PGM3 (also called AGM1 or phosphoacetylglucosamine mutase, PAGM) is a cytosolic, Mg2+-dependent enzyme of the alpha-D-phosphohexomutase superfamily that catalyzes the reversible interconversion of N-acetyl-D-glucosamine 6-phosphate (GlcNAc-6-P) and N-acetyl-alpha-D-glucosamine 1-phosphate (GlcNAc-1-P) (EC 5.4.2.3). This is the third step of the hexosamine biosynthetic pathway; the GlcNAc-1-P product is the substrate of UDP-N-acetylglucosamine pyrophosphorylase (UAP1), which generates UDP-GlcNAc, the activated sugar-nucleotide donor used across N-linked and O-linked protein glycosylation, proteoglycan and glycolipid synthesis, GPI-anchor assembly, and nucleocytoplasmic O-GlcNAcylation. Like other phosphohexomutases, PGM3 uses an intramolecular phosphoryl-transfer mechanism proceeding through a phospho-serine enzyme intermediate (active-site Ser64) and a glucose-1,6-bisphosphate / GlcNAc-1,6-bisphosphate cofactor, with a bound Mg2+ ion required for catalysis. It is broadly expressed across human tissues. Biallelic hypomorphic PGM3 variants cause a congenital disorder of glycosylation (PGM3-CDG; immunodeficiency-23, MIM:615816) presenting with severe atopy and elevated serum IgE, recurrent bacterial and viral infections, T- and B-cell lymphopenia, autoimmunity, skeletal dysplasia, and neurocognitive impairment with hypomyelination.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004610 phosphoacetylglucosamine mutase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the core catalytic activity of PGM3. This is the defining molecular function of the gene and is corroborated by multiple experimental annotations (IDA, EXP, IMP) and by the UniProt-curated EC 5.4.2.3 catalytic activity. Reason: PGM3 is the human phosphoacetylglucosamine mutase (AGM1); the term is at the correct level of specificity for its evolutionarily conserved enzymatic function. Supporting Evidence: file:human/PGM3/PGM3-uniprot.txt Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during |
| GO:0030097 hemopoiesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) annotation to hemopoiesis, propagated from the mouse ortholog (MGI:97566). PGM3 is a ubiquitous housekeeping metabolic enzyme; its requirement in hematopoiesis is an indirect, tissue-level consequence of UDP-GlcNAc supply rather than a distinct molecular activity of the protein. In mice, Pgm3-mediated UDP-GlcNAc synthesis is essential for hematopoiesis, and human patients show lymphopenia and bone-marrow failure. Reason: This is a downstream/pleiotropic developmental process reflecting the general requirement for glycosylation precursor supply, not the core biochemical function of PGM3. Retain as non-core context. Supporting Evidence: PMID:24698316 Pgm3-mediated UDP- GlcNAc synthesis is essential for hematopoiesis and development |
| GO:0006048 UDP-N-acetylglucosamine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to UDP-GlcNAc biosynthesis, the pathway in which PGM3 acts. PGM3 performs the penultimate step (GlcNAc-6-P to GlcNAc-1-P) of this pathway, generating the direct substrate for UAP1. This is a core biological process for PGM3 and is supported by multiple experimental annotations. Reason: Correct process at the appropriate level of specificity; the mutase step is a committed part of UDP-N-acetyl-alpha-D-glucosamine biosynthesis. Supporting Evidence: file:human/PGM3/PGM3-uniprot.txt Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during |
| GO:0000287 magnesium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based (IEA) annotation to magnesium ion binding. PGM3 is a Mg2+-dependent phosphohexomutase; UniProt curates a Mg2+ cofactor bound one per subunit, coordinated by residues including Asp276/278/280 and via the active-site phospho-Ser64. Supported and biologically appropriate. Reason: Consistent with the Mg2+-dependent catalytic mechanism and curated cofactor binding sites in UniProt; a genuine, relevant molecular function. Supporting Evidence: file:human/PGM3/PGM3-uniprot.txt Note=Binds 1 Mg(2+) ion per subunit. |
| GO:0004610 phosphoacetylglucosamine mutase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) annotation to the core catalytic activity via ARBA/InterPro and Rhea/EC mapping (RHEA:23804, EC:5.4.2.3). Redundant with, and fully consistent with, the experimental (IDA/EXP/IMP) annotations of the same activity. Reason: Electronic annotation of the correct, experimentally established enzymatic function; consistent with UniProt EC 5.4.2.3. Supporting Evidence: file:human/PGM3/PGM3-uniprot.txt Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro-based (IEA) annotation to the broad parent process carbohydrate metabolic process. This is correct but far more general than the specific role captured by UDP-N-acetylglucosamine biosynthetic process, which is separately and experimentally annotated. Reason: Overly general grandparent term; the specific, experimentally supported process (GO:0006048) already covers PGM3's role, making this parent uninformative. Supporting Evidence: file:human/PGM3/PGM3-uniprot.txt Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during |
| GO:0016868 intramolecular phosphotransferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro-based (IEA) annotation to the parent activity class of the mutase reaction. PGM3 does catalyze an intramolecular phosphoryl transfer (GlcNAc-6-P to GlcNAc-1-P), so this parent is correct, but the specific child term phosphoacetylglucosamine mutase activity (GO:0004610) is separately annotated with experimental evidence and is preferred. Reason: Redundant parent of the specific, experimentally supported GO:0004610; retaining the specific mutase activity is sufficient and more informative. Supporting Evidence: file:human/PGM3/PGM3-uniprot.txt Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during |
| GO:0006048 UDP-N-acetylglucosamine biosynthetic process | TAS Reactome:R-HSA-446210 | ACCEPT | Summary: Reactome (TAS) annotation to UDP-GlcNAc biosynthesis, the pathway module (Synthesis of UDP-N-acetyl-glucosamine) that includes the PGM3-catalyzed isomerization step. Correct core process; consistent with the IBA and IMP annotations to the same term. Reason: Traceable author statement placing PGM3 in the correct UDP-GlcNAc biosynthetic pathway at the appropriate level of specificity. Supporting Evidence: file:human/PGM3/PGM3-uniprot.txt Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during |
| GO:0006048 UDP-N-acetylglucosamine biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) annotation to UDP-GlcNAc biosynthesis via ARBA/UniPathway (UPA00113). Redundant with the IBA, TAS, and IMP annotations to the same, correct process term. Reason: Electronic support for the correct core biosynthetic process; consistent with the curated UniProt pathway annotation. Supporting Evidence: file:human/PGM3/PGM3-uniprot.txt Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during |
| GO:0004610 phosphoacetylglucosamine mutase activity | TAS Reactome:R-HSA-446185 | ACCEPT | Summary: Reactome (TAS) annotation to the core catalytic activity, corresponding to the reaction Isomerization of GlcNAc6P to GlcNAc1P. Correct and consistent with the experimental annotations of the same activity. Reason: Traceable author statement for the defining enzymatic function of PGM3. Supporting Evidence: file:human/PGM3/PGM3-uniprot.txt Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during |
| GO:0004610 phosphoacetylglucosamine mutase activity | EXP PMID:24698316 Hypomorphic homozygous mutations in phosphoglucomutase 3 (PG... | ACCEPT | Summary: Experimental (EXP) annotation to phosphoacetylglucosamine mutase activity. Sassi et al. directly assayed PGM3 catalytic activity, showing disease-associated mutants retain substrate specificity but have reduced GlcNAc-6-P to GlcNAc-1-P conversion (20-30% residual activity), confirming this is the enzyme's activity. Reason: Direct enzymatic assay of the GlcNAc-6-P to GlcNAc-1-P mutase reaction confirms the core molecular function; the annotation is at the correct level of specificity. Supporting Evidence: PMID:24698316 catalyzes the conversion of GlcNAc-6-P to GlcNAc-1-P, which is required for the biosynthesis of UDP-GlcNAc, an essential precursor for protein glycosylation PMID:24698316 the catalytic activity is reduced in mutant PGM3 |
| GO:0004610 phosphoacetylglucosamine mutase activity | EXP PMID:24931394 PGM3 mutations cause a congenital disorder of glycosylation ... | ACCEPT | Summary: Experimental (EXP) annotation to phosphoacetylglucosamine mutase activity. Stray-Pedersen et al. expressed disease-associated PGM3 variants in E. coli and measured reduced PGM3 activity for all mutants, directly demonstrating that PGM3 catalyzes the GlcNAc-6-P to GlcNAc-1-P conversion. Reason: Functional enzymatic study of PGM3 variants confirms the core catalytic activity. Supporting Evidence: PMID:24931394 reduced PGM3 activity for all mutants tested |
| GO:0004610 phosphoacetylglucosamine mutase activity | IMP PMID:24589341 Autosomal recessive phosphoglucomutase 3 (PGM3) mutations li... | ACCEPT | Summary: IMP annotation to phosphoacetylglucosamine mutase activity. Zhang et al. developed an enzymatic assay measuring GlcNAc-1-P formation from GlcNAc-6-P and showed patient fibroblasts carrying hypomorphic PGM3 mutations had substantially decreased activity, directly linking PGM3 function to this reaction. Reason: Mutation-based functional evidence that PGM3 enables the mutase activity; correct and specific. Supporting Evidence: PMID:24589341 All patients had substantially decreased PGM3 activity compared to control cells PMID:24589341 PGM3 is a member of the hexose phosphate mutase family and catalyzes the reversible conversion of GlcNAc-6-phosphate (GlcNAc-6-P) to GlcNAc-1-P |
| GO:0006048 UDP-N-acetylglucosamine biosynthetic process | IMP PMID:24589341 Autosomal recessive phosphoglucomutase 3 (PGM3) mutations li... | ACCEPT | Summary: IMP annotation to UDP-GlcNAc biosynthesis. Zhang et al. showed PGM3-deficient patient cells have significantly reduced UDP-GlcNAc, which was restored by GlcNAc supplementation, demonstrating PGM3's requirement in generating this sugar nucleotide. Core biological process for PGM3. Reason: Mutation-based evidence directly ties PGM3 loss of function to reduced UDP-GlcNAc, supporting its involvement in this biosynthetic process. Supporting Evidence: PMID:24589341 PGM3-deficient cells showed significant reduction of UDP-GlcNAc |
| GO:0006487 protein N-linked glycosylation | IMP PMID:24589341 Autosomal recessive phosphoglucomutase 3 (PGM3) mutations li... | KEEP AS NON CORE | Summary: IMP annotation to protein N-linked glycosylation. Zhang et al. found decreased N-linked protein glycosylation (under-galactosylation of N-glycans) in patient cells, and the companion study (Sassi et al.) showed reduced tri-/tetra-antennary N-glycans. This is a downstream consequence of reduced UDP-GlcNAc supply rather than a direct enzymatic activity of PGM3 on proteins. Reason: PGM3 supplies the UDP-GlcNAc precursor; the effect on N-glycosylation is indirect (via the shared sugar-nucleotide pool). Biologically important but not PGM3's core direct function, so retain as non-core. Supporting Evidence: PMID:24589341 along with decreased O- and N-linked protein |
| GO:0006493 protein O-linked glycosylation | IMP PMID:24589341 Autosomal recessive phosphoglucomutase 3 (PGM3) mutations li... | KEEP AS NON CORE | Summary: IMP annotation to protein O-linked glycosylation. Zhang et al. observed abnormal O-linked glycosylation (increased T antigen, hyposialylation) in patient cells, consistent with reduced UDP-GlcNAc. As with N-glycosylation, this is a downstream consequence of PGM3-dependent precursor supply rather than a direct activity. Reason: Indirect effect mediated by the UDP-GlcNAc pool; retain as non-core downstream process. Supporting Evidence: PMID:24589341 along with decreased O- and N-linked protein |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446185 | ACCEPT | Summary: Reactome (TAS) annotation localizing PGM3 to the cytosol, where the hexosamine pathway operates. Consistent with the protein's role as a soluble cytosolic metabolic enzyme and with large-scale proteomics. Reason: Correct subcellular location for this cytosolic phosphohexomutase. Supporting Evidence: Reactome:R-HSA-446185 Cytosolic PGM3 catalyzes the isomerization of N-acetyl-D-glucosamine 6-phosphate |
| GO:0004610 phosphoacetylglucosamine mutase activity | IDA PMID:11004509 Functional cloning and mutational analysis of the human cDNA... | ACCEPT | Summary: IDA annotation to phosphoacetylglucosamine mutase activity. Mio et al. functionally cloned human AGM1 (PGM3), expressed it as a GST fusion in E. coli, and demonstrated phosphoacetylglucosamine mutase activity, and it rescued a yeast agm1-delta null. This is the foundational direct assay of PGM3's core activity. Reason: Direct assay of purified/recombinant human PGM3 established the mutase activity; the defining core molecular function. Supporting Evidence: PMID:11004509 both HsAgm1 and CaAgm1 proteins displayed |
| GO:0006041 D-glucosamine metabolic process | NAS PMID:11004509 Functional cloning and mutational analysis of the human cDNA... | MARK AS OVER ANNOTATED | Summary: NAS annotation to D-glucosamine metabolic process. PGM3 acts on the N-acetylated hexosamine phosphates (GlcNAc-6-P / GlcNAc-1-P) within the hexosamine pathway. This is a broad parent process; the specific, experimentally supported process for PGM3 is UDP-N-acetylglucosamine biosynthetic process (GO:0006048), which is preferred over this general glucosamine-metabolism term. Reason: Overly general (author-stated, non-experimental) process; the specific UDP-GlcNAc biosynthetic process already captures PGM3's role more precisely. Supporting Evidence: PMID:11004509 demonstrating that Arg(496) serves as a binding |
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)