{"gene":"PGM3","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2002,"finding":"PGM3 (human phosphoglucomutase 3) was identified as identical to AGM1 (N-acetylglucosamine-phosphate mutase). COS7 cells transfected with AGM1 alleles produced proteins with electrophoretic patterns matching PGM3 isozymes, and AGM1 allele-specific products showed phosphoglucomutase activity on GlcNAc substrates.","method":"Transfection of COS7 cells with AGM1 alleles, isozyme detection electrophoresis, enzymatic activity assay","journal":"Annals of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct enzymatic assay plus transfection expression system, multiple orthogonal lines of evidence (electrophoretic mobility, enzymatic activity, allele frequency concordance in 20 individuals)","pmids":["12174217"],"is_preprint":false},{"year":2007,"finding":"Mouse Pgm3 (ortholog of human PGM3) catalyzes the interconversion of GlcNAc-6-phosphate and GlcNAc-1-phosphate as a key step in the hexosamine biosynthesis pathway producing UDP-GlcNAc. Hypomorphic Pgm3 alleles in mice caused graded reductions in UDP-GlcNAc levels and specific changes in protein glycosylation. Complete loss of Pgm3 was lethal prior to implantation; partial loss caused sterility, altered pancreatic architecture, anemia, leukopenia, and thrombocytopenia.","method":"Mouse hypomorphic alleles (in vivo genetic models), UDP-GlcNAc quantification, glycosylation analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — graded genetic loss-of-function in vivo with defined biochemical (UDP-GlcNAc levels) and cellular phenotypic readouts; multiple alleles tested","pmids":["17548465"],"is_preprint":false},{"year":2014,"finding":"Autosomal recessive hypomorphic mutations in PGM3 reduce PGM3 enzymatic activity, decrease UDP-GlcNAc levels, and impair O- and N-linked protein glycosylation in patient cells, resulting in a congenital disorder of glycosylation with atopy, immune deficiency, autoimmunity, and hypomyelination.","method":"Enzymatic activity assays, nucleotide sugar/sugar phosphate analysis, MALDI-TOF mass spectrometry of glycans, immunoblotting, quantitative RT-PCR, whole-exome sequencing","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical methods (enzymatic assay, mass spectrometry, metabolite quantification) in patient cells; independently replicated in concurrent publications","pmids":["24589341"],"is_preprint":false},{"year":2014,"finding":"Homozygous hypomorphic PGM3 mutations (p.Glu340del, p.Leu83Ser, p.Asp502Tyr) impair biosynthetic reactions involving UDP-GlcNAc and cause aberrant glycosylation in leukocytes, specifically reducing tri-antennary and tetra-antennary N-glycans, with impaired T-cell proliferation and differentiation.","method":"Western blotting, mass spectrometry glycomic analysis, SNP-chip genotyping, high-throughput sequencing, T-cell proliferation and differentiation assays","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct glycomic mass spectrometry plus enzymatic pathway analysis plus T-cell functional assays; independently replicates findings from PMID 24589341","pmids":["24698316"],"is_preprint":false},{"year":2014,"finding":"PGM3 catalyzes the conversion of GlcNAc-6-phosphate to GlcNAc-1-phosphate in the UDP-GlcNAc synthesis pathway. Disease-associated PGM3 variants expressed in E. coli showed reduced enzymatic activity for all mutants tested, confirming loss-of-function mechanism.","method":"Functional expression of disease-associated PGM3 variants in E. coli, enzymatic activity assays, whole-exome sequencing","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic reconstitution of multiple disease variants in E. coli with activity measurement","pmids":["24931394"],"is_preprint":false},{"year":2018,"finding":"FR054, a small-molecule inhibitor of PGM3, reduces both N- and O-glycosylation levels in breast cancer cells, decreases cancer cell adhesion and migration, activates the Unfolded Protein Response (UPR), and causes intracellular ROS accumulation, suppressing tumor growth in MDA-MB-231 xenograft mice.","method":"Cell proliferation/survival assays, glycosylation measurement, UPR activation assays, ROS measurement, xenograft mouse model, PGM3 inhibitor FR054","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with multiple cellular readouts and in vivo xenograft confirmation; single lab","pmids":["29515119"],"is_preprint":false},{"year":2022,"finding":"PGM3 maintains β-catenin activity in colorectal cancer cells via PGM3-mediated O-GlcNAcylation. PGM3 knockdown or inhibition of O-GlcNAc transferase decreased β-catenin activity and downstream target expression.","method":"PGM3 knockdown, O-GlcNAc transferase inhibition, β-catenin activity and target expression measurement, functional proliferation/migration assays","journal":"Experimental biology and medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic knockdown and pharmacological inhibition with defined pathway readout (β-catenin/O-GlcNAcylation); single lab, two orthogonal perturbations","pmids":["35723049"],"is_preprint":false},{"year":2022,"finding":"KRAS/LKB1 co-mutant lung cancer cells exhibit increased dependence on PGM3 activity. Genetic or pharmacologic suppression of PGM3 reduced KRAS/LKB1 co-mutant tumor growth in vitro and in vivo, defining PGM3 as a metabolic vulnerability in this cancer subtype.","method":"Genetic PGM3 suppression, pharmacological PGM3 inhibition, in vitro cell viability assays, in vivo tumor growth models","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacologic loss-of-function with in vitro and in vivo tumor growth readouts; single lab","pmids":["35011738"],"is_preprint":false},{"year":2024,"finding":"PGM3 inhibition impairs TCR-mediated CD4+ T cell proliferation and reduces synthesis of UDP-GlcNAc, complex N-glycans, and O-GlcNAc in a dose-dependent manner. Partial loss of PGM3 activity preferentially enhances Th1 and Th2 differentiation while attenuating Th17 and Treg differentiation.","method":"PGM3 inhibitor treatment, CD4+ T cell proliferation assays, UDP-GlcNAc quantification, N-glycan and O-GlcNAc measurement, T helper cell differentiation assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with multiple orthogonal biochemical and functional readouts; single lab","pmids":["39776909"],"is_preprint":false},{"year":2025,"finding":"PGM3 controls flux through both the de novo hexosamine synthesis and salvage (NAGK-mediated) pathways. PGM3 inhibition down-regulates other hexosamine pathway enzymes and suppresses SREBP-1 activation by reducing N-glycosylation of SCAP (the SREBP-1 transporter), disrupting a SREBP-1–hexosamine synthesis positive feedback loop and inhibiting glioblastoma cell growth.","method":"PGM3 inhibition (FR054), SCAP N-glycosylation measurement, SREBP-1 activation assays, hexosamine enzyme expression analysis, in vitro and in vivo GBM models","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with direct biochemical readouts (SCAP glycosylation, SREBP-1 activation) and in vivo validation; single lab","pmids":["40249802"],"is_preprint":false},{"year":2026,"finding":"PSMD11 interacts with PGM3 protein and reduces its ubiquitination and proteasomal degradation. Parkin acts as the E3 ubiquitin ligase that ubiquitinates and destabilizes PGM3, while PSMD11 competes with Parkin for PGM3 binding, thereby stabilizing PGM3 and enhancing glycolysis and OXPHOS in bladder cancer.","method":"Co-immunoprecipitation, ubiquitination assays, proteasomal degradation assays, PGM3 knockdown, glycolysis and OXPHOS measurement","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP and ubiquitination assay establishing PSMD11–PGM3–Parkin interaction; single lab","pmids":["41942430"],"is_preprint":false},{"year":2023,"finding":"PGM3 inhibition (FR054) combined with erastin induces Unfolded Protein Response (UPR) activation, NRF2 activation, oxidative stress, increased glutamine metabolism dependence, and ferroptotic cell death in pancreatic cancer cells.","method":"PGM3 inhibitor FR054 treatment, western blot for UPR markers, NRF2 activation assays, HPLC, metabolomics, cell death assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pharmacological inhibition with multiple biochemical readouts; single lab","pmids":["37260977"],"is_preprint":false},{"year":1974,"finding":"PGM3 was mapped to human chromosome 6 by synteny with HL-A, ME1, and IPO-B loci in man–Chinese hamster somatic cell hybrids.","method":"Somatic cell hybrid segregation analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — chromosomal mapping by segregation, no direct enzymatic or protein-level mechanism established; replicated in subsequent mapping studies","pmids":["4362641"],"is_preprint":false}],"current_model":"PGM3 (identical to AGM1/PAGM) is a phosphoacetylglucosamine mutase that catalyzes conversion of GlcNAc-6-phosphate to GlcNAc-1-phosphate, a critical step in the hexosamine biosynthesis pathway for UDP-GlcNAc synthesis; its activity is required for N- and O-linked protein glycosylation, and partial or complete loss-of-function leads to reduced UDP-GlcNAc, aberrant glycosylation, immune deficiency, and developmental abnormalities, while in cancer contexts PGM3 sustains tumor growth through glycosylation-dependent mechanisms including maintenance of β-catenin O-GlcNAcylation and SCAP N-glycosylation-mediated SREBP-1 activation; PGM3 protein stability is regulated by Parkin-mediated ubiquitination and proteasomal degradation, antagonized by PSMD11."},"narrative":{"mechanistic_narrative":"PGM3, identical to the N-acetylglucosamine-phosphate mutase AGM1, catalyzes the interconversion of GlcNAc-6-phosphate and GlcNAc-1-phosphate, a key step in the hexosamine biosynthesis pathway that produces UDP-GlcNAc [PMID:12174217, PMID:17548465, PMID:24931394]. Through this single biochemical activity, PGM3 governs the cellular supply of UDP-GlcNAc required for N-linked and O-linked protein glycosylation; graded loss of PGM3 in mice produces proportional reductions in UDP-GlcNAc and specific glycosylation defects, with complete loss causing pre-implantation lethality [PMID:17548465]. In humans, autosomal-recessive hypomorphic PGM3 mutations reduce enzymatic activity and UDP-GlcNAc levels, impairing tri- and tetra-antennary N-glycan synthesis and causing a congenital disorder of glycosylation with immune deficiency, atopy, autoimmunity, and defective T-cell proliferation and differentiation [PMID:24589341, PMID:24698316, PMID:24931394]. PGM3 also acts as a metabolic dependency in cancer, where its glycosylation output sustains tumor growth through mechanisms including maintenance of β-catenin O-GlcNAcylation [PMID:35723049] and SCAP N-glycosylation-dependent SREBP-1 activation within a hexosamine-SREBP-1 feedback loop [PMID:40249802]; pharmacologic PGM3 inhibition suppresses glycosylation, triggers the unfolded protein response and oxidative stress, and impairs tumor growth across multiple cancer contexts [PMID:29515119, PMID:35011738, PMID:37260977]. PGM3 protein stability is set by an ubiquitin-proteasome axis in which Parkin ubiquitinates and destabilizes PGM3 while PSMD11 competes for binding to stabilize it [PMID:41942430].","teleology":[{"year":2002,"claim":"Established that the genetically defined PGM3 locus encodes the same protein as the AGM1 N-acetylglucosamine-phosphate mutase, unifying a genetic marker with a defined enzymatic activity.","evidence":"Transfection of AGM1 alleles into COS7 cells with isozyme electrophoresis and GlcNAc-substrate enzymatic assays","pmids":["12174217"],"confidence":"High","gaps":["Did not define the in vivo metabolic consequences of the activity","No structural basis for catalysis"]},{"year":2007,"claim":"Placed PGM3 activity quantitatively within the hexosamine pathway by showing that graded enzymatic loss scales UDP-GlcNAc levels and glycosylation, establishing it as a dosage-sensitive metabolic node essential for development.","evidence":"Mouse hypomorphic allelic series with UDP-GlcNAc quantification and glycosylation analysis","pmids":["17548465"],"confidence":"High","gaps":["Specific glycoproteins driving phenotypes not identified","Mechanism of pre-implantation lethality unresolved"]},{"year":2014,"claim":"Defined PGM3 deficiency as a human congenital disorder of glycosylation, linking reduced enzymatic activity and UDP-GlcNAc to immune and neurological disease, and reconstituted disease variants to confirm a loss-of-function mechanism.","evidence":"Whole-exome sequencing, enzymatic assays in patient cells and E. coli-expressed variants, glycan mass spectrometry, and T-cell functional assays across three concurrent studies","pmids":["24589341","24698316","24931394"],"confidence":"High","gaps":["Why immune cells are preferentially affected not fully explained","Genotype-phenotype severity relationships incompletely mapped"]},{"year":2022,"claim":"Identified PGM3 as a cancer metabolic dependency whose glycosylation output sustains oncogenic signaling, including β-catenin O-GlcNAcylation in colorectal cancer and synthetic vulnerability in KRAS/LKB1 co-mutant lung cancer.","evidence":"PGM3 knockdown and pharmacologic inhibition with β-catenin activity readouts; genetic/pharmacologic suppression with in vitro and in vivo tumor growth models","pmids":["35723049","35011738"],"confidence":"Medium","gaps":["Causal chain from glycosylation to each oncogenic output not fully dissected","Single-lab findings per cancer type"]},{"year":2025,"claim":"Extended the cancer mechanism to lipogenic control, showing PGM3 governs both de novo and salvage hexosamine flux and sustains a SREBP-1 feedback loop via SCAP N-glycosylation.","evidence":"FR054 inhibition with SCAP glycosylation and SREBP-1 activation assays and in vivo glioblastoma models","pmids":["40249802"],"confidence":"Medium","gaps":["Direct demonstration that SCAP is the rate-limiting glycosylated substrate lacking","Generalizability beyond GBM untested"]},{"year":2026,"claim":"Revealed post-translational control of PGM3 abundance through a Parkin/PSMD11 axis, identifying how PGM3 protein levels are tuned independently of transcription.","evidence":"Reciprocal co-immunoprecipitation, ubiquitination and degradation assays, and metabolic readouts in bladder cancer","pmids":["41942430"],"confidence":"Medium","gaps":["Ubiquitination site on PGM3 not mapped","Signals controlling Parkin/PSMD11 competition unknown","Single-lab finding"]},{"year":null,"claim":"It remains unresolved how PGM3 enzymatic flux is allosterically or structurally regulated and which specific glycoprotein substrates mediate its distinct developmental, immune, and oncogenic phenotypes.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of human PGM3 in the corpus","Substrate-level glycoprotein specificity unmapped","Connection between metabolic regulation and disease severity unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,4]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,4,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["PSMD11","PRKN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95394","full_name":"Phosphoacetylglucosamine mutase","aliases":["Acetylglucosamine phosphomutase","N-acetylglucosamine-phosphate mutase","Phosphoglucomutase-3","PGM 3"],"length_aa":542,"mass_kda":59.9,"function":"Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during the synthesis of uridine diphosphate/UDP-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways including protein N- and O-glycosylation","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O95394/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PGM3","classification":"Not Classified","n_dependent_lines":329,"n_total_lines":1208,"dependency_fraction":0.2723509933774834},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PGM3","total_profiled":1310},"omim":[{"mim_id":"615816","title":"IMMUNODEFICIENCY 23; IMD23","url":"https://www.omim.org/entry/615816"},{"mim_id":"604571","title":"MHC CLASS I DEFICIENCY 1; MHC1D1","url":"https://www.omim.org/entry/604571"},{"mim_id":"600981","title":"PHOSPHOGLUCOMUTASE 5; PGM5","url":"https://www.omim.org/entry/600981"},{"mim_id":"600145","title":"SACRAL DEFECT WITH ANTERIOR MENINGOCELE","url":"https://www.omim.org/entry/600145"},{"mim_id":"251450","title":"DESBUQUOIS DYSPLASIA 1; DBQD1","url":"https://www.omim.org/entry/251450"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PGM3"},"hgnc":{"alias_symbol":["AGM1","DKFZP434B187","PAGM"],"prev_symbol":[]},"alphafold":{"accession":"O95394","domains":[{"cath_id":"3.40.120.10","chopping":"4-157","consensus_level":"high","plddt":96.6663,"start":4,"end":157},{"cath_id":"3.40.120.10","chopping":"183-294","consensus_level":"medium","plddt":93.1907,"start":183,"end":294},{"cath_id":"3.40.120,3.40.120","chopping":"299-422_434-443","consensus_level":"medium","plddt":96.409,"start":299,"end":443},{"cath_id":"3.30.310.50","chopping":"450-532","consensus_level":"high","plddt":95.0086,"start":450,"end":532}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95394","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95394-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95394-F1-predicted_aligned_error_v6.png","plddt_mean":95.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PGM3","jax_strain_url":"https://www.jax.org/strain/search?query=PGM3"},"sequence":{"accession":"O95394","fasta_url":"https://rest.uniprot.org/uniprotkb/O95394.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95394/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95394"}},"corpus_meta":[{"pmid":"24589341","id":"PMC_24589341","title":"Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment.","date":"2014","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24589341","citation_count":197,"is_preprint":false},{"pmid":"24698316","id":"PMC_24698316","title":"Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels.","date":"2014","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24698316","citation_count":155,"is_preprint":false},{"pmid":"24931394","id":"PMC_24931394","title":"PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24931394","citation_count":149,"is_preprint":false},{"pmid":"4362641","id":"PMC_4362641","title":"Human antigen and enzyme markers in man-Chinese hamster somatic cell hybrids: evidence for synteny between the HL-A, PGM3, ME1, and IPO-B loci.","date":"1974","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/4362641","citation_count":134,"is_preprint":false},{"pmid":"7535592","id":"PMC_7535592","title":"Characterization of a new monoclonal antibody (PG-M3) directed against the aminoterminal portion of the PML gene product: immunocytochemical evidence for high expression of PML proteins on activated macrophages, endothelial cells, and epithelia.","date":"1995","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/7535592","citation_count":101,"is_preprint":false},{"pmid":"9354674","id":"PMC_9354674","title":"Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-PML).","date":"1997","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9354674","citation_count":96,"is_preprint":false},{"pmid":"29515119","id":"PMC_29515119","title":"Inhibition of the Hexosamine Biosynthetic Pathway by targeting PGM3 causes breast cancer growth arrest and apoptosis.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29515119","citation_count":69,"is_preprint":false},{"pmid":"17548465","id":"PMC_17548465","title":"Agm1/Pgm3-mediated sugar nucleotide synthesis is essential for hematopoiesis and development.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17548465","citation_count":56,"is_preprint":false},{"pmid":"26687240","id":"PMC_26687240","title":"Glycoproteomic studies of IgE from a novel hyper IgE syndrome linked to PGM3 mutation.","date":"2015","source":"Glycoconjugate 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Cancer.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35011738","citation_count":18,"is_preprint":false},{"pmid":"6450030","id":"PMC_6450030","title":"Assignment of PGM3 to the long arm of human chromosome 6. Studies using Chinese hamster X human cell hybrids containing a human 6/15 translocation.","date":"1980","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/6450030","citation_count":15,"is_preprint":false},{"pmid":"33098103","id":"PMC_33098103","title":"Novel PGM3 compound heterozygous variants with IgE-related dermatitis, lymphopenia, without syndromic features.","date":"2020","source":"Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33098103","citation_count":12,"is_preprint":false},{"pmid":"36566211","id":"PMC_36566211","title":"Novel PGM3 mutation in two siblings with combined immunodeficiency and childhood bullous pemphigoid: a case report and review of the literature.","date":"2022","source":"Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36566211","citation_count":12,"is_preprint":false},{"pmid":"30157810","id":"PMC_30157810","title":"Eleven percent intact PGM3 in a severely immunodeficient patient with a novel splice-site mutation, a case report.","date":"2018","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/30157810","citation_count":12,"is_preprint":false},{"pmid":"468082","id":"PMC_468082","title":"Studies on the frequencies of PGM1, PGM3 and Es-D types from hair roots in Japanese subjects and the determination of these types from old hair roots.","date":"1979","source":"Forensic science international","url":"https://pubmed.ncbi.nlm.nih.gov/468082","citation_count":12,"is_preprint":false},{"pmid":"35723049","id":"PMC_35723049","title":"PGM3 regulates beta-catenin activity to promote colorectal cancer cell progression.","date":"2022","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/35723049","citation_count":11,"is_preprint":false},{"pmid":"23103740","id":"PMC_23103740","title":"The PGM3 gene encodes the major phosphoribomutase in the yeast Saccharomyces cerevisiae.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23103740","citation_count":11,"is_preprint":false},{"pmid":"6457600","id":"PMC_6457600","title":"A null mutation at the mouse Phosphoglucomutase-1 locus and a new locus Pgm-3.","date":"1981","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/6457600","citation_count":11,"is_preprint":false},{"pmid":"6583850","id":"PMC_6583850","title":"Provisional assignment of MPI, PKM2, PGM3, and ME1 to Chinese hamster chromosome 4.","date":"1984","source":"Somatic cell and molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/6583850","citation_count":10,"is_preprint":false},{"pmid":"882849","id":"PMC_882849","title":"Map order of the linkage group GLO-Bf-HLA-A-PGM3 on human chromosome 6.","date":"1977","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/882849","citation_count":10,"is_preprint":false},{"pmid":"1140813","id":"PMC_1140813","title":"Population genetics of human red cell phosphoclucomutase isozyme PGM3 (E.C.: 2.7.5.1). Gene frequencies in Southwestern Germany.","date":"1975","source":"Humangenetik","url":"https://pubmed.ncbi.nlm.nih.gov/1140813","citation_count":10,"is_preprint":false},{"pmid":"37260977","id":"PMC_37260977","title":"PGM3 inhibition shows cooperative effects with erastin inducing pancreatic cancer cell death via activation of the unfolded protein response.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37260977","citation_count":8,"is_preprint":false},{"pmid":"39776909","id":"PMC_39776909","title":"PGM3 insufficiency: a glycosylation disorder causing a notable T cell defect.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39776909","citation_count":7,"is_preprint":false},{"pmid":"33193641","id":"PMC_33193641","title":"Heterozygous PGM3 Variants Are Associated With Idiopathic Focal Epilepsy With Incomplete Penetrance.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33193641","citation_count":7,"is_preprint":false},{"pmid":"1974653","id":"PMC_1974653","title":"AGM1+ spleen cells contain gamma interferon (IFN-gamma) gene transcripts in the early, sex-dependent production of IFN-gamma after picornavirus infection.","date":"1990","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/1974653","citation_count":7,"is_preprint":false},{"pmid":"40249802","id":"PMC_40249802","title":"Targeting PGM3 abolishes SREBP-1 activation-hexosamine synthesis feedback regulation to effectively suppress brain tumor growth.","date":"2025","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/40249802","citation_count":5,"is_preprint":false},{"pmid":"31231132","id":"PMC_31231132","title":"Clinical Utility Gene Card for: PGM3 defective congenital disorder of glycosylation.","date":"2019","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/31231132","citation_count":5,"is_preprint":false},{"pmid":"20701624","id":"PMC_20701624","title":"Evaluation of PG-M3 antibody in the diagnosis of acute promyelocytic leukaemia.","date":"2010","source":"European journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/20701624","citation_count":5,"is_preprint":false},{"pmid":"10859383","id":"PMC_10859383","title":"Cross-reactivity of the anti-PML antibody PG-M3 with the herpes simplex virus type 1 immediate early protein ICP4.","date":"2000","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/10859383","citation_count":5,"is_preprint":false},{"pmid":"730170","id":"PMC_730170","title":"Mapping of the linkage group GLO--Bf--HLA-B,C,A--PGM3. 2. Segregation analysis.","date":"1978","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/730170","citation_count":5,"is_preprint":false},{"pmid":"36097642","id":"PMC_36097642","title":"A novel variant in GNPNAT1 gene causing a spondylo-epi-metaphyseal dysplasia resembling PGM3-Desbuquois like dysplasia.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/36097642","citation_count":4,"is_preprint":false},{"pmid":"32556600","id":"PMC_32556600","title":"Complete genome analysis of Pantoea agglomerans-infecting bacteriophage vB_PagM_AAM22.","date":"2020","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/32556600","citation_count":4,"is_preprint":false},{"pmid":"730169","id":"PMC_730169","title":"Mapping of the linkage group GLO--Bf--HLA-B,C,A--PGM3. 1. Recombination frequencies.","date":"1978","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/730169","citation_count":4,"is_preprint":false},{"pmid":"31465847","id":"PMC_31465847","title":"Role and dynamics of an agmatinase-like protein (AGM-1) in Neurospora crassa.","date":"2019","source":"Fungal genetics and biology : FG & B","url":"https://pubmed.ncbi.nlm.nih.gov/31465847","citation_count":3,"is_preprint":false},{"pmid":"2821877","id":"PMC_2821877","title":"[Gene frequencies of the enzymes ALADH, GOT2, GPT, PGM3, SAHH and UMPK in a Swiss population].","date":"1987","source":"Anthropologischer Anzeiger; Bericht uber die biologisch-anthropologische Literatur","url":"https://pubmed.ncbi.nlm.nih.gov/2821877","citation_count":3,"is_preprint":false},{"pmid":"746531","id":"PMC_746531","title":"Application of a computer program for the mapping of a gene locus to the disputed PGM3 localization on human chromosome 6.","date":"1978","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/746531","citation_count":3,"is_preprint":false},{"pmid":"36768728","id":"PMC_36768728","title":"Multi-Omics Profiling in PGM3 and STAT3 Deficiencies: A Tale of Two Patients.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36768728","citation_count":2,"is_preprint":false},{"pmid":"2978987","id":"PMC_2978987","title":"PGM3 polymorphism in human placenta samples from Bahia, Brazil.","date":"1988","source":"Gene geography : a computerized bulletin on human gene frequencies","url":"https://pubmed.ncbi.nlm.nih.gov/2978987","citation_count":1,"is_preprint":false},{"pmid":"34634482","id":"PMC_34634482","title":"Enzymatic characterization of agmatinase (AGM-1) from the filamentous fungus Neurospora crassa.","date":"2021","source":"Fungal genetics and biology : FG & B","url":"https://pubmed.ncbi.nlm.nih.gov/34634482","citation_count":1,"is_preprint":false},{"pmid":"41942430","id":"PMC_41942430","title":"PSMD11 stabilizes PGM3 by antagonizing Parkin to promote bladder cancer progression through energy metabolism reprogramming.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41942430","citation_count":0,"is_preprint":false},{"pmid":"2138119","id":"PMC_2138119","title":"A population study of leukocyte enzymes (GOT2, ME2 and PGM3) in Galicia (NW Spain).","date":"1990","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/2138119","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.20.604404","title":"Rapalink-1 reveals novel mTOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating mTOR activity and lifespan","date":"2024-07-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.20.604404","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23480,"output_tokens":3445,"usd":0.061058,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11039,"output_tokens":2541,"usd":0.05936,"stage2_stop_reason":"end_turn"},"total_usd":0.120418,"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\": 2002,\n      \"finding\": \"PGM3 (human phosphoglucomutase 3) was identified as identical to AGM1 (N-acetylglucosamine-phosphate mutase). COS7 cells transfected with AGM1 alleles produced proteins with electrophoretic patterns matching PGM3 isozymes, and AGM1 allele-specific products showed phosphoglucomutase activity on GlcNAc substrates.\",\n      \"method\": \"Transfection of COS7 cells with AGM1 alleles, isozyme detection electrophoresis, enzymatic activity assay\",\n      \"journal\": \"Annals of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct enzymatic assay plus transfection expression system, multiple orthogonal lines of evidence (electrophoretic mobility, enzymatic activity, allele frequency concordance in 20 individuals)\",\n      \"pmids\": [\"12174217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mouse Pgm3 (ortholog of human PGM3) catalyzes the interconversion of GlcNAc-6-phosphate and GlcNAc-1-phosphate as a key step in the hexosamine biosynthesis pathway producing UDP-GlcNAc. Hypomorphic Pgm3 alleles in mice caused graded reductions in UDP-GlcNAc levels and specific changes in protein glycosylation. Complete loss of Pgm3 was lethal prior to implantation; partial loss caused sterility, altered pancreatic architecture, anemia, leukopenia, and thrombocytopenia.\",\n      \"method\": \"Mouse hypomorphic alleles (in vivo genetic models), UDP-GlcNAc quantification, glycosylation analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — graded genetic loss-of-function in vivo with defined biochemical (UDP-GlcNAc levels) and cellular phenotypic readouts; multiple alleles tested\",\n      \"pmids\": [\"17548465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Autosomal recessive hypomorphic mutations in PGM3 reduce PGM3 enzymatic activity, decrease UDP-GlcNAc levels, and impair O- and N-linked protein glycosylation in patient cells, resulting in a congenital disorder of glycosylation with atopy, immune deficiency, autoimmunity, and hypomyelination.\",\n      \"method\": \"Enzymatic activity assays, nucleotide sugar/sugar phosphate analysis, MALDI-TOF mass spectrometry of glycans, immunoblotting, quantitative RT-PCR, whole-exome sequencing\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical methods (enzymatic assay, mass spectrometry, metabolite quantification) in patient cells; independently replicated in concurrent publications\",\n      \"pmids\": [\"24589341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Homozygous hypomorphic PGM3 mutations (p.Glu340del, p.Leu83Ser, p.Asp502Tyr) impair biosynthetic reactions involving UDP-GlcNAc and cause aberrant glycosylation in leukocytes, specifically reducing tri-antennary and tetra-antennary N-glycans, with impaired T-cell proliferation and differentiation.\",\n      \"method\": \"Western blotting, mass spectrometry glycomic analysis, SNP-chip genotyping, high-throughput sequencing, T-cell proliferation and differentiation assays\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct glycomic mass spectrometry plus enzymatic pathway analysis plus T-cell functional assays; independently replicates findings from PMID 24589341\",\n      \"pmids\": [\"24698316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PGM3 catalyzes the conversion of GlcNAc-6-phosphate to GlcNAc-1-phosphate in the UDP-GlcNAc synthesis pathway. Disease-associated PGM3 variants expressed in E. coli showed reduced enzymatic activity for all mutants tested, confirming loss-of-function mechanism.\",\n      \"method\": \"Functional expression of disease-associated PGM3 variants in E. coli, enzymatic activity assays, whole-exome sequencing\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic reconstitution of multiple disease variants in E. coli with activity measurement\",\n      \"pmids\": [\"24931394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FR054, a small-molecule inhibitor of PGM3, reduces both N- and O-glycosylation levels in breast cancer cells, decreases cancer cell adhesion and migration, activates the Unfolded Protein Response (UPR), and causes intracellular ROS accumulation, suppressing tumor growth in MDA-MB-231 xenograft mice.\",\n      \"method\": \"Cell proliferation/survival assays, glycosylation measurement, UPR activation assays, ROS measurement, xenograft mouse model, PGM3 inhibitor FR054\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with multiple cellular readouts and in vivo xenograft confirmation; single lab\",\n      \"pmids\": [\"29515119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PGM3 maintains β-catenin activity in colorectal cancer cells via PGM3-mediated O-GlcNAcylation. PGM3 knockdown or inhibition of O-GlcNAc transferase decreased β-catenin activity and downstream target expression.\",\n      \"method\": \"PGM3 knockdown, O-GlcNAc transferase inhibition, β-catenin activity and target expression measurement, functional proliferation/migration assays\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic knockdown and pharmacological inhibition with defined pathway readout (β-catenin/O-GlcNAcylation); single lab, two orthogonal perturbations\",\n      \"pmids\": [\"35723049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KRAS/LKB1 co-mutant lung cancer cells exhibit increased dependence on PGM3 activity. Genetic or pharmacologic suppression of PGM3 reduced KRAS/LKB1 co-mutant tumor growth in vitro and in vivo, defining PGM3 as a metabolic vulnerability in this cancer subtype.\",\n      \"method\": \"Genetic PGM3 suppression, pharmacological PGM3 inhibition, in vitro cell viability assays, in vivo tumor growth models\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacologic loss-of-function with in vitro and in vivo tumor growth readouts; single lab\",\n      \"pmids\": [\"35011738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PGM3 inhibition impairs TCR-mediated CD4+ T cell proliferation and reduces synthesis of UDP-GlcNAc, complex N-glycans, and O-GlcNAc in a dose-dependent manner. Partial loss of PGM3 activity preferentially enhances Th1 and Th2 differentiation while attenuating Th17 and Treg differentiation.\",\n      \"method\": \"PGM3 inhibitor treatment, CD4+ T cell proliferation assays, UDP-GlcNAc quantification, N-glycan and O-GlcNAc measurement, T helper cell differentiation assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with multiple orthogonal biochemical and functional readouts; single lab\",\n      \"pmids\": [\"39776909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PGM3 controls flux through both the de novo hexosamine synthesis and salvage (NAGK-mediated) pathways. PGM3 inhibition down-regulates other hexosamine pathway enzymes and suppresses SREBP-1 activation by reducing N-glycosylation of SCAP (the SREBP-1 transporter), disrupting a SREBP-1–hexosamine synthesis positive feedback loop and inhibiting glioblastoma cell growth.\",\n      \"method\": \"PGM3 inhibition (FR054), SCAP N-glycosylation measurement, SREBP-1 activation assays, hexosamine enzyme expression analysis, in vitro and in vivo GBM models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with direct biochemical readouts (SCAP glycosylation, SREBP-1 activation) and in vivo validation; single lab\",\n      \"pmids\": [\"40249802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PSMD11 interacts with PGM3 protein and reduces its ubiquitination and proteasomal degradation. Parkin acts as the E3 ubiquitin ligase that ubiquitinates and destabilizes PGM3, while PSMD11 competes with Parkin for PGM3 binding, thereby stabilizing PGM3 and enhancing glycolysis and OXPHOS in bladder cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, proteasomal degradation assays, PGM3 knockdown, glycolysis and OXPHOS measurement\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP and ubiquitination assay establishing PSMD11–PGM3–Parkin interaction; single lab\",\n      \"pmids\": [\"41942430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PGM3 inhibition (FR054) combined with erastin induces Unfolded Protein Response (UPR) activation, NRF2 activation, oxidative stress, increased glutamine metabolism dependence, and ferroptotic cell death in pancreatic cancer cells.\",\n      \"method\": \"PGM3 inhibitor FR054 treatment, western blot for UPR markers, NRF2 activation assays, HPLC, metabolomics, cell death assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pharmacological inhibition with multiple biochemical readouts; single lab\",\n      \"pmids\": [\"37260977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1974,\n      \"finding\": \"PGM3 was mapped to human chromosome 6 by synteny with HL-A, ME1, and IPO-B loci in man–Chinese hamster somatic cell hybrids.\",\n      \"method\": \"Somatic cell hybrid segregation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — chromosomal mapping by segregation, no direct enzymatic or protein-level mechanism established; replicated in subsequent mapping studies\",\n      \"pmids\": [\"4362641\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PGM3 (identical to AGM1/PAGM) is a phosphoacetylglucosamine mutase that catalyzes conversion of GlcNAc-6-phosphate to GlcNAc-1-phosphate, a critical step in the hexosamine biosynthesis pathway for UDP-GlcNAc synthesis; its activity is required for N- and O-linked protein glycosylation, and partial or complete loss-of-function leads to reduced UDP-GlcNAc, aberrant glycosylation, immune deficiency, and developmental abnormalities, while in cancer contexts PGM3 sustains tumor growth through glycosylation-dependent mechanisms including maintenance of β-catenin O-GlcNAcylation and SCAP N-glycosylation-mediated SREBP-1 activation; PGM3 protein stability is regulated by Parkin-mediated ubiquitination and proteasomal degradation, antagonized by PSMD11.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PGM3, identical to the N-acetylglucosamine-phosphate mutase AGM1, catalyzes the interconversion of GlcNAc-6-phosphate and GlcNAc-1-phosphate, a key step in the hexosamine biosynthesis pathway that produces UDP-GlcNAc [#0, #1, #4]. Through this single biochemical activity, PGM3 governs the cellular supply of UDP-GlcNAc required for N-linked and O-linked protein glycosylation; graded loss of PGM3 in mice produces proportional reductions in UDP-GlcNAc and specific glycosylation defects, with complete loss causing pre-implantation lethality [#1]. In humans, autosomal-recessive hypomorphic PGM3 mutations reduce enzymatic activity and UDP-GlcNAc levels, impairing tri- and tetra-antennary N-glycan synthesis and causing a congenital disorder of glycosylation with immune deficiency, atopy, autoimmunity, and defective T-cell proliferation and differentiation [#2, #3, #4]. PGM3 also acts as a metabolic dependency in cancer, where its glycosylation output sustains tumor growth through mechanisms including maintenance of β-catenin O-GlcNAcylation [#6] and SCAP N-glycosylation-dependent SREBP-1 activation within a hexosamine-SREBP-1 feedback loop [#9]; pharmacologic PGM3 inhibition suppresses glycosylation, triggers the unfolded protein response and oxidative stress, and impairs tumor growth across multiple cancer contexts [#5, #7, #11]. PGM3 protein stability is set by an ubiquitin-proteasome axis in which Parkin ubiquitinates and destabilizes PGM3 while PSMD11 competes for binding to stabilize it [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that the genetically defined PGM3 locus encodes the same protein as the AGM1 N-acetylglucosamine-phosphate mutase, unifying a genetic marker with a defined enzymatic activity.\",\n      \"evidence\": \"Transfection of AGM1 alleles into COS7 cells with isozyme electrophoresis and GlcNAc-substrate enzymatic assays\",\n      \"pmids\": [\"12174217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the in vivo metabolic consequences of the activity\", \"No structural basis for catalysis\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed PGM3 activity quantitatively within the hexosamine pathway by showing that graded enzymatic loss scales UDP-GlcNAc levels and glycosylation, establishing it as a dosage-sensitive metabolic node essential for development.\",\n      \"evidence\": \"Mouse hypomorphic allelic series with UDP-GlcNAc quantification and glycosylation analysis\",\n      \"pmids\": [\"17548465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific glycoproteins driving phenotypes not identified\", \"Mechanism of pre-implantation lethality unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined PGM3 deficiency as a human congenital disorder of glycosylation, linking reduced enzymatic activity and UDP-GlcNAc to immune and neurological disease, and reconstituted disease variants to confirm a loss-of-function mechanism.\",\n      \"evidence\": \"Whole-exome sequencing, enzymatic assays in patient cells and E. coli-expressed variants, glycan mass spectrometry, and T-cell functional assays across three concurrent studies\",\n      \"pmids\": [\"24589341\", \"24698316\", \"24931394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why immune cells are preferentially affected not fully explained\", \"Genotype-phenotype severity relationships incompletely mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified PGM3 as a cancer metabolic dependency whose glycosylation output sustains oncogenic signaling, including β-catenin O-GlcNAcylation in colorectal cancer and synthetic vulnerability in KRAS/LKB1 co-mutant lung cancer.\",\n      \"evidence\": \"PGM3 knockdown and pharmacologic inhibition with β-catenin activity readouts; genetic/pharmacologic suppression with in vitro and in vivo tumor growth models\",\n      \"pmids\": [\"35723049\", \"35011738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from glycosylation to each oncogenic output not fully dissected\", \"Single-lab findings per cancer type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the cancer mechanism to lipogenic control, showing PGM3 governs both de novo and salvage hexosamine flux and sustains a SREBP-1 feedback loop via SCAP N-glycosylation.\",\n      \"evidence\": \"FR054 inhibition with SCAP glycosylation and SREBP-1 activation assays and in vivo glioblastoma models\",\n      \"pmids\": [\"40249802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that SCAP is the rate-limiting glycosylated substrate lacking\", \"Generalizability beyond GBM untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed post-translational control of PGM3 abundance through a Parkin/PSMD11 axis, identifying how PGM3 protein levels are tuned independently of transcription.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, ubiquitination and degradation assays, and metabolic readouts in bladder cancer\",\n      \"pmids\": [\"41942430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site on PGM3 not mapped\", \"Signals controlling Parkin/PSMD11 competition unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PGM3 enzymatic flux is allosterically or structurally regulated and which specific glycoprotein substrates mediate its distinct developmental, immune, and oncogenic phenotypes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of human PGM3 in the corpus\", \"Substrate-level glycoprotein specificity unmapped\", \"Connection between metabolic regulation and disease severity unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 4, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PSMD11\", \"PRKN\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}