Affinage

PGM3

Phosphoacetylglucosamine mutase · UniProt O95394

Length
542 aa
Mass
59.9 kDa
Annotated
2026-06-10
49 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2002 High

    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

    PMID:12174217

    Open questions at the time
    • Did not define the in vivo metabolic consequences of the activity
    • No structural basis for catalysis
  2. 2007 High

    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

    PMID:17548465

    Open questions at the time
    • Specific glycoproteins driving phenotypes not identified
    • Mechanism of pre-implantation lethality unresolved
  3. 2014 High

    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

    PMID:24589341 PMID:24698316 PMID:24931394

    Open questions at the time
    • Why immune cells are preferentially affected not fully explained
    • Genotype-phenotype severity relationships incompletely mapped
  4. 2022 Medium

    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

    PMID:35011738 PMID:35723049

    Open questions at the time
    • Causal chain from glycosylation to each oncogenic output not fully dissected
    • Single-lab findings per cancer type
  5. 2025 Medium

    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

    PMID:40249802

    Open questions at the time
    • Direct demonstration that SCAP is the rate-limiting glycosylated substrate lacking
    • Generalizability beyond GBM untested
  6. 2026 Medium

    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

    PMID:41942430

    Open questions at the time
    • Ubiquitination site on PGM3 not mapped
    • Signals controlling Parkin/PSMD11 competition unknown
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No structural model of human PGM3 in the corpus
  • Substrate-level glycoprotein specificity unmapped
  • Connection between metabolic regulation and disease severity unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0016853 isomerase activity 3
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 2
Partners
PRKNPSMD11

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 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. Transfection of COS7 cells with AGM1 alleles, isozyme detection electrophoresis, enzymatic activity assay Annals of human genetics High 12174217
2007 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. Mouse hypomorphic alleles (in vivo genetic models), UDP-GlcNAc quantification, glycosylation analysis Molecular and cellular biology High 17548465
2014 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. Enzymatic activity assays, nucleotide sugar/sugar phosphate analysis, MALDI-TOF mass spectrometry of glycans, immunoblotting, quantitative RT-PCR, whole-exome sequencing The Journal of allergy and clinical immunology High 24589341
2014 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. Western blotting, mass spectrometry glycomic analysis, SNP-chip genotyping, high-throughput sequencing, T-cell proliferation and differentiation assays The Journal of allergy and clinical immunology High 24698316
2014 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. Functional expression of disease-associated PGM3 variants in E. coli, enzymatic activity assays, whole-exome sequencing American journal of human genetics High 24931394
2018 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. Cell proliferation/survival assays, glycosylation measurement, UPR activation assays, ROS measurement, xenograft mouse model, PGM3 inhibitor FR054 Cell death & disease Medium 29515119
2022 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. PGM3 knockdown, O-GlcNAc transferase inhibition, β-catenin activity and target expression measurement, functional proliferation/migration assays Experimental biology and medicine Medium 35723049
2022 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. Genetic PGM3 suppression, pharmacological PGM3 inhibition, in vitro cell viability assays, in vivo tumor growth models Cells Medium 35011738
2024 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. PGM3 inhibitor treatment, CD4+ T cell proliferation assays, UDP-GlcNAc quantification, N-glycan and O-GlcNAc measurement, T helper cell differentiation assays Frontiers in immunology Medium 39776909
2025 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. PGM3 inhibition (FR054), SCAP N-glycosylation measurement, SREBP-1 activation assays, hexosamine enzyme expression analysis, in vitro and in vivo GBM models Science advances Medium 40249802
2026 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. Co-immunoprecipitation, ubiquitination assays, proteasomal degradation assays, PGM3 knockdown, glycolysis and OXPHOS measurement Cell death & disease Medium 41942430
2023 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. PGM3 inhibitor FR054 treatment, western blot for UPR markers, NRF2 activation assays, HPLC, metabolomics, cell death assays Frontiers in oncology Medium 37260977
1974 PGM3 was mapped to human chromosome 6 by synteny with HL-A, ME1, and IPO-B loci in man–Chinese hamster somatic cell hybrids. Somatic cell hybrid segregation analysis Proceedings of the National Academy of Sciences of the United States of America Low 4362641

Source papers

Stage 0 corpus · 49 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment. The Journal of allergy and clinical immunology 197 24589341
2014 Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. The Journal of allergy and clinical immunology 155 24698316
2014 PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia. American journal of human genetics 149 24931394
1974 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. Proceedings of the National Academy of Sciences of the United States of America 134 4362641
1995 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. Blood 101 7535592
1997 Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-PML). Blood 96 9354674
2018 Inhibition of the Hexosamine Biosynthetic Pathway by targeting PGM3 causes breast cancer growth arrest and apoptosis. Cell death & disease 69 29515119
2007 Agm1/Pgm3-mediated sugar nucleotide synthesis is essential for hematopoiesis and development. Molecular and cellular biology 56 17548465
2015 Glycoproteomic studies of IgE from a novel hyper IgE syndrome linked to PGM3 mutation. Glycoconjugate journal 34 26687240
2017 A founder mutation underlies a severe form of phosphoglutamase 3 (PGM3) deficiency in Tunisian patients. Molecular immunology 30 28704707
2014 Hyper-IgE syndromes: reviewing PGM3 deficiency. Current opinion in pediatrics 29 25365149
2015 Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in the phosphoglucomutase 3 (PGM3) gene. Clinical immunology (Orlando, Fla.) 28 26482871
2002 Identification of human phosphoglucomutase 3 (PGM3) as N-acetylglucosamine-phosphate mutase (AGM1). Annals of human genetics 27 12174217
2017 A Novel PGM3 Mutation Is Associated With a Severe Phenotype of Bone Marrow Failure, Severe Combined Immunodeficiency, Skeletal Dysplasia, and Congenital Malformations. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 26 28543917
1981 Linkage of Pgm-3 in the house mouse and homologies of three phosphoglucomutase loci in mouse and man. Biochemical genetics 23 6457599
2004 Immunofluorescent analysis with the anti-PML monoclonal antibody PG-M3 for rapid and accurate genetic diagnosis of acute promyelocytic leukemia. Annals of hematology 21 15278297
2000 Rapid diagnosis of acute promyelocytic leukemia by analyzing the immunocytochemical pattern of the PML protein with the monoclonal antibody PG-M3. American journal of clinical pathology 21 11068554
2022 Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer. Cells 18 35011738
1980 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. Cytogenetics and cell genetics 15 6450030
2022 Novel PGM3 mutation in two siblings with combined immunodeficiency and childhood bullous pemphigoid: a case report and review of the literature. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 12 36566211
2020 Novel PGM3 compound heterozygous variants with IgE-related dermatitis, lymphopenia, without syndromic features. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology 12 33098103
2018 Eleven percent intact PGM3 in a severely immunodeficient patient with a novel splice-site mutation, a case report. BMC pediatrics 12 30157810
1979 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. Forensic science international 12 468082
2022 PGM3 regulates beta-catenin activity to promote colorectal cancer cell progression. Experimental biology and medicine (Maywood, N.J.) 11 35723049
2012 The PGM3 gene encodes the major phosphoribomutase in the yeast Saccharomyces cerevisiae. FEBS letters 11 23103740
1981 A null mutation at the mouse Phosphoglucomutase-1 locus and a new locus Pgm-3. Biochemical genetics 11 6457600
1984 Provisional assignment of MPI, PKM2, PGM3, and ME1 to Chinese hamster chromosome 4. Somatic cell and molecular genetics 10 6583850
1977 Map order of the linkage group GLO-Bf-HLA-A-PGM3 on human chromosome 6. Scandinavian journal of immunology 10 882849
1975 Population genetics of human red cell phosphoclucomutase isozyme PGM3 (E.C.: 2.7.5.1). Gene frequencies in Southwestern Germany. Humangenetik 10 1140813
2023 PGM3 inhibition shows cooperative effects with erastin inducing pancreatic cancer cell death via activation of the unfolded protein response. Frontiers in oncology 8 37260977
2024 PGM3 insufficiency: a glycosylation disorder causing a notable T cell defect. Frontiers in immunology 7 39776909
2020 Heterozygous PGM3 Variants Are Associated With Idiopathic Focal Epilepsy With Incomplete Penetrance. Frontiers in genetics 7 33193641
1990 AGM1+ spleen cells contain gamma interferon (IFN-gamma) gene transcripts in the early, sex-dependent production of IFN-gamma after picornavirus infection. Journal of virology 7 1974653
2025 Targeting PGM3 abolishes SREBP-1 activation-hexosamine synthesis feedback regulation to effectively suppress brain tumor growth. Science advances 5 40249802
2019 Clinical Utility Gene Card for: PGM3 defective congenital disorder of glycosylation. European journal of human genetics : EJHG 5 31231132
2010 Evaluation of PG-M3 antibody in the diagnosis of acute promyelocytic leukaemia. European journal of clinical investigation 5 20701624
2000 Cross-reactivity of the anti-PML antibody PG-M3 with the herpes simplex virus type 1 immediate early protein ICP4. The Journal of general virology 5 10859383
1978 Mapping of the linkage group GLO--Bf--HLA-B,C,A--PGM3. 2. Segregation analysis. Human genetics 5 730170
2022 A novel variant in GNPNAT1 gene causing a spondylo-epi-metaphyseal dysplasia resembling PGM3-Desbuquois like dysplasia. American journal of medical genetics. Part A 4 36097642
2020 Complete genome analysis of Pantoea agglomerans-infecting bacteriophage vB_PagM_AAM22. Archives of virology 4 32556600
1978 Mapping of the linkage group GLO--Bf--HLA-B,C,A--PGM3. 1. Recombination frequencies. Human genetics 4 730169
2019 Role and dynamics of an agmatinase-like protein (AGM-1) in Neurospora crassa. Fungal genetics and biology : FG & B 3 31465847
1987 [Gene frequencies of the enzymes ALADH, GOT2, GPT, PGM3, SAHH and UMPK in a Swiss population]. Anthropologischer Anzeiger; Bericht uber die biologisch-anthropologische Literatur 3 2821877
1978 Application of a computer program for the mapping of a gene locus to the disputed PGM3 localization on human chromosome 6. Tissue antigens 3 746531
2023 Multi-Omics Profiling in PGM3 and STAT3 Deficiencies: A Tale of Two Patients. International journal of molecular sciences 2 36768728
2021 Enzymatic characterization of agmatinase (AGM-1) from the filamentous fungus Neurospora crassa. Fungal genetics and biology : FG & B 1 34634482
1988 PGM3 polymorphism in human placenta samples from Bahia, Brazil. Gene geography : a computerized bulletin on human gene frequencies 1 2978987
2026 PSMD11 stabilizes PGM3 by antagonizing Parkin to promote bladder cancer progression through energy metabolism reprogramming. Cell death & disease 0 41942430
1990 A population study of leukocyte enzymes (GOT2, ME2 and PGM3) in Galicia (NW Spain). Human heredity 0 2138119

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