id: Q06203
gene_symbol: PPAT
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PPAT is human amidophosphoribosyltransferase (ATase; glutamine
  phosphoribosylpyrophosphate amidotransferase, GPAT; EC 2.4.2.14), the enzyme
  that catalyses the first committed and rate-limiting step of de novo purine
  nucleotide biosynthesis. It transfers the amide nitrogen of L-glutamine to
  5-phospho-alpha-D-ribose 1-diphosphate (PRPP), producing 5-phospho-beta-D-
  ribosylamine (PRA) plus L-glutamate and diphosphate; PRA is the entry
  metabolite for the entire de novo purine branch leading to IMP and thence to
  AMP and GMP. The protein has an N-terminal type-2 glutamine amidotransferase
  domain (with an N-terminal-nucleophile cysteine exposed only after removal of
  an 11-residue propeptide) and a C-terminal phosphoribosyltransferase domain,
  binds Mg2+, and carries a [4Fe-4S] cluster required for activity. As the
  pathway's committed entry point it is allosterically feedback-inhibited by the
  purine mononucleotide end products AMP, GMP and IMP (which promote an inactive
  tetramer) and activated by its substrate PRPP (which favours the active
  dimer). It acts in the cytosol.
existing_annotations:
- term:
    id: GO:0004044
    label: amidophosphoribosyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core molecular function. PPAT is amidophosphoribosyltransferase (EC
      2.4.2.14), transferring the L-glutamine amide nitrogen to PRPP to give
      5-phospho-beta-D-ribosylamine. This IBA is well supported across the
      orthologous family (E. coli PurF, B. subtilis, yeast ADE4, etc.) and
      matches direct human evidence.
    action: ACCEPT
    reason: >-
      Phylogenetically conserved and experimentally established core catalytic
      activity of the gene product.
    supported_by:
    - reference_id: file:human/PPAT/PPAT-uniprot.txt
      supporting_text: "Catalyzes the formation of phosphoribosylamine from"
- term:
    id: GO:0006164
    label: purine nucleotide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      PPAT catalyses the committed step of de novo purine nucleotide synthesis,
      so the general process "purine nucleotide biosynthetic process" correctly
      captures its biological role at an appropriate level.
    action: ACCEPT
    reason: >-
      Accurate, appropriately general process annotation supported by the
      conserved catalytic role and human literature.
    supported_by:
    - reference_id: file:human/PPAT/PPAT-uniprot.txt
      supporting_text: "IMP biosynthesis via de novo pathway"
- term:
    id: GO:0004044
    label: amidophosphoribosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assertion of the core amidophosphoribosyltransferase activity,
      backed by the RHEA:14905 / EC 2.4.2.14 reaction and InterPro PurF
      signature. Consistent with the IBA/ISS/TAS evidence for the same term.
    action: ACCEPT
    reason: >-
      Correct MF; duplicate of the core catalytic activity supported by
      additional evidence codes.
    supported_by:
    - reference_id: file:human/PPAT/PPAT-uniprot.txt
      supporting_text: "Catalyzes the formation of phosphoribosylamine from"
- term:
    id: GO:0009113
    label: purine nucleobase biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO maps the PurF signature to "purine nucleobase biosynthetic
      process". PPAT actually produces the ribonucleotide precursor
      5-phospho-beta-D-ribosylamine, not a free purine nucleobase, so
      nucleobase biosynthesis is a slightly imprecise process; the accurate
      downstream process is de novo IMP biosynthesis.
    action: MODIFY
    reason: >-
      The essence (purine biosynthesis) is correct but the branch (nucleobase
      vs nucleotide) is imprecise for this enzyme, which makes the nucleotide
      precursor PRA. Replace with the accurate de novo IMP biosynthetic
      process.
    proposed_replacement_terms:
    - id: GO:0006189
      label: "'de novo' IMP biosynthetic process"
    supported_by:
    - reference_id: file:human/PPAT/PPAT-uniprot.txt
      supporting_text: "IMP biosynthesis via de novo pathway"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from a high-throughput AP-MS interactome screen
      (BioPlex; IntAct-derived interaction with NUDT5, Q9UKK9). This term is
      uninformative about PPAT's molecular function and the interaction has no
      established functional consequence for the enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" from a proteome-scale screen; retained (an
      experimental IPI) but flagged as over-annotation because it does not
      convey a meaningful molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from the second BioPlex proteome-scale interactome
      (again the NUDT5 interaction, Q9UKK9). Uninformative regarding PPAT's
      catalytic function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative high-throughput "protein binding"; retained as an
      experimental IPI but flagged as over-annotation.
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transfer (Ensembl Compara) annotation to the GMP-specific branch.
      PPAT catalyses only the single committed step producing PRA, upstream of
      IMP; the GMP-specific conversions are carried out by dedicated downstream
      enzymes (IMPDH, GMP synthase). Annotating PPAT directly to GMP
      biosynthesis over-states its involvement.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Downstream branch-specific process; PPAT contributes only the shared
      upstream precursor. Over-propagated automated ortholog transfer rather
      than a directly supported role (kept, not removed).
- term:
    id: GO:0006189
    label: "'de novo' IMP biosynthetic process"
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      PPAT's product 5-phospho-beta-D-ribosylamine is the first intermediate of
      the de novo IMP biosynthetic pathway (UniPathway UPA00074, step 1). This
      is the accurate de novo purine process for the enzyme.
    action: ACCEPT
    reason: >-
      Correct and precise process annotation; PPAT performs step 1/2 of the de
      novo IMP pathway per UniProt/UniPathway.
    supported_by:
    - reference_id: file:human/PPAT/PPAT-uniprot.txt
      supporting_text: "IMP biosynthesis via de novo pathway"
- term:
    id: GO:0044208
    label: "'de novo' AMP biosynthetic process"
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transfer annotation to the AMP-specific de novo branch. As with
      the GMP branch, PPAT only provides the shared upstream precursor (PRA ->
      IMP); the AMP-specific steps use adenylosuccinate synthase/lyase.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Downstream branch-specific process beyond PPAT's single committed step;
      over-propagated automated ortholog transfer (kept, not removed).
- term:
    id: GO:0097294
    label: "'de novo' XMP biosynthetic process"
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transfer annotation to the XMP-specific de novo branch. XMP is
      produced from IMP by IMPDH, several steps downstream of PPAT's committed
      reaction; PPAT does not itself act in XMP-specific synthesis.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Downstream branch-specific process; PPAT contributes only the shared
      precursor. Over-propagated automated ortholog transfer (kept, not
      removed).
- term:
    id: GO:0004044
    label: amidophosphoribosyltransferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity transfer of the core amidophosphoribosyltransferase
      activity from rat ortholog (UniProtKB:P35433). Concordant with the
      IBA/IEA/TAS evidence for the same MF.
    action: ACCEPT
    reason: >-
      Correct core catalytic activity supported by ortholog similarity and
      direct human evidence.
    supported_by:
    - reference_id: file:human/PPAT/PPAT-uniprot.txt
      supporting_text: "Catalyzes the formation of phosphoribosylamine from"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-111285
  qualifier: located_in
  review:
    summary: >-
      PPAT is a cytosolic enzyme. Reactome describes cytosolic PPAT and its
      allosteric assembly, in which AMP, GMP and IMP promote dimer-to-tetramer
      association (the feedback-inhibited state).
    action: ACCEPT
    reason: >-
      Correct subcellular localization, consistent across Reactome and UniProt.
    supported_by:
    - reference_id: Reactome:R-HSA-111285
      supporting_text: >-
        Cytosolic AMP, GMP, and IMP stimulate the association of phosphoribosyl
        pyrophosphate amidotransferase (PPAT) dimers to form tetramers
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-111289
  qualifier: located_in
  review:
    summary: >-
      Cytosolic localization. Reactome documents that the substrate PRPP drives
      dissociation of the inactive tetramer into the active dimer, part of
      PPAT's cytosolic allosteric regulation.
    action: ACCEPT
    reason: >-
      Correct subcellular localization.
    supported_by:
    - reference_id: Reactome:R-HSA-111289
      supporting_text: >-
        PRPP stimulates the dissociation of phosphoribosyl pyrophosphate
        amidotransferase tetramers to form dimers
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73815
  qualifier: located_in
  review:
    summary: >-
      Cytosolic localization tied to the catalytic reaction itself. Reactome
      states that cytosolic PPAT catalyses the committed step of de novo purine
      synthesis, pulled forward by pyrophosphate hydrolysis.
    action: ACCEPT
    reason: >-
      Correct subcellular localization, from the reaction event where PPAT acts.
    supported_by:
    - reference_id: Reactome:R-HSA-73815
      supporting_text: >-
        This event is the committed step in de novo purine synthesis.
- term:
    id: GO:0004044
    label: amidophosphoribosyltransferase activity
  evidence_type: TAS
  original_reference_id: PMID:8106516
  qualifier: enables
  review:
    summary: >-
      Human GPAT/PPAT cDNA was cloned and expressed to yield functional enzyme
      catalysing step one of de novo purine nucleotide synthesis, directly
      supporting the amidophosphoribosyltransferase activity for the human
      protein.
    action: ACCEPT
    reason: >-
      Author statement (TAS) directly establishing the enzyme's identity and
      catalytic role in human.
    supported_by:
    - reference_id: PMID:8106516
      supporting_text: >-
        A cDNA encoding human glutamine phosphoribosylpyrophosphate
        amidotransferase for
- term:
    id: GO:0006164
    label: purine nucleotide biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:8106516
  qualifier: involved_in
  review:
    summary: >-
      The cloned human enzyme performs step one in de novo purine nucleotide
      synthesis, supporting involvement in the purine nucleotide biosynthetic
      process.
    action: ACCEPT
    reason: >-
      Author statement directly supporting the process role in human.
    supported_by:
    - reference_id: PMID:8106516
      supporting_text: >-
        step one in de novo purine nucleotide synthesis was cloned, sequenced,
        and
core_functions:
- description: >-
    Amidophosphoribosyltransferase catalysing the first committed, rate-limiting
    step of de novo purine biosynthesis: transfer of the L-glutamine amide
    nitrogen to PRPP to form 5-phospho-beta-D-ribosylamine, L-glutamate and
    diphosphate.
  molecular_function:
    id: GO:0004044
    label: amidophosphoribosyltransferase 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/PPAT/PPAT-uniprot.txt
    supporting_text: "IMP biosynthesis via de novo pathway"
  - reference_id: PMID:8106516
    supporting_text: >-
      A cDNA encoding human glutamine phosphoribosylpyrophosphate
      amidotransferase for
- description: >-
    Contribution of the committed PPAT-catalysed reaction to the broader purine
    nucleotide biosynthetic process; its product PRA is the entry metabolite for
    the de novo purine branch leading to IMP, AMP and GMP.
  molecular_function:
    id: GO:0004044
    label: amidophosphoribosyltransferase activity
  directly_involved_in:
  - id: GO:0006164
    label: purine nucleotide biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: Reactome:R-HSA-73815
    supporting_text: >-
      This event is the committed step in de novo purine synthesis.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale AP-MS interactome (BioPlex). Source of a bare "protein
      binding" IPI (PPAT-NUDT5); no functional consequence established for
      PPAT's catalytic role.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Second proteome-scale BioPlex interactome. Source of a bare "protein
      binding" IPI (PPAT-NUDT5); uninformative about molecular function.
- id: PMID:8106516
  title: Two genes for de novo purine nucleotide synthesis on human chromosome 4 are
    closely linked and divergently transcribed.
  findings:
  - statement: >-
      Human GPAT/PPAT cDNA was cloned, sequenced and expressed to yield
      functional glutamine phosphoribosylpyrophosphate amidotransferase, the
      enzyme for step one of de novo purine nucleotide synthesis, whose activity
      requires removal of an 11-residue propeptide.
    supporting_text: >-
      A cDNA encoding human glutamine phosphoribosylpyrophosphate
      amidotransferase for
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary human cloning/expression paper establishing PPAT (GPAT) as the
      step-1 de novo purine enzyme; supports the TAS MF and process annotations.
- id: Reactome:R-HSA-111285
  title: Formation of phosphoribosyl pyrophosphate amidotransferase tetramer
  findings: []
- id: Reactome:R-HSA-111289
  title: Dissociation of phosphoribosyl pyrophosphate amidotransferase tetramer
  findings: []
- id: Reactome:R-HSA-73815
  title: 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) + H2O + L-glutamine <=> 5-phosphoribosylamine
    + L-glutamate +pyrophosphate
  findings: []