id: P22102
gene_symbol: GART
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GART encodes the trifunctional purine biosynthetic protein adenosine-3, a single
  cytosolic polypeptide that carries three consecutive activities of the de novo purine
  (IMP) biosynthesis pathway on separate structural domains. Its N-terminal ATP-grasp
  domain provides phosphoribosylamine--glycine ligase (GAR synthetase; EC 6.3.4.13),
  which condenses 5-phospho-beta-D-ribosylamine with glycine and ATP to give
  N(1)-(5-phospho-beta-D-ribosyl)glycinamide (GAR) at step 2. Its C-terminal GART
  domain provides phosphoribosylglycinamide formyltransferase (GAR transformylase;
  EC 2.1.2.2), which transfers a formyl group from 10-formyltetrahydrofolate onto GAR
  to give FGAR at step 3; this folate-dependent transformylase is a validated target
  of antifolate chemotherapeutics such as lometrexol and pemetrexed. Its central AIRS
  domain provides phosphoribosylformylglycinamidine cyclo-ligase (AIR synthetase;
  EC 6.3.3.1), which cyclizes FGAM with ATP to 5-aminoimidazole ribonucleotide (AIR)
  at step 5. The enzyme uses ATP and a divalent metal (Mg2+ or Mn2+) cofactor and acts
  as a homodimer. As a housekeeping enzyme of nucleotide metabolism it is broadly
  expressed; its gene lies on human chromosome 21 within the Down syndrome region.
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12450384
  title: Crystal structures of human GAR Tfase at low and high pH and with substrate
    beta-GAR.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache. Crystal structures of the human GAR transformylase (purN)
      domain with substrate beta-GAR; provides EXP support for GO:0004644 and establishes
      GAR Tfase as a folate-dependent antitumor drug target. PubMed-verified.
- id: PMID:12755606
  title: 'Rational design, synthesis, evaluation, and crystal structure of a potent
    inhibitor of human GAR Tfase: 10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic
    acid.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache. Structure-based folate-analogue inhibitor of human GAR
      Tfase (Ki=15 nM), an improvement over Lometrexol; supports GO:0004644 (EXP) and
      the antifolate-target framing. PubMed-verified.
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional
    implications for exosome biogenesis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Abstract-only. A B-cell exosome proteome MS survey that identified 539 proteins;
      the basis of the extracellular-exosome HDA localization. High-throughput bulk
      proteomics, not a specific GART localization or function claim.
- id: PMID:2050105
  title: Cloning and in vivo expression of the human GART gene using yeast artificial
    chromosomes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only. YAC cloning of the full-length human GART gene; confirms the
      trifunctional GARS-GART-AIRS protein and maps it to 21q22.1. TAS basis for the
      GAR transformylase activity.
- id: PMID:2183217
  title: Cloning of three human multifunctional de novo purine biosynthetic genes
    by functional complementation of yeast mutations.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache. Functional complementation of yeast ade5/ade7/ade8
      mutations by a single human cDNA establishes the trifunctional GARS-AIRS-GART
      protein; primary basis of the MGI IDA annotations for the three activities,
      cytosol, and de novo IMP biosynthesis. PubMed-verified.
- id: Reactome:R-HSA-73810
  title: FGAM + ATP => AIR + ADP + Pi
  findings: []
- id: Reactome:R-HSA-73813
  title: GAR + 10-Formyl-THF => FGAR + THF
  findings: []
- id: Reactome:R-HSA-73814
  title: 5-Phosphoribosylamine + Glycine + ATP => GAR + ADP + Pi
  findings: []
- id: Reactome:R-HSA-73817
  title: Purine ribonucleoside monophosphate biosynthesis
  findings: []
- id: file:human/GART/GART-uniprot.txt
  title: UniProt entry P22102 (PUR2_HUMAN) - Trifunctional purine biosynthetic protein
    adenosine-3
  findings: []
existing_annotations:
- term:
    id: GO:0004641
    label: phosphoribosylformylglycinamidine cyclo-ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      AIR synthetase (EC 6.3.3.1), the central AIRS domain activity of the trifunctional
      GART protein, catalyzing the ATP-dependent cyclization of FGAM to AIR (step 5 of
      de novo IMP biosynthesis). A core molecular function, well supported phylogenetically.
    action: ACCEPT
    reason: >-
      This is one of the three defining catalytic activities of GART, carried by the
      central AIRS domain, and is consistent across IBA, IDA, IEA, and TAS lines.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        The central AIRS domain carries the
        phosphoribosylformylglycinamidine cyclo-ligase activity.
- term:
    id: GO:0006164
    label: purine nucleotide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      GART participates in de novo purine nucleotide biosynthesis. This is a correct but
      broad parent of the more specific 'de novo' IMP biosynthetic process (GO:0006189).
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but general; the specific process for GART is 'de novo' IMP biosynthetic
      process (GO:0006189), which is captured separately and is the core process term.
      Retain this broader IBA parent as supporting, non-core context.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      GART is a cytosolic enzyme; the de novo purine pathway operates in the cytosol
      (with transient purinosome assembly under low-purine conditions).
    action: ACCEPT
    reason: >-
      Cytosolic localization is the core location for this pathway, consistent across
      IBA, IDA (PMID:2183217), IEA, and Reactome TAS lines.
    supported_by:
    - reference_id: Reactome:R-HSA-73814
      supporting_text: The active form of the protein is cytosolic
- term:
    id: GO:0004637
    label: phosphoribosylamine-glycine ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      GAR synthetase (EC 6.3.4.13), the N-terminal ATP-grasp domain activity, condensing
      phosphoribosylamine, glycine, and ATP to GAR (step 2 of de novo IMP biosynthesis).
      A core molecular function.
    action: ACCEPT
    reason: >-
      One of the three defining catalytic activities of GART, carried by the N-terminal
      ATP-grasp domain; well supported phylogenetically and by structure.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        The N-terminal ATP-grasp domain carries the
        phosphoribosylamine--glycine ligase activity.
- term:
    id: GO:0046084
    label: adenine biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      IBA-projected term for synthesis of the free purine base adenine. Human GART
      contributes to de novo purine NUCLEOTIDE synthesis (IMP and downstream AMP), not
      to synthesis of the free adenine base.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Human de novo purine biosynthesis produces IMP and thence the nucleotides AMP/GMP,
      not free adenine base; adenine biosynthetic process is a taxonomically skewed
      projection (CGD/PANTHER) that does not accurately describe GART's role. The
      correct process is 'de novo' IMP biosynthetic process (GO:0006189).
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - LINEAGE_OR_TAXON_MISMATCH
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: PANTHER:PTN000055158
        source_label: Trifunctional purine biosynthetic protein family node
        comment: >-
          The 'adenine biosynthetic process' projection is contributed via a Candida
          (CGD:CAL0000199243) family member; in human, GART makes the nucleotide IMP,
          not the free adenine base, so the term mis-scopes the biosynthetic product.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      Root-level molecular function term; correct but uninformative given that the three
      specific catalytic activities of GART are annotated explicitly.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GART is an enzyme, so this ARBA-derived term is not wrong, but it is far too general
      to be informative when the specific EC 6.3.4.13 / 2.1.2.2 / 6.3.3.1 activities are
      already annotated.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0004637
    label: phosphoribosylamine-glycine ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (InterPro/RHEA/EC) support for GAR synthetase activity (EC 6.3.4.13),
      duplicating the IBA/IDA/TAS lines for this core activity.
    action: ACCEPT
    reason: >-
      Correct and specific; the IEA mapping via InterPro, RHEA:17453 and EC:6.3.4.13 is
      consistent with the experimentally supported activity.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        The N-terminal ATP-grasp domain carries the
        phosphoribosylamine--glycine ligase activity.
- term:
    id: GO:0004641
    label: phosphoribosylformylglycinamidine cyclo-ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (InterPro/RHEA/EC) support for AIR synthetase activity (EC 6.3.3.1),
      duplicating the IBA/IDA/TAS lines for this core activity.
    action: ACCEPT
    reason: >-
      Correct and specific; the IEA mapping via InterPro:IPR004733, RHEA:23032 and
      EC:6.3.3.1 is consistent with the experimentally supported activity.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        The central AIRS domain carries the
        phosphoribosylformylglycinamidine cyclo-ligase activity.
- term:
    id: GO:0004644
    label: phosphoribosylglycinamide formyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (InterPro/RHEA/EC) support for GAR transformylase activity (EC 2.1.2.2),
      duplicating the EXP/IDA/TAS lines for this core, experimentally validated activity.
    action: ACCEPT
    reason: >-
      Correct and specific; the IEA mapping via InterPro:IPR004607, RHEA:15053 and
      EC:2.1.2.2 agrees with the experimental (EXP) annotations of this activity.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        The C-terminal GART domain carries the
        phosphoribosylglycinamide formyltransferase activity.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      ATP is a substrate of both the GAR synthetase (ATP-grasp) and AIR synthetase
      domains; ATP-binding residues are defined in the ATP-grasp domain by crystallography.
    action: ACCEPT
    reason: >-
      Supported by the ATP-grasp domain and mapped ATP-binding residues (BINDING 190-193,
      197, 220, 229 to ATP); a genuine, if supporting rather than defining, molecular
      function.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        The N-terminal ATP-grasp domain carries the
        phosphoribosylamine--glycine ligase activity.
- term:
    id: GO:0006189
    label: "'de novo' IMP biosynthetic process"
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      The core biological process for GART: it catalyzes three consecutive steps of the
      de novo IMP biosynthesis pathway.
    action: ACCEPT
    reason: >-
      This is the defining process for GART. Electronic support here is corroborated by
      the IDA annotations from PMID:2183217 and the UniProt PATHWAY statements.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0009113
    label: purine nucleobase biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-derived term for synthesis of purine nucleobases. GART's role is in de
      novo purine NUCLEOTIDE (IMP) biosynthesis rather than free nucleobase synthesis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broad and slightly imprecise (nucleobase vs nucleotide), but defensible as an
      ancestor of the purine-synthesis role. The precise term is 'de novo' IMP
      biosynthetic process (GO:0006189); retain this as non-core.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      GART binds one divalent metal ion (Mg2+ or Mn2+) per subunit, required for the
      ATP-dependent ligase/synthetase reactions.
    action: ACCEPT
    reason: >-
      Supported by the UniProt cofactor annotation and mapped Mg2+-binding residues
      (BINDING 288, 290). A genuine supporting molecular function.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: Binds 1 magnesium or manganese ion per subunit.
- term:
    id: GO:0003360
    label: brainstem development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Developmental term transferred electronically from a rat ortholog via Ensembl
      Compara (GO_REF:0000107). GART is a broadly expressed housekeeping de novo purine
      enzyme, not a brainstem-specific developmental regulator.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This reflects expression/phenotype transfer from a rodent ortholog, not a specific
      molecular role of GART in brainstem development. A ubiquitous nucleotide-metabolism
      enzyme; the term over-specifies a generic housekeeping requirement.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: >-
      Cytosolic localization transferred electronically from a mouse ortholog; consistent
      with the experimentally supported cytosolic localization of human GART.
    action: ACCEPT
    reason: >-
      Redundant with the IDA/IBA/TAS cytosol annotations but correct; cytosol is the core
      location.
    supported_by:
    - reference_id: Reactome:R-HSA-73814
      supporting_text: The active form of the protein is cytosolic
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      GMP is synthesized from IMP, downstream of the GART-catalyzed steps. GART supplies
      the IMP precursor but does not itself perform GMP-specific biosynthetic reactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GART acts before the IMP branch point; GMP biosynthesis (IMP -> XMP -> GMP) is
      carried out by IMPDH and GMPS. involved_in overstates GART's participation; its
      contribution is upstream provision of IMP, better captured by GO:0006189.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0021549
    label: cerebellum development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Developmental term transferred electronically from a rat ortholog via Ensembl
      Compara. GART is a broadly expressed housekeeping enzyme, not a cerebellum-specific
      developmental regulator.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      As with the other brain-development terms, this is ortholog expression/phenotype
      transfer, not a specific developmental function of GART.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0021987
    label: cerebral cortex development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Developmental term transferred electronically from a rat ortholog via Ensembl
      Compara. GART is a broadly expressed housekeeping enzyme, not a cortex-specific
      developmental regulator.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Ortholog expression/phenotype transfer, not a specific molecular role of GART in
      cerebral cortex development.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0044208
    label: "'de novo' AMP biosynthetic process"
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      AMP is synthesized from IMP, downstream of the GART-catalyzed steps. GART supplies
      the IMP precursor but does not itself perform AMP-specific biosynthetic reactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GART acts before the IMP branch point; AMP biosynthesis (IMP -> adenylosuccinate ->
      AMP) is carried out by ADSS and ADSL. involved_in overstates its participation; the
      accurate role is upstream IMP provision (GO:0006189).
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0097294
    label: "'de novo' XMP biosynthetic process"
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      XMP is synthesized from IMP, downstream of the GART-catalyzed steps. GART supplies
      the IMP precursor but does not itself perform XMP-specific biosynthetic reactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GART acts before the IMP branch point; XMP biosynthesis (IMP -> XMP) is carried out
      by IMPDH. involved_in overstates its participation; the accurate role is upstream
      IMP provision (GO:0006189).
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- 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-asserted involvement in purine ribonucleoside monophosphate (IMP)
      biosynthesis; the pathway assembles IMP on PRPP, and GART catalyzes three of its
      steps.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but a broader parent of 'de novo' IMP biosynthetic process (GO:0006189).
      Retain as supporting, non-core context; the specific IMP term is the core process.
    supported_by:
    - reference_id: Reactome:R-HSA-73817
      supporting_text: >-
        The purine ribonucleotide inosine 5'-monophosphate (IMP) is assembled on
        5-phospho-alpha-D-ribose 1-diphosphate (PRPP)
- term:
    id: GO:0004637
    label: phosphoribosylamine-glycine ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73814
  qualifier: enables
  review:
    summary: >-
      Reactome (TAS) annotation of GAR synthetase activity: synthesis of GAR from
      5-phosphoribosylamine, glycine and ATP. A core catalytic activity.
    action: ACCEPT
    reason: >-
      Matches the experimentally and phylogenetically supported GAR synthetase activity
      of the N-terminal ATP-grasp domain.
    supported_by:
    - reference_id: Reactome:R-HSA-73814
      supporting_text: >-
        is catalyzed by the phosphoribosylglycinamide synthetase domain of the trifunctional
        protein
- term:
    id: GO:0004641
    label: phosphoribosylformylglycinamidine cyclo-ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73810
  qualifier: enables
  review:
    summary: >-
      Reactome (TAS) annotation of AIR synthetase activity: irreversible ATP-dependent
      synthesis of AIR from FGAM. A core catalytic activity.
    action: ACCEPT
    reason: >-
      Matches the experimentally and phylogenetically supported AIR synthetase activity
      of the central AIRS domain.
    supported_by:
    - reference_id: Reactome:R-HSA-73810
      supporting_text: >-
        is catalyzed by the phosphoribosylaminoimidazole synthetase domain of the
        trifunctional protein
- term:
    id: GO:0004644
    label: phosphoribosylglycinamide formyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73813
  qualifier: enables
  review:
    summary: >-
      Reactome (TAS) annotation of GAR transformylase activity: folate-dependent formyl
      transfer from 10-formyl-THF to GAR to give FGAR. A core catalytic activity.
    action: ACCEPT
    reason: >-
      Matches the experimentally supported (EXP; PMID:12450384, PMID:12755606) GAR
      transformylase activity of the C-terminal GART domain.
    supported_by:
    - reference_id: Reactome:R-HSA-73813
      supporting_text: >-
        is catalyzed by the phosphoribosylglycinamide formyltransferase domain of the
        trifunctional protein
- term:
    id: GO:0004644
    label: phosphoribosylglycinamide formyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:12450384
  qualifier: enables
  review:
    summary: >-
      GAR transformylase (GAR Tfase) activity established by crystal structures of the
      human enzyme with its substrate beta-GAR and pH-dependent activity measurements.
      A core, experimentally validated catalytic activity and antitumor drug target.
    action: ACCEPT
    reason: >-
      Strong experimental support: structures of the human purN domain with substrate and
      pH-dependent enzyme activity. This is the best-supported of GART's three activities.
    supported_by:
    - reference_id: PMID:12450384
      supporting_text: >-
        Glycinamide ribonucleotide transformylase (GAR Tfase) is a key folate-dependent
        enzyme in the de novo purine biosynthesis pathway
- term:
    id: GO:0004644
    label: phosphoribosylglycinamide formyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:12755606
  qualifier: enables
  review:
    summary: >-
      GAR transformylase activity confirmed via a structure-based folate-analogue
      inhibitor (Ki=15 nM) and its crystal structure with human GAR Tfase; reinforces the
      folate-dependent catalytic activity and antifolate-target role.
    action: ACCEPT
    reason: >-
      Experimental support for GO:0004644 through selective inhibition of recombinant human
      GAR Tfase and co-crystal structure. Consistent with the other EXP/IDA/TAS lines.
    supported_by:
    - reference_id: PMID:12755606
      supporting_text: >-
        which specifically inhibits recombinant human GAR Tfase
        (K(i) = 15 nM)
- term:
    id: GO:0004641
    label: phosphoribosylformylglycinamidine cyclo-ligase activity
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: enables
  review:
    summary: >-
      AIR synthetase activity demonstrated by functional complementation of a yeast ade7
      (AIRS) mutation by the human GART cDNA, establishing this as one of GART's three
      activities.
    action: ACCEPT
    reason: >-
      Complementation of the yeast ade7 (AIRS/PAIS) mutation by the human trifunctional
      cDNA directly supports the AIR synthetase activity. Curator (MGI) IDA annotation.
    supported_by:
    - reference_id: PMID:2183217
      supporting_text: >-
        also complemented the ade5 (phosphoribosylglycinamide synthetase) and ade7
        [phosphoribosylaminoimidazole synthetase (AIRS; also known as PAIS)] mutations,
        indicating that it is the human trifunctional GART gene
- term:
    id: GO:0004644
    label: phosphoribosylglycinamide formyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: enables
  review:
    summary: >-
      GAR transformylase activity demonstrated by functional complementation of a yeast
      ade8 (GART) mutation by the human GART cDNA.
    action: ACCEPT
    reason: >-
      Complementation of the yeast ade8 (phosphoribosylglycinamide formyltransferase, GART)
      mutation by the human cDNA directly supports this activity. Curator (MGI) IDA
      annotation, also independently supported by EXP structures.
    supported_by:
    - reference_id: PMID:2183217
      supporting_text: >-
        The cDNA that complemented the ade8
        (phosphoribosylglycinamide formyltransferase, GART) mutation
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: located_in
  review:
    summary: >-
      Cytosolic localization of GART; the core location of the de novo purine biosynthesis
      machinery.
    action: ACCEPT
    reason: >-
      Curator IDA annotation for cytosolic localization, consistent with all other location
      evidence (IBA, IEA, Reactome TAS).
    supported_by:
    - reference_id: Reactome:R-HSA-73814
      supporting_text: The active form of the protein is cytosolic
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      GART provides IMP, the precursor from which GMP is made. GART does not itself perform
      GMP-specific biosynthetic reactions; GMP synthesis (IMP -> XMP -> GMP) is carried out
      by IMPDH and GMPS downstream of GART.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GART acts before the IMP branch point and is not part of GMP-specific biosynthesis.
      Even with the acts_upstream_of_or_within qualifier this term over-specifies GART's
      role; its accurate direct process is de novo IMP biosynthesis (GO:0006189). Marked
      over-annotated to keep review actions consistent across all GO:0006177 lines.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0006189
    label: "'de novo' IMP biosynthetic process"
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      GART catalyzes three consecutive steps of de novo IMP biosynthesis; established by
      complementation of yeast ade5/ade7/ade8 mutations by the single human cDNA.
    action: ACCEPT
    reason: >-
      The defining biological process for GART, directly supported by the complementation
      experiments. (The involved_in duplicate of this term is the core-process form.)
    supported_by:
    - reference_id: PMID:2183217
      supporting_text: >-
        clone three multifunctional human genes involved in de novo
        purine biosynthesis
- term:
    id: GO:0044208
    label: "'de novo' AMP biosynthetic process"
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      GART provides IMP, the precursor from which AMP is made. GART does not itself perform
      AMP-specific biosynthetic reactions; AMP synthesis (IMP -> adenylosuccinate -> AMP)
      is carried out by ADSS and ADSL downstream of GART.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GART acts before the IMP branch point and is not part of AMP-specific biosynthesis.
      Even with the acts_upstream_of_or_within qualifier this over-specifies GART's role;
      its accurate direct process is de novo IMP biosynthesis (GO:0006189). Marked
      over-annotated to keep review actions consistent across all GO:0044208 lines.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0097294
    label: "'de novo' XMP biosynthetic process"
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      GART provides IMP, the precursor from which XMP is made. GART does not itself perform
      XMP-specific biosynthetic reactions; XMP synthesis (IMP -> XMP) is carried out by
      IMPDH downstream of GART.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GART acts before the IMP branch point and is not part of XMP-specific biosynthesis.
      Even with the acts_upstream_of_or_within qualifier this over-specifies GART's role;
      its accurate direct process is de novo IMP biosynthesis (GO:0006189). Marked
      over-annotated to keep review actions consistent across all GO:0097294 lines.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0097294
    label: "'de novo' XMP biosynthetic process"
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: involved_in
  review:
    summary: >-
      involved_in duplicate of the XMP biosynthesis annotation. XMP is made from IMP,
      downstream of GART; GART does not perform XMP-specific reactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The involved_in qualifier asserts GART is part of XMP-specific biosynthesis, which
      overstates its role. GART's direct process is de novo IMP biosynthesis (GO:0006189);
      XMP synthesis (IMP -> XMP) is done by IMPDH.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: involved_in
  review:
    summary: >-
      involved_in duplicate of the GMP biosynthesis annotation. GMP is made from IMP,
      downstream of GART; GART does not perform GMP-specific reactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The involved_in qualifier asserts GART is part of GMP-specific biosynthesis, which
      overstates its role. GART's direct process is de novo IMP biosynthesis (GO:0006189);
      GMP synthesis is done by IMPDH and GMPS.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0006189
    label: "'de novo' IMP biosynthetic process"
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: involved_in
  review:
    summary: >-
      The core biological process for GART: it catalyzes three consecutive steps of de novo
      IMP biosynthesis (GAR synthetase, GAR transformylase, AIR synthetase).
    action: ACCEPT
    reason: >-
      Directly supported by the yeast-complementation experiments establishing the
      trifunctional de novo purine enzyme; this is the core process term for GART.
    supported_by:
    - reference_id: PMID:2183217
      supporting_text: >-
        clone three multifunctional human genes involved in de novo
        purine biosynthesis
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: is_active_in
  review:
    summary: >-
      GART is active in the cytosol; the core location of de novo purine biosynthesis.
    action: ACCEPT
    reason: >-
      Consistent with all other cytosol evidence; is_active_in appropriately captures where
      the enzyme functions.
    supported_by:
    - reference_id: Reactome:R-HSA-73814
      supporting_text: The active form of the protein is cytosolic
- term:
    id: GO:0044208
    label: "'de novo' AMP biosynthetic process"
  evidence_type: IDA
  original_reference_id: PMID:2183217
  qualifier: involved_in
  review:
    summary: >-
      involved_in duplicate of the AMP biosynthesis annotation. AMP is made from IMP,
      downstream of GART; GART does not perform AMP-specific reactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The involved_in qualifier asserts GART is part of AMP-specific biosynthesis, which
      overstates its role. GART's direct process is de novo IMP biosynthesis (GO:0006189);
      AMP synthesis is done by ADSS and ADSL.
    supported_by:
    - reference_id: file:human/GART/GART-uniprot.txt
      supporting_text: >-
        Trifunctional enzyme that catalyzes three distinct reactions
        as part of the 'de novo' inosine monophosphate biosynthetic pathway.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: >-
      Detected in a high-throughput MS survey of the B-cell exosome proteome (539 proteins),
      not a specific localization study. GART is a cytosolic de novo purine enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This HDA annotation derives from bulk exosome proteomics; cytosolic enzymes are common
      passenger contaminants in such datasets. It does not represent a specific or core
      extracellular/exosomal function of GART, whose established location is the cytosol.
    supported_by:
    - reference_id: PMID:20458337
      supporting_text: >-
        analyzed the total
        proteome of highly purified B cell-derived exosomes using sensitive and accurate
        mass spectrometry (MS), and identified 539 proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73810
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) cytosolic localization associated with the AIR synthetase reaction; the
      core location of GART.
    action: ACCEPT
    reason: >-
      Consistent with all other cytosol evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-73810
      supporting_text: The active form of the protein is cytosolic
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73813
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) cytosolic localization associated with the GAR transformylase reaction;
      the core location of GART.
    action: ACCEPT
    reason: >-
      Consistent with all other cytosol evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-73813
      supporting_text: >-
        Fluoresence microscopy
        studies of cultured human cells have shown that GART is cytosolic
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73814
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) cytosolic localization associated with the GAR synthetase reaction; the
      core location of GART.
    action: ACCEPT
    reason: >-
      Consistent with all other cytosol evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-73814
      supporting_text: The active form of the protein is cytosolic
- term:
    id: GO:0004644
    label: phosphoribosylglycinamide formyltransferase activity
  evidence_type: TAS
  original_reference_id: PMID:2050105
  qualifier: enables
  review:
    summary: >-
      Traceable author statement (TAS) for GAR transformylase activity from the paper cloning
      the full-length human GART gene, which describes the trifunctional GARS-GART-AIRS protein.
    action: ACCEPT
    reason: >-
      Consistent with the EXP/IDA/TAS/IEA support for GO:0004644; the reference describes the
      trifunctional protein including the GART (formyltransferase) function.
    supported_by:
    - reference_id: PMID:2050105
      supporting_text: >-
        the trifunctional protein containing
        phosphoribosylglycinamide synthetase (GARS), phosphoribosylglycinamide
        formyltransferase (GART) and phosphoribosylaminoimidazole synthetase (AIRS)
core_functions:
- description: >-
    Phosphoribosylamine--glycine ligase (GAR synthetase, EC 6.3.4.13) activity of the
    N-terminal ATP-grasp domain, catalyzing step 2 of de novo IMP biosynthesis
    (5-phospho-beta-D-ribosylamine + glycine + ATP -> GAR + ADP + Pi).
  molecular_function:
    id: GO:0004637
    label: phosphoribosylamine-glycine ligase activity
  directly_involved_in:
  - id: GO:0006189
    label: "'de novo' IMP biosynthetic process"
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/GART/GART-uniprot.txt
    supporting_text: >-
      The N-terminal ATP-grasp domain carries the
      phosphoribosylamine--glycine ligase activity.
- description: >-
    Phosphoribosylglycinamide formyltransferase (GAR transformylase, EC 2.1.2.2) activity of
    the C-terminal GART domain, the folate-dependent step 3 of de novo IMP biosynthesis
    (GAR + 10-formyl-THF -> FGAR + THF) and a validated antifolate chemotherapy target.
  molecular_function:
    id: GO:0004644
    label: phosphoribosylglycinamide formyltransferase activity
  directly_involved_in:
  - id: GO:0006189
    label: "'de novo' IMP biosynthetic process"
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:12450384
    supporting_text: >-
      Glycinamide ribonucleotide transformylase (GAR Tfase) is a key folate-dependent
      enzyme in the de novo purine biosynthesis pathway
- description: >-
    Phosphoribosylformylglycinamidine cyclo-ligase (AIR synthetase, EC 6.3.3.1) activity of
    the central AIRS domain, catalyzing step 5 of de novo IMP biosynthesis
    (FGAM + ATP -> AIR + ADP + Pi).
  molecular_function:
    id: GO:0004641
    label: phosphoribosylformylglycinamidine cyclo-ligase activity
  directly_involved_in:
  - id: GO:0006189
    label: "'de novo' IMP biosynthetic process"
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/GART/GART-uniprot.txt
    supporting_text: >-
      The central AIRS domain carries the
      phosphoribosylformylglycinamidine cyclo-ligase activity.
proposed_new_terms: []
suggested_questions:
- question: >-
    Under what physiological/metabolic conditions does human GART assemble into the transient
    cytosolic purinosome with other de novo purine enzymes, and how does this affect flux?
- question: >-
    Do the reported phosphorylation and acetylation sites (e.g. Ser-10, Ser-440, Lys-350)
    regulate GART activity, purinosome assembly, or turnover?
suggested_experiments:
- description: >-
    Domain-swap or point-mutant complementation in GART-null cells to confirm the independent
    contribution of each of the three catalytic domains to de novo IMP biosynthesis in human cells.
- description: >-
    Live-cell imaging under purine-replete vs purine-depleted conditions to quantify GART
    incorporation into the purinosome.