GMPS encodes GMP synthase [glutamine-hydrolyzing] (GMP synthetase, EC 6.3.5.2), the enzyme that catalyzes the final, committed step of de novo guanine-nucleotide biosynthesis. It performs the ATP-dependent amination of xanthosine-5'-monophosphate (XMP) to guanosine-5'-monophosphate (GMP), using the amide nitrogen donated by L-glutamine (XMP + L-glutamine + ATP + H2O -> GMP + L-glutamate + AMP + diphosphate). It acts immediately downstream of IMP dehydrogenase (IMPDH1/2), which oxidizes IMP to XMP. The protein is a bifunctional enzyme comprising an N-terminal class-I glutamine amidotransferase (GATase) domain that hydrolyzes glutamine to release ammonia and a C-terminal ATP-pyrophosphatase domain that adenylates XMP; ammonia then attacks the adenyl-XMP intermediate to yield GMP. The enzyme requires Mg2+ and acts in the cytosol. Beyond its metabolic role, GMPS also has a reported nuclear moonlighting function in USP7 (HAUSP)-dependent deubiquitination that stabilizes p53 and in epigenetic regulation; this is a secondary, non-core activity relative to its enzymatic role in GMP synthesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred cytosolic localization of GMP synthase. This is consistent with the experimentally determined localization of human GMPS and its role in cytosolic de novo purine metabolism. Reason: GMPS is a soluble cytosolic enzyme; the IBA localization agrees with direct experimental evidence for human GMPS. Supporting Evidence: file:human/GMPS/GMPS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0003921 GMP synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred GMP synthase molecular function. This is the correct, well-conserved catalytic activity for GMPS across the PANTHER family, and is directly supported for the human enzyme. Reason: Correct core molecular function. GO:0003921 is the general (grouping) GMP synthase term; the more specific glutamine-hydrolyzing form (GO:0003922) is also annotated and is the preferred core MF term. Retained as a valid conserved call. Supporting Evidence: file:human/GMPS/GMPS-uniprot.txt RecName: Full=GMP synthase [glutamine-hydrolyzing] |
| GO:0006177 GMP biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred involvement in GMP biosynthesis, the core biological process for this enzyme family. GMPS catalyzes the terminal step of de novo GMP synthesis. Reason: Correct core biological process, supported by the enzyme's characterized reaction and UniProt pathway assignment. Supporting Evidence: file:human/GMPS/GMPS-uniprot.txt PATHWAY: Purine metabolism; GMP biosynthesis; GMP from XMP |
| GO:0003921 GMP synthase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping (IPR025777, GMPS ATP-PPase domain) assigning GMP synthase activity. Correct, agrees with experimental and phylogenetic annotations. Reason: The InterPro domain-to-GO mapping correctly recovers the GMP synthase molecular function; consistent with all other lines. Supporting Evidence: file:human/GMPS/GMPS-uniprot.txt PROSITE; PS51553; GMPS_ATP_PPASE |
| GO:0003922 GMP synthase (glutamine-hydrolyzing) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (ARBA/EC 6.3.5.2, RHEA:11680) assignment of the specific glutamine-hydrolyzing GMP synthase activity. This is the precise, correct molecular function of GMPS and matches the experimentally determined catalytic activity. Reason: Most specific and correct molecular-function term for GMPS; matches the UniProt EC number and Rhea reaction, and the experimental EC assignment (PubMed:8089153). Supporting Evidence: file:human/GMPS/GMPS-uniprot.txt EC=6.3.5.2 {ECO:0000269|PubMed:8089153} |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping assigning ATP binding, consistent with the ATP-pyrophosphatase domain of GMPS. ATP is a co-substrate that adenylates XMP during catalysis; the crystal structure defines a specific ATP-binding site. Reason: ATP binding is a real, structurally-defined feature of the ATP-PPase domain and is mechanistically required (adenyl-XMP intermediate). Supporting molecular function, retained. Supporting Evidence: file:human/GMPS/GMPS-uniprot.txt /ligand="ATP" |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt Subcellular Location keyword mapping to cytosol. Correct and consistent with experimental localization data. Reason: Agrees with the experimentally determined cytosolic localization of GMPS. Supporting Evidence: file:human/GMPS/GMPS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0006164 purine nucleotide biosynthetic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping to the broad process purine nucleotide biosynthesis. This is a correct but general parent of the specific GMP biosynthetic process. Reason: Not wrong, but this is a high-level parent term. The specific core process for GMPS is GMP biosynthetic process (GO:0006177). Kept as a valid but non-core, broader annotation. Supporting Evidence: file:human/GMPS/GMPS-uniprot.txt PATHWAY: Purine metabolism; GMP biosynthesis; GMP from XMP |
| GO:0006177 GMP biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (UniPathway UPA00189) assignment of GMP biosynthetic process, the core biological process for GMPS. Correct and specific. Reason: Correct core biological process, matching UniProt pathway (GMP biosynthesis; GMP from XMP, L-Gln route). Supporting Evidence: file:human/GMPS/GMPS-uniprot.txt PATHWAY: Purine metabolism; GMP biosynthesis; GMP from XMP |
| GO:0009168 purine ribonucleoside monophosphate biosynthetic process | TAS Reactome:R-HSA-73817 | KEEP AS NON CORE | Summary: Reactome pathway-level (Purine ribonucleoside monophosphate biosynthesis) assignment. GMP is a purine ribonucleoside monophosphate, so GMPS participates in this pathway; however this term is broader than the specific GMP biosynthetic process. Reason: Correct but a broader grouping term relative to GMP biosynthetic process (GO:0006177). Retained as a valid non-core, pathway-level annotation. Supporting Evidence: Reactome:R-HSA-73817 Guanosine 5'-monophosphate (GMP) and adenosine 5'-monophosphate (AMP) are synthesized from IMP. |
| GO:0003922 GMP synthase (glutamine-hydrolyzing) activity | EXP PMID:7706277 Biochemical characterization of human GMP synthetase. | ACCEPT | Summary: Direct biochemical characterization of purified human GMP synthetase (kinetics, Mg2+ requirement, XMP cooperativity, decoyinine inhibition), establishing its glutamine-hydrolyzing GMP synthase activity. Reason: Experimental (EXP) evidence directly supporting the core glutamine-hydrolyzing GMP synthase activity. The characterized enzyme is human GMP synthetase (EC 6.3.5.2) and its properties (Mg2+ dependence, XMP as substrate) match the annotated function. Supporting Evidence: PMID:7706277 GMP synthetase (EC 6.3.5.2) plays a key role in the de novo synthesis of guanine nucleotides. PMID:7706277 Interaction of GMP synthetase with xanthosine 5'-monophosphate (XMP), a substrate, exhibits sigmoidal kinetics |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based (HPA) direct assay localizing GMPS to the cytosol, consistent with all other localization evidence. Reason: Direct experimental (IDA) localization to cytosol; concordant with UniProt and other IDA/TAS lines. Supporting Evidence: file:human/GMPS/GMPS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0003922 GMP synthase (glutamine-hydrolyzing) activity | IDA PMID:8089153 Human GMP synthetase. Protein purification, cloning, and fun... | ACCEPT | Summary: Purification of human GMP synthetase to homogeneity and functional expression of the cloned cDNA, which complements an E. coli guaA (GMP synthetase) mutant, directly demonstrating glutamine-hydrolyzing GMP synthase activity. Reason: Direct experimental (IDA) evidence for the core molecular function; this is also the UniProt reference for the EC 6.3.5.2 catalytic-activity assignment. Supporting Evidence: PMID:8089153 GMP synthetase is a key enzyme in the de novo synthesis of guanine nucleotides. PMID:8089153 The cDNA complements a guaA mutant of Escherichia coli, which lacks a functional GMP synthetase and extracts from the transformed E. coli exhibit GMP synthetase activity, which is absent in the parental strain. |
| GO:0003921 GMP synthase activity | IDA PMID:8081953 Enhanced in vitro growth of glomerular cells derived from ra... | ACCEPT | Summary: GMP synthase molecular function annotated with IDA evidence. The annotated function (GMP synthase activity for GMPS) is correct and independently well supported, but the cited reference (PMID:8081953) does not concern GMP synthase. Reason: The molecular function is correct for GMPS and is independently supported by direct experimental evidence (PMID:8089153) and biochemical characterization (PMID:7706277). The annotation is therefore accepted, but the supporting reference is a wrong-identifier citation - PMID:8081953 is a paper on in vitro growth of rat glomerular mesangial cells with no relation to GMP synthase (the intended reference is almost certainly PMID:8089153, the human GMP synthetase cloning paper). See reference_review for PMID:8081953. Supporting Evidence: PMID:8089153 GMP synthetase is a key enzyme in the de novo synthesis of guanine nucleotides. |
| GO:0005829 cytosol | IDA PMID:8089153 Human GMP synthetase. Protein purification, cloning, and fun... | ACCEPT | Summary: Cytosolic localization of human GMP synthetase determined during its purification and characterization. Reason: Direct experimental localization to the cytosol; this is the UniProt-cited evidence for the SUBCELLULAR LOCATION (Cytoplasm, cytosol) of GMPS. Supporting Evidence: file:human/GMPS/GMPS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:8089153}. |
| GO:0006177 GMP biosynthetic process | IDA PMID:8089153 Human GMP synthetase. Protein purification, cloning, and fun... | ACCEPT | Summary: Human GMP synthetase demonstrated to be a key enzyme in de novo guanine-nucleotide synthesis, placing it within the GMP biosynthetic process. Reason: Direct experimental support for the core biological process. GMPS catalyzes the final step (XMP -> GMP) of de novo GMP biosynthesis. Supporting Evidence: PMID:8089153 GMP synthetase is a key enzyme in the de novo synthesis of guanine nucleotides. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-73792 | ACCEPT | Summary: Reactome reaction (XMP + L-Glutamine + ATP + H2O => GMP + ...) describing cytosolic GMP synthase, supporting cytosolic localization. Reason: Traceable localization consistent with all experimental evidence; Reactome explicitly describes cytosolic GMPS. Supporting Evidence: Reactome:R-HSA-73792 Cytosolic GMP synthase (GMPS) catalyzes the reaction of xanthosine 5'-monophosphate (XMP), ATP, glutamine and water to form guanosine 5'-monophosphate (GMP), AMP, glutamate and pyrophosphate. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9748957 | ACCEPT | Summary: Reactome reaction (GMPS dimer transforms 6TXMP to 6TGMP, thiopurine drug activation) placing GMPS in the cytosol; duplicate cytosol localization support. Reason: Traceable localization concordant with the other cytosol annotations. Supporting Evidence: Reactome:R-HSA-9748957 GMP synthase (glutamine-hydrolyzing) (GMPS) is involved in the de novo synthesis of guanine nucleotides |
| GO:0003921 GMP synthase activity | TAS PMID:8089153 Human GMP synthetase. Protein purification, cloning, and fun... | ACCEPT | Summary: Traceable author statement (from the human GMP synthetase cloning/characterization paper) supporting GMP synthase activity. Reason: Correct molecular function, traceable to the primary characterization paper. The more specific glutamine-hydrolyzing form (GO:0003922) is the preferred core MF term. Supporting Evidence: PMID:8089153 GMP synthetase is a key enzyme in the de novo synthesis of guanine nucleotides. |
| GO:0009113 purine nucleobase biosynthetic process | TAS PMID:8089153 Human GMP synthetase. Protein purification, cloning, and fun... | KEEP AS NON CORE | Summary: Traceable assignment to purine nucleobase biosynthesis. GMPS produces the guanine nucleotide GMP, so it contributes to purine (guanine) biosynthesis, but this term is broader/adjacent to the precise nucleotide-level GMP biosynthetic process. Reason: Correct in spirit (GMPS makes a guanine nucleotide) but a broad/adjacent grouping term; the specific core process is GMP biosynthetic process (GO:0006177). Retained as a valid non-core annotation. Supporting Evidence: PMID:8089153 GMP synthetase is a key enzyme in the de novo synthesis of guanine nucleotides. |
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