id: P49915
gene_symbol: GMPS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: '1'
  id: P49915-1
- name: '2'
  id: P49915-2
  sequence_note: VSP_053933
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    reason: GMPS is a soluble cytosolic enzyme; the IBA localization agrees with direct
      experimental evidence for human GMPS.
    supported_by:
    - reference_id: file:human/GMPS/GMPS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0003921
    label: GMP synthase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/GMPS/GMPS-uniprot.txt
      supporting_text: 'RecName: Full=GMP synthase [glutamine-hydrolyzing]'
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Correct core biological process, supported by the enzyme's characterized
      reaction and UniProt pathway assignment.
    supported_by:
    - reference_id: file:human/GMPS/GMPS-uniprot.txt
      supporting_text: 'PATHWAY: Purine metabolism; GMP biosynthesis; GMP from XMP'
- term:
    id: GO:0003921
    label: GMP synthase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO mapping (IPR025777, GMPS ATP-PPase domain) assigning GMP
      synthase activity. Correct, agrees with experimental and phylogenetic annotations.
    action: ACCEPT
    reason: The InterPro domain-to-GO mapping correctly recovers the GMP synthase
      molecular function; consistent with all other lines.
    supported_by:
    - reference_id: file:human/GMPS/GMPS-uniprot.txt
      supporting_text: PROSITE; PS51553; GMPS_ATP_PPASE
- term:
    id: GO:0003922
    label: GMP synthase (glutamine-hydrolyzing) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: file:human/GMPS/GMPS-uniprot.txt
      supporting_text: EC=6.3.5.2 {ECO:0000269|PubMed:8089153}
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/GMPS/GMPS-uniprot.txt
      supporting_text: /ligand="ATP"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt Subcellular Location keyword mapping to cytosol. Correct and
      consistent with experimental localization data.
    action: ACCEPT
    reason: Agrees with the experimentally determined cytosolic localization of GMPS.
    supported_by:
    - reference_id: file:human/GMPS/GMPS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0006164
    label: purine nucleotide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO mapping to the broad process purine nucleotide biosynthesis.
      This is a correct but general parent of the specific GMP biosynthetic process.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/GMPS/GMPS-uniprot.txt
      supporting_text: 'PATHWAY: Purine metabolism; GMP biosynthesis; GMP from XMP'
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Automated (UniPathway UPA00189) assignment of GMP biosynthetic process,
      the core biological process for GMPS. Correct and specific.
    action: ACCEPT
    reason: Correct core biological process, matching UniProt pathway (GMP biosynthesis;
      GMP from XMP, L-Gln route).
    supported_by:
    - reference_id: file:human/GMPS/GMPS-uniprot.txt
      supporting_text: 'PATHWAY: Purine metabolism; GMP biosynthesis; GMP from XMP'
- term:
    id: GO:0009168
    label: purine ribonucleoside monophosphate biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73817
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Correct but a broader grouping term relative to GMP biosynthetic process
      (GO:0006177). Retained as a valid non-core, pathway-level annotation.
    supported_by:
    - reference_id: Reactome:R-HSA-73817
      supporting_text: Guanosine 5'-monophosphate (GMP) and adenosine 5'-monophosphate
        (AMP) are synthesized from IMP.
- term:
    id: GO:0003922
    label: GMP synthase (glutamine-hydrolyzing) activity
  evidence_type: EXP
  original_reference_id: PMID:7706277
  qualifier: enables
  review:
    summary: Direct biochemical characterization of purified human GMP synthetase
      (kinetics, Mg2+ requirement, XMP cooperativity, decoyinine inhibition), establishing
      its glutamine-hydrolyzing GMP synthase activity.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7706277
      supporting_text: GMP synthetase (EC 6.3.5.2) plays a key role in the de novo
        synthesis of guanine nucleotides.
    - reference_id: PMID:7706277
      supporting_text: Interaction of GMP synthetase with xanthosine 5'-monophosphate
        (XMP), a substrate, exhibits sigmoidal kinetics
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence-based (HPA) direct assay localizing GMPS to the cytosol,
      consistent with all other localization evidence.
    action: ACCEPT
    reason: Direct experimental (IDA) localization to cytosol; concordant with UniProt
      and other IDA/TAS lines.
    supported_by:
    - reference_id: file:human/GMPS/GMPS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0003922
    label: GMP synthase (glutamine-hydrolyzing) activity
  evidence_type: IDA
  original_reference_id: PMID:8089153
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:8089153
      supporting_text: GMP synthetase is a key enzyme in the de novo synthesis of
        guanine nucleotides.
    - reference_id: PMID:8089153
      supporting_text: 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.
- term:
    id: GO:0003921
    label: GMP synthase activity
  evidence_type: IDA
  original_reference_id: PMID:8081953
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:8089153
      supporting_text: GMP synthetase is a key enzyme in the de novo synthesis of
        guanine nucleotides.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:8089153
  qualifier: located_in
  review:
    summary: Cytosolic localization of human GMP synthetase determined during its
      purification and characterization.
    action: ACCEPT
    reason: Direct experimental localization to the cytosol; this is the UniProt-cited
      evidence for the SUBCELLULAR LOCATION (Cytoplasm, cytosol) of GMPS.
    supported_by:
    - reference_id: file:human/GMPS/GMPS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:8089153}.'
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:8089153
  qualifier: acts_upstream_of_or_within
  review:
    summary: Human GMP synthetase demonstrated to be a key enzyme in de novo guanine-nucleotide
      synthesis, placing it within the GMP biosynthetic process.
    action: ACCEPT
    reason: Direct experimental support for the core biological process. GMPS catalyzes
      the final step (XMP -> GMP) of de novo GMP biosynthesis.
    supported_by:
    - reference_id: PMID:8089153
      supporting_text: GMP synthetase is a key enzyme in the de novo synthesis of
        guanine nucleotides.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73792
  qualifier: located_in
  review:
    summary: Reactome reaction (XMP + L-Glutamine + ATP + H2O => GMP + ...) describing
      cytosolic GMP synthase, supporting cytosolic localization.
    action: ACCEPT
    reason: Traceable localization consistent with all experimental evidence; Reactome
      explicitly describes cytosolic GMPS.
    supported_by:
    - reference_id: Reactome:R-HSA-73792
      supporting_text: 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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9748957
  qualifier: located_in
  review:
    summary: Reactome reaction (GMPS dimer transforms 6TXMP to 6TGMP, thiopurine drug
      activation) placing GMPS in the cytosol; duplicate cytosol localization support.
    action: ACCEPT
    reason: Traceable localization concordant with the other cytosol annotations.
    supported_by:
    - reference_id: Reactome:R-HSA-9748957
      supporting_text: GMP synthase (glutamine-hydrolyzing) (GMPS) is involved in
        the de novo synthesis of guanine nucleotides
- term:
    id: GO:0003921
    label: GMP synthase activity
  evidence_type: TAS
  original_reference_id: PMID:8089153
  qualifier: enables
  review:
    summary: Traceable author statement (from the human GMP synthetase cloning/characterization
      paper) supporting GMP synthase activity.
    action: ACCEPT
    reason: Correct molecular function, traceable to the primary characterization
      paper. The more specific glutamine-hydrolyzing form (GO:0003922) is the preferred
      core MF term.
    supported_by:
    - reference_id: PMID:8089153
      supporting_text: GMP synthetase is a key enzyme in the de novo synthesis of
        guanine nucleotides.
- term:
    id: GO:0009113
    label: purine nucleobase biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:8089153
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:8089153
      supporting_text: GMP synthetase is a key enzyme in the de novo synthesis of
        guanine nucleotides.
core_functions:
- description: Catalyzes the final, glutamine-dependent step of de novo GMP biosynthesis,
    the ATP-dependent amination of XMP to GMP.
  molecular_function:
    id: GO:0003922
    label: GMP synthase (glutamine-hydrolyzing) activity
  directly_involved_in:
  - id: GO:0006177
    label: GMP biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:8089153
    supporting_text: GMP synthetase is a key enzyme in the de novo synthesis of guanine
      nucleotides.
  - reference_id: file:human/GMPS/GMPS-uniprot.txt
    supporting_text: EC=6.3.5.2 {ECO:0000269|PubMed:8089153}
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:7706277
  title: Biochemical characterization of human GMP synthetase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified primary biochemical/kinetic characterization of
      purified human GMP synthetase (Nakamura & Lou 1995, JBC); directly supports
      the glutamine-hydrolyzing GMP synthase activity. Abstract-only in cache.
- id: PMID:8081953
  title: Enhanced in vitro growth of glomerular cells derived from rats with immune-mediated
    mesangial injury.
  findings: []
  reference_review:
    relevance: NONE
    correctness: WRONG_IDENTIFIER
    review_notes: 'Cited by the MGI GO:0003921 (GMP synthase activity) IDA annotation,
      but this PMID resolves to a rat glomerular mesangial-cell growth paper (Harendza
      et al. 1993, Exp Nephrol) with no relation to GMP synthase. Wrong/transposed
      identifier; the intended reference is almost certainly PMID:8089153 (human GMP
      synthetase cloning). The annotated function is correct and independently supported,
      so the annotation is retained.'
- id: PMID:8089153
  title: Human GMP synthetase. Protein purification, cloning, and functional expression
    of cDNA.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Primary paper purifying human GMP synthetase, cloning
      its cDNA, and showing functional complementation of an E. coli guaA mutant.
      This is the UniProt evidence for EC 6.3.5.2, function, and cytosolic localization.
      Abstract-only in cache.
- id: Reactome:R-HSA-73792
  title: XMP + L-Glutamine + ATP + H2O => GMP + L-Glutamate + AMP + pyrophosphate
  findings: []
- id: Reactome:R-HSA-73817
  title: Purine ribonucleoside monophosphate biosynthesis
  findings: []
- id: Reactome:R-HSA-9748957
  title: GMPS dimer transforms 6TXMP to 6TGMP
  findings: []
- id: file:human/GMPS/GMPS-uniprot.txt
  title: GMPS UniProtKB record (P49915)
  findings: []
- id: file:human/GMPS/GMPS-notes.md
  title: Manual GMPS curation notes
  findings: []