mitochondrial dysfunction or transient hypoxia. Loss of PYGL-1 impairs the ability of neurons to upregulate glycolysis under these conditions and disrupts the synaptic vesicle cycle, demonstrating a cell-autonomous role for neuronal glycogenolysis in sustaining synaptic function.\",\n      \"method\": \"RNAi screen in C. elegans, glycolytic sensor (HYlight) imaging in single neurons, genetic epistasis with mitochondrial function mutants, synaptic vesicle cycle assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo RNAi with live glycolytic sensor imaging and functional synaptic readout; C. elegans ortholog study; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.04.10.648039\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PYGL encodes liver glycogen phosphorylase, an enzyme that catalyzes glycogenolysis by releasing glucose-1-phosphate from glycogen; its activity is positively regulated by phosphorylation of Ser15 and O-GlcNAcylation of Ser430 (which mutually reinforce each other), its transcription is induced by HIF1α under hypoxia and by FOXO3a, it interacts with LDHA to channel glycolytic flux, and loss-of-function mutations cause glycogen storage disease type VI, while its aberrant upregulation in cancer fuels glycolysis to drive EMT, metastasis, and therapy resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PYGL encodes liver glycogen phosphorylase, the enzyme that mobilizes hepatic glycogen by liberating glucose-1-phosphate, and loss-of-function mutations in its conserved catalytic residues cause glycogen storage disease type VI (Hers disease) with hepatic glycogen accumulation [#0]. Its activity is positively controlled by reciprocal covalent modification: O-GlcNAcylation at Ser430 and phosphorylation at the activating Ser15 mutually reinforce one another, with both modifications rising under glucagon or hypoxic conditions and falling under glucose/insulin [#1]. Beyond hormonal control, PYGL transcription is driven by HIF1\\u03b1 under hypoxia [#2, #7] and by FOXO3a binding directly to its promoter [#3], and is repressed by promoter hypermethylation in a model of maternal diet-induced metabolic dysfunction [#4]. By processing glycogen stores to feed glycolysis, PYGL couples glycogenolysis to downstream cellular programs: it fuels NADPH oxidase-driven oxidative stress and neutrophil-mediated inflammation [#5], sustains neuronal glycolytic plasticity and the synaptic vesicle cycle [#10], and in multiple cancers drives glycolytic flux that promotes EMT, metastasis, proliferation, and therapy resistance [#2, #6, #7, #9]. PYGL physically interacts with lactate dehydrogenase A (LDHA), an interaction that can be disrupted pharmacologically to accelerate LDHA degradation and reduce glycolytic flux [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that PYGL is a disease gene answered whether hepatic glycogen accumulation could arise from a defect in the glycogen-degrading enzyme itself, linking PYGL catalytic function to human metabolic disease.\",\n      \"evidence\": \"Sequencing of GSD VI patients identifying active-site missense mutations (N338S, N376K) at absolutely conserved residues and splice-site mutations\",\n      \"pmids\": [\"9529348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the enzyme's regulatory inputs\", \"No structural mechanism for how each mutation impairs catalysis\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of Ser430 O-GlcNAcylation answered how nutrient signaling tunes PYGL activity, revealing a post-translational layer beyond classical Ser15 phosphorylation.\",\n      \"evidence\": \"Site-directed mutagenesis of Ser430, OGT/OGA manipulation, phosphorylation and phosphorylase activity assays in HEK293T and HCT116 cells\",\n      \"pmids\": [\"34939084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mutual reinforcement between O-GlcNAcylation and pSer15 not structurally defined\", \"Physiological significance in liver not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating direct FOXO3a binding to the PYGL promoter answered how transcriptional inputs couple glycogenolysis to lipogenic metabolism under selenium supranutrition.\",\n      \"evidence\": \"ChIP of FOXO3a at the PYGL promoter and SELENOF/PYGL RNAi epistasis with lipid accumulation readouts\",\n      \"pmids\": [\"35439639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of the SELENOF-AKT1-FOXO3a-PYGL axis beyond selenium context unknown\", \"Direct enzymatic contribution to lipogenesis not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking Pygl promoter methylation to maternal diet answered how environmental/epigenetic programming can suppress hepatic glycogenolysis and produce offspring metabolic defects.\",\n      \"evidence\": \"Mouse maternal high-fat/high-sucrose dietary model with bisulfite methylation analysis, expression profiling, and osteocalcin rescue via CREBH/ATF4\",\n      \"pmids\": [\"34673295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of Pygl downregulation vs other genes to phenotype not isolated\", \"Human relevance of the methylation event unestablished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Inhibiting Pygl in zebrafish answered whether glycogen processed by phosphorylase functions as a substrate source for inflammatory oxidative stress, connecting glycogenolysis to NADPH oxidase and NF-kB.\",\n      \"evidence\": \"Pharmacological Pygl inhibition in zebrafish skin inflammation models with neutrophil, ROS, and Nfkb readouts\",\n      \"pmids\": [\"32126244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from glucose-1-phosphate to NADPH oxidase substrate supply not biochemically traced\", \"Mammalian inflammation relevance untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placing PYGL downstream of HIF1\\u03b1 answered how hypoxic tumor cells mobilize glycogen to feed glycolysis and drive EMT and metastasis.\",\n      \"evidence\": \"HIF1\\u03b1 and PYGL gain/loss-of-function, glycogen and glycolysis assays, 2-DG rescue, and in vivo liver metastasis models in pancreatic cancer\",\n      \"pmids\": [\"37063425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cancer type\", \"Whether glycogenolysis is rate-limiting for metastasis in vivo not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirming HIF1\\u03b1-driven PYGL transcription across glioma and ccRCC established the hypoxia-PYGL-glycolysis axis as a recurrent oncogenic dependency and a therapeutic target for restoring drug sensitivity.\",\n      \"evidence\": \"ChIP of HIF1\\u03b1 at PYGL promoter, PYGL knockdown with Seahorse/apoptosis assays, and CP-91149 inhibition restoring sunitinib sensitivity\",\n      \"pmids\": [\"39525037\", \"38545181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of HIF1\\u03b1 occupancy at the PYGL locus\", \"Resistance-reversal mechanism beyond glycolytic suppression not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identifying PYGL's allosteric inhibitor binding site and its physical interaction with LDHA answered how PYGL is coupled to glycolytic flux at the protein level, defining a druggable PYGL-LDHA node.\",\n      \"evidence\": \"Molecular docking, SPR, CETSA, mutagenesis of Glu162/Arg247/Glu273, Co-IP of PYGL-LDHA, proteasome rescue, and xenografts in NSCLC\",\n      \"pmids\": [\"42056865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reciprocal validation and stoichiometry of the PYGL-LDHA complex not fully resolved\", \"Whether the interaction is direct or scaffold-mediated unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placing PYGL downstream of extracellular ATP-P2Y12-AhR signaling answered how a receptor-driven pathway converges on glycogenolysis to confer endocrine therapy resistance.\",\n      \"evidence\": \"P2Y12/AhR inhibition, PYGL knockdown, glycolysis and endocrine resistance assays in ER+ breast cancer cells and organoids\",\n      \"pmids\": [\"41974649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional vs indirect control of PYGL by AhR not distinguished\", \"Mechanism of glycolysis-to-resistance coupling not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating a cell-autonomous neuronal requirement for the PYGL ortholog answered whether neuronal glycogenolysis sustains glycolytic plasticity and synaptic function under metabolic stress.\",\n      \"evidence\": \"RNAi screen in C. elegans with single-neuron HYlight glycolytic sensor imaging, mitochondrial epistasis, and synaptic vesicle cycle assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.10.648039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog study not yet peer-reviewed\", \"Conservation of neuronal glycogenolytic plasticity in mammals untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple transcriptional, epigenetic, and post-translational inputs are integrated to set PYGL activity in a tissue- and context-specific manner, and the structural basis of its LDHA interaction, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating Ser15/Ser430 modifications with catalysis\", \"Direct vs indirect nature and stoichiometry of PYGL-LDHA complex unresolved\", \"Tissue-specific hierarchy of HIF1\\u03b1, FOXO3a, and methylation control unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LDHA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}