UAP1 (UDP-N-acetylhexosamine pyrophosphorylase; historically AGX/AgX, SPAG2) catalyzes the final step of the hexosamine biosynthetic pathway, condensing N-acetyl-alpha-D-glucosamine 1-phosphate (GlcNAc-1-P) with UTP to produce UDP-N-acetylglucosamine (UDP-GlcNAc) plus diphosphate (EC 2.7.7.23). It also acts on N-acetyl-alpha-D-galactosamine 1-phosphate (GalNAc-1-P) to generate UDP-N-acetylgalactosamine (UDP-GalNAc; EC 2.7.7.83). UDP-GlcNAc is the universal amino-sugar nucleotide donor used for N- and O-linked protein glycosylation, O-GlcNAcylation, GPI-anchor and proteoglycan synthesis, and (via GNE) sialic acid biosynthesis, placing UAP1 at a central metabolic node. The cytosolic enzyme exists as a monomer and homodimer; two major splice isoforms (AGX1 and AGX2) differ by a 17-amino-acid insert near the C-terminus that shifts substrate preference between GalNAc-1-P and GlcNAc-1-P. Beyond metabolism, UAP1 additionally functions as a protein serine pyrophosphorylase that pyrophosphorylates IRF3 at Ser-386 following TBK1 phosphorylation, promoting IRF3 dimerization and type I interferon responses during antiviral innate immunity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003977 UDP-N-acetylglucosamine diphosphorylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. Phylogenetic (IBA) inference of the UDP-GlcNAc pyrophosphorylase activity, fully concordant with the experimental and TAS annotations to the same term and with UniProt. Supporting Evidence: file:human/UAP1/UAP1-uniprot.txt Catalyzes the last step in biosynthesis of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) by converting UTP and |
| GO:0005829 cytosol | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Correct subcellular location; UAP1 is a cytosolic enzyme. Location term, retained as non-core relative to the catalytic function. Supporting Evidence: file:human/UAP1/UAP1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0006048 UDP-N-acetylglucosamine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. UAP1 performs the terminal, committed step of UDP-GlcNAc biosynthesis (the hexosamine biosynthetic pathway). Supporting Evidence: file:human/UAP1/UAP1-uniprot.txt UDP-N-acetyl-alpha-D-glucosamine biosynthesis; UDP-N-acetyl-alpha-D- |
| GO:0003977 UDP-N-acetylglucosamine diphosphorylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (Rhea/EC 2.7.7.23) assertion of the core UDP-GlcNAc pyrophosphorylase activity. Redundant with, and confirmed by, the EXP and TAS annotations to the same term. Supporting Evidence: file:human/UAP1/UAP1-uniprot.txt EC=2.7.7.23; |
| GO:0005829 cytosol | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic (UniProt SubCell SL-0091) location assertion, consistent with experimental cytosol annotations. Retained as non-core location. Supporting Evidence: file:human/UAP1/UAP1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0016772 transferase activity, transferring phosphorus-containing groups | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: High-level parent term (ARBA). The specific activity (UDP-N-acetylglucosamine diphosphorylase, GO:0003977, a nucleotidyltransferase) is already captured with experimental evidence, so this general grouping term is an over-annotation. Proposed replacements: UDP-N-acetylglucosamine diphosphorylase activity |
| GO:0052630 UDP-N-acetylgalactosamine diphosphorylase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Genuine secondary activity (EC 2.7.7.83), also supported experimentally (PMID:9765219). Real but not the principal physiological function, so retained as non-core. Supporting Evidence: file:human/UAP1/UAP1-uniprot.txt EC=2.7.7.83; |
| GO:0070569 uridylyltransferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: General parent term (InterPro2GO, IPR002618). The precise activities (UDP-GlcNAc/UDP-GalNAc diphosphorylase, GO:0003977/GO:0052630) are already annotated with better evidence, so this broad uridylyltransferase grouping is an over-annotation. Proposed replacements: UDP-N-acetylglucosamine diphosphorylase activity |
| GO:0141090 protein serine pyrophosphorylase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Electronic (Rhea) assertion of the moonlighting protein serine pyrophosphorylase activity, corroborated by the experimental IDA annotation from PMID:36603579. A real, non-canonical activity distinct from the metabolic core. Supporting Evidence: file:human/UAP1/UAP1-uniprot.txt acts as a regulator of innate immunity in response to virus infection |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Self-interaction from a proteome-scale binary interactome screen (IntAct), consistent with the well-established UAP1 homodimer. As a bare protein-binding term it is uninformative about molecular function; retained (IPI evidence) but marked over-annotated. The homodimeric assembly is documented in UniProt SUBUNIT and by the crystal structures. |
| GO:0006048 UDP-N-acetylglucosamine biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: Electronic (UniPathway UPA00113) assertion of the core UDP-GlcNAc biosynthetic process. Redundant with, and confirmed by, the IBA and TAS annotations to the same term. Supporting Evidence: file:human/UAP1/UAP1-uniprot.txt PATHWAY: Nucleotide-sugar biosynthesis; UDP-N-acetyl-alpha-D- |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Direct (HPA immunofluorescence) evidence for cytosolic localization, consistent with the enzyme's role in cytosolic UDP-GlcNAc synthesis. Non-core location. Supporting Evidence: file:human/UAP1/UAP1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0003977 UDP-N-acetylglucosamine diphosphorylase activity | EXP PMID:9765219 A 17-amino acid insert changes UDP-N-acetylhexosamine pyroph... | ACCEPT | Summary: Core molecular function with direct experimental support. Recombinant AGX1/AGX2 proteins synthesize UDP-GlcNAc from GlcNAc-1-P and UTP; AGX2 is strongly GlcNAc-1-P preferring. Supporting Evidence: PMID:9765219 had 8-fold better activity with GlcNAc-1-P than with GalNAc-1-P |
| GO:0052630 UDP-N-acetylgalactosamine diphosphorylase activity | EXP PMID:9765219 A 17-amino acid insert changes UDP-N-acetylhexosamine pyroph... | KEEP AS NON CORE | Summary: Experimentally demonstrated UDP-GalNAc pyrophosphorylase activity of the same enzyme; AGX1 is 2-3x more active toward GalNAc-1-P. A genuine dual specificity, but the physiological core output is UDP-GlcNAc, so retained as non-core. Supporting Evidence: PMID:9765219 was 2-3 times more active with GalNAc-1-P than with GlcNAc-1-P |
| GO:0005829 cytosol | IDA PMID:8025165 Characterization of a human antigen with sera from infertile... | KEEP AS NON CORE | Summary: Direct evidence for cytosolic (cytoplasmic) localization of the AgX/UAP1 protein, including sperm-tail localization by immunofluorescence. Non-core location. Supporting Evidence: PMID:8025165 AgX was localized by immunofluorescence to the principal piece of the sperm tail |
| GO:0032481 positive regulation of type I interferon production | IDA PMID:36603579 Metabolic enzyme UAP1 mediates IRF3 pyrophosphorylation to f... | KEEP AS NON CORE | Summary: Moonlighting role in antiviral signaling. UAP1 pyrophosphorylates IRF3 at Ser-386 to promote IRF3 dimerization/activation and robust type I IFN responses; Uap1 deficiency impairs virus-induced type I IFN. Genuine but non-canonical relative to the metabolic core function. Supporting Evidence: PMID:36603579 catalyzing the pyrophosphorylation of interferon regulatory factor 3 (IRF3) at serine (Ser) 386 to promote robust type I interferon (IFN) responses |
| GO:0140374 antiviral innate immune response | IDA PMID:36603579 Metabolic enzyme UAP1 mediates IRF3 pyrophosphorylation to f... | KEEP AS NON CORE | Summary: Moonlighting antiviral role. Uap1-deficient mice are highly susceptible to lethal viral infection and virus-induced type I IFN pathways are impaired. Non-core relative to the enzyme's metabolic function. Supporting Evidence: PMID:36603579 the Uap1-deficient mice are highly susceptible to lethal viral infection |
| GO:0141090 protein serine pyrophosphorylase activity | IDA PMID:36603579 Metabolic enzyme UAP1 mediates IRF3 pyrophosphorylation to f... | KEEP AS NON CORE | Summary: Experimentally demonstrated non-canonical catalytic activity. UAP1 acts as a pyrophosphorylase for protein serine pyrophosphorylation (IRF3 Ser-386). Mutations that abolish the sugar-nucleotide pyrophosphorylase activity also abolish protein pyrophosphorylation, indicating a shared active site. Real, but non-core relative to UDP-GlcNAc synthesis. Supporting Evidence: PMID:36603579 as a pyrophosphorylase for protein serine pyrophosphorylation, by catalyzing the pyrophosphorylation of interferon regulatory factor 3 (IRF3) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446204 | KEEP AS NON CORE | Summary: Reactome traceable-author statement for cytosolic localization of UAP1, the site of UDP-GlcNAc synthesis. Non-core location, concordant with the IDA/IBA cytosol annotations. Supporting Evidence: Reactome:R-HSA-446204 Cytosolic UAP1 catalyzes the reaction of N-acetyl-D-glucosamine 1-phosphate (GlcNAc1P) and UTP to UDP-N-acetyl-D-glucosamine and pyrophosphate |
| GO:0003977 UDP-N-acetylglucosamine diphosphorylase activity | TAS PMID:9603950 The eukaryotic UDP-N-acetylglucosamine pyrophosphorylases. G... | ACCEPT | Summary: Core molecular function (traceable author statement). Mio et al. cloned human UAP1 (identical to AGX1) and showed recombinant HsUap1p has UDP-GlcNAc pyrophosphorylase activity; the yeast ortholog is essential and rescued by the human gene. Supporting Evidence: PMID:9603950 recombinant ScUap1p, CaUap1p, and HsUap1p possessed UDP-N-acetylglucosamine pyrophosphorylase |
| GO:0006048 UDP-N-acetylglucosamine biosynthetic process | TAS PMID:9603950 The eukaryotic UDP-N-acetylglucosamine pyrophosphorylases. G... | ACCEPT | Summary: Core biological process (traceable author statement). UAP1 produces UDP-GlcNAc, the final step of the hexosamine biosynthetic pathway; the essentiality of the yeast ortholog underscores the pathway's importance. Supporting Evidence: PMID:9603950 it produced UDP-N-acetylglucosamine from |
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