id: P60891
gene_symbol: PRPS1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PRPS1 encodes phosphoribosyl pyrophosphate synthetase 1 (ribose-phosphate
  pyrophosphokinase 1; PRS-I; EC 2.7.6.1), a cytosolic Mg2+-dependent enzyme that
  transfers the beta,gamma-diphosphoryl group of ATP to D-ribose 5-phosphate,
  producing 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) plus AMP. PRPP is the
  essential activated precursor for de novo and salvage biosynthesis of purine,
  pyrimidine, and pyridine (NAD) nucleotides, so PRPS1 forms the metabolic bridge
  connecting the pentose phosphate pathway (ribose 5-phosphate) to nucleotide
  metabolism. The enzyme assembles into homodimers that further oligomerize
  (probably a hexamer of three dimers) and is regulated allosterically, being
  activated by inorganic phosphate and Mg2+ and feedback-inhibited by ADP and GDP.
  PRPS1 is X-linked and shows strong dosage sensitivity: loss-of-function variants
  cause Arts syndrome, X-linked Charcot-Marie-Tooth disease type 5
  (CMTX5/Rosenberg-Chutorian), and X-linked nonsyndromic sensorineural deafness
  (DFN2/DFNX1), whereas feedback-resistant gain-of-function variants cause PRPP
  synthetase superactivity with purine overproduction, hyperuricemia, and gout.
alternative_products:
- name: '1'
  id: P60891-1
- name: '2'
  id: P60891-2
  sequence_note: VSP_056028
existing_annotations:
- term:
    id: GO:0004749
    label: ribose phosphate diphosphokinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) annotation to the defining catalytic activity of PRPS1,
      the transfer of a diphosphoryl group from ATP to ribose-5-phosphate to make PRPP.
      This is the core molecular function and is corroborated by direct experimental
      evidence for the human enzyme.
    action: ACCEPT
    reason: Correct and appropriately specific molecular function term for the PRPS
      family; supported experimentally in human (PMID:16939420, PMID:7593598).
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "Catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP)"
    - reference_id: PMID:16939420
      supporting_text: "catalyses synthesis of PRPP from"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic annotation placing PRPS1 activity in the cytoplasm, consistent
      with the enzyme being a soluble cytosolic housekeeping metabolic enzyme.
    action: ACCEPT
    reason: Correct localization; the more specific cytosol annotation is captured
      separately (GO:0005829). Retained as accurate but general.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "Belongs to the ribose-phosphate pyrophosphokinase family."
- term:
    id: GO:0006164
    label: purine nucleotide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic annotation to purine nucleotide biosynthesis. PRPP produced
      by PRPS1 is the activated ribose donor for both de novo purine synthesis and
      purine salvage (HGPRT/APRT), so the process is directly downstream of PRPS1 catalysis.
    action: ACCEPT
    reason: Well supported; loss-of-function PRPS1 variants impair purine biosynthesis
      in patients (PMID:17701896).
    supported_by:
    - reference_id: PMID:17701896
      supporting_text: "likely result in impaired purine biosynthesis"
- term:
    id: GO:0006015
    label: 5-phosphoribose 1-diphosphate biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic annotation to PRPP biosynthesis, the specific pathway step
      catalyzed by PRPS1 (route I, step 1/1). This is the most precise biological-process
      term for the enzyme's direct action.
    action: ACCEPT
    reason: Precisely matches the reaction catalyzed; strongly supported experimentally
      and by pathway assignment.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "PATHWAY: Metabolic intermediate biosynthesis; 5-phospho-alpha-D-ribose"
- term:
    id: GO:0002189
    label: ribose phosphate diphosphokinase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic annotation placing PRPS1 in the PRPP synthetase complex.
      PRPS1 functions as a homodimer that oligomerizes (probably a hexamer of three
      dimers) and also associates with regulatory subunits (PRPSAP1/PRPSAP2), consistent
      with this complex assignment.
    action: ACCEPT
    reason: Supported by the demonstrated oligomeric assembly of the human enzyme.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer. The active form is probably a hexamer composed of 3"
- term:
    id: GO:0000287
    label: magnesium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic annotation to magnesium ion binding. PRPS1 requires
      Mg2+ as cofactor; the crystal structure resolves metal ion coordination at the
      active site and UniProt annotates Mg2+-binding residues.
    action: ACCEPT
    reason: Correct; Mg2+ is a required cofactor and binding residues are annotated
      (BINDING 130/139/143).
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "Name=Mg(2+); Xref=ChEBI:CHEBI:18420;"
- term:
    id: GO:0004749
    label: ribose phosphate diphosphokinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation of the core catalytic activity via InterPro/EC 2.7.6.1/RHEA:15609
      mapping. Redundant with the experimentally supported MF annotation.
    action: ACCEPT
    reason: Correct EC/RHEA-based mapping to the enzyme's defining activity.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "D-ribose 5-phosphate + ATP = 5-phospho-alpha-D-ribose 1-"
- term:
    id: GO:0009156
    label: ribonucleoside monophosphate biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based annotation to ribonucleoside monophosphate biosynthesis.
      PRPP supplied by PRPS1 is the ribose-phosphate donor for the pathways generating
      purine and pyrimidine (ribo)nucleoside monophosphates.
    action: ACCEPT
    reason: Consistent with the enzyme's role upstream of NMP synthesis; a broader
      but correct grouping alongside GO:0006164/GO:0006221.
    supported_by:
    - reference_id: PMID:16939420
      supporting_text: "important metabolite essential for"
- term:
    id: GO:0009165
    label: nucleotide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based annotation to the general nucleotide biosynthetic process.
      Correct but general; PRPP is the shared precursor for purine, pyrimidine, and
      pyridine nucleotide synthesis.
    action: ACCEPT
    reason: Accurate high-level grouping term; more specific children (GO:0006015,
      GO:0006164) are also present.
    supported_by:
    - reference_id: PMID:16939420
      supporting_text: "important metabolite essential for"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a proteome-scale two-hybrid interactome
      screen. The specific, biologically meaningful self-association is captured by
      GO:0042802/GO:0042803.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" is uninformative about molecular function and derives
      from high-throughput interactome mapping; per curation guidance a more specific
      MF term should be used instead.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a proteome-scale interactome map.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding" from high-throughput mapping; more
      specific self-association terms already capture the meaningful function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a large-scale interactome perturbation
      study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding" from high-throughput mapping.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a quantitative interactome study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding" from high-throughput mapping.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from an interactome-architecture study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding" from high-throughput mapping.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29892012
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from an interactome-perturbation framework.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding" from high-throughput mapping.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a population-scale variant interactome
      study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding" from high-throughput mapping.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a reference binary interactome
      map.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding" from high-throughput mapping; the
      meaningful PRPS1 self-association is captured by GO:0042802.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a neurodegenerative-disease interactome
      screen reporting dozens of candidate partners for PRPS1. These are unvalidated
      high-throughput hits and do not define a specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding" from a large high-throughput screen;
      no specific functional partnership is established.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a proteome-scale cell-specific
      interactome study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding" from high-throughput mapping.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a multimodal cell-map interactome
      study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding" from high-throughput mapping.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: Self-association (PRPS1-PRPS1) detected by interactome mapping. This is
      biologically meaningful because PRPS1 functions as a homodimer that further oligomerizes.
    action: ACCEPT
    reason: Consistent with the well-established homo-oligomeric assembly of the enzyme
      (crystal structure PMID:16939420).
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer. The active form is probably a hexamer composed of 3"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: PRPS1 self-association detected in a proteome-scale interactome map, consistent
      with the enzyme's homo-oligomeric quaternary structure.
    action: ACCEPT
    reason: Meaningful self-interaction supporting the homodimer/hexamer assembly.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer. The active form is probably a hexamer composed of 3"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25502805
  qualifier: enables
  review:
    summary: PRPS1 self-association reported in a parallel clone/variant molecular-phenotyping
      study, consistent with the enzyme's homo-oligomeric assembly.
    action: ACCEPT
    reason: Consistent with the demonstrated homodimer/hexamer quaternary structure.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer. The active form is probably a hexamer composed of 3"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: PRPS1 self-association reported in an interactome-perturbation study, consistent
      with homo-oligomerization.
    action: ACCEPT
    reason: Consistent with the demonstrated homodimer/hexamer quaternary structure.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer. The active form is probably a hexamer composed of 3"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: PRPS1 self-association reported in a population-scale variant interactome
      study, consistent with homo-oligomerization.
    action: ACCEPT
    reason: Consistent with the demonstrated homodimer/hexamer quaternary structure.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer. The active form is probably a hexamer composed of 3"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: PRPS1 self-association reported in a reference binary interactome map,
      consistent with homo-oligomerization.
    action: ACCEPT
    reason: Consistent with the demonstrated homodimer/hexamer quaternary structure.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer. The active form is probably a hexamer composed of 3"
- term:
    id: GO:0008584
    label: male gonad development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Electronic annotation transferred from a rat ortholog via Ensembl Compara.
      There is no human evidence that PRPS1 has a specific role in testis development;
      PRPS1 is a ubiquitously expressed housekeeping metabolic enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: Single-organism electronic transfer of a tissue-specific developmental
      process to a ubiquitous housekeeping enzyme; not a demonstrated PRPS1 function
      in human and likely reflects the enzyme's general requirement in proliferating
      tissue rather than a specific developmental role.
- term:
    id: GO:0006164
    label: purine nucleotide biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity annotation (from PRPS2) to purine nucleotide biosynthesis,
      duplicating the IBA and IMP annotations to the same process.
    action: ACCEPT
    reason: Correct; PRPP is the ribose-phosphate donor for de novo and salvage purine
      nucleotide synthesis.
    supported_by:
    - reference_id: PMID:17701896
      supporting_text: "likely result in impaired purine biosynthesis"
- term:
    id: GO:0034214
    label: protein hexamerization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity annotation (from PRPS2) to protein hexamerization.
      The active human enzyme is proposed to be a hexamer assembled from three homodimers,
      consistent with this annotation.
    action: ACCEPT
    reason: Consistent with the demonstrated oligomeric assembly of PRPS1.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer. The active form is probably a hexamer composed of 3"
- term:
    id: GO:0006015
    label: 5-phosphoribose 1-diphosphate biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-based electronic annotation to PRPP biosynthesis, the direct
      pathway step catalyzed by PRPS1. Redundant with the IBA annotation to the same
      term.
    action: ACCEPT
    reason: Precisely matches the enzyme's pathway role (UPA00087, route I step 1/1).
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "PATHWAY: Metabolic intermediate biosynthesis; 5-phospho-alpha-D-ribose"
- term:
    id: GO:0004749
    label: ribose phosphate diphosphokinase activity
  evidence_type: EXP
  original_reference_id: PMID:7593598
  qualifier: enables
  review:
    summary: Experimental (kinetic) characterization of recombinant human PRS1, including
      wild-type and superactivity variants, confirming PRPP synthetase activity and
      its allosteric regulation by inorganic phosphate and purine nucleotides.
    action: ACCEPT
    reason: Direct experimental support for the core catalytic activity in human, with
      measured kinetic parameters (KM 23 uM ATP, 54 uM R5P).
    supported_by:
    - reference_id: PMID:7593598
      supporting_text: "Kinetic analysis of recombinant mutant PRS1s"
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "KM=23 uM for ATP"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-111215
  qualifier: located_in
  review:
    summary: Reactome traceable-author annotation placing PRPS1 catalysis in the cytosol,
      the compartment where PRPP synthesis occurs.
    action: ACCEPT
    reason: Correct and specific subcellular localization for this soluble cytosolic
      enzyme.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "Belongs to the ribose-phosphate pyrophosphokinase family."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73580
  qualifier: located_in
  review:
    summary: Reactome traceable-author annotation placing the PRPS dimer-catalyzed reaction
      in the cytosol.
    action: ACCEPT
    reason: Correct and specific cytosolic localization; duplicate of the other Reactome
      cytosol annotation.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "Belongs to the ribose-phosphate pyrophosphokinase family."
- term:
    id: GO:0004749
    label: ribose phosphate diphosphokinase activity
  evidence_type: IMP
  original_reference_id: PMID:12847698
  qualifier: enables
  review:
    summary: A PRPS1 mutation causing enzyme overactivity underlies uric acid overproduction
      in a patient, providing mutant-phenotype support for PRPS1 possessing PRPP synthetase
      activity.
    action: ACCEPT
    reason: Mutant-phenotype evidence linking the PRPS1 gene product to the catalytic
      activity via disordered allosteric regulation.
    supported_by:
    - reference_id: PMID:12847698
      supporting_text: "defective allosteric regulation \nof PRS activity"
- term:
    id: GO:0004749
    label: ribose phosphate diphosphokinase activity
  evidence_type: IMP
  original_reference_id: PMID:17701896
  qualifier: enables
  review:
    summary: Loss-of-function PRPS1 missense mutations (L152P, Q133P) reduce PRPP synthetase
      activity in patient erythrocytes and fibroblasts, demonstrating the gene product
      carries this catalytic activity.
    action: ACCEPT
    reason: Mutant-phenotype evidence in human patient cells directly supports the core
      catalytic activity.
    supported_by:
    - reference_id: PMID:17701896
      supporting_text: "result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity"
- term:
    id: GO:0006144
    label: purine nucleobase metabolic process
  evidence_type: IMP
  original_reference_id: PMID:8253776
  qualifier: involved_in
  review:
    summary: PRPS1 superactivity variants perturb purine metabolism, causing uric acid
      overproduction. PRPP supply by PRPS1 governs flux through purine nucleobase salvage
      and de novo synthesis.
    action: ACCEPT
    reason: Correct, if broad; PRPS1 is central to purine nucleobase/nucleotide metabolism
      and gain-of-function variants dysregulate it.
    supported_by:
    - reference_id: PMID:8253776
      supporting_text: "X \nchromosome-linked disorder of purine metabolism"
- term:
    id: GO:0006164
    label: purine nucleotide biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:12847698
  qualifier: involved_in
  review:
    summary: A gain-of-function PRPS1 variant accelerates purine nucleotide production,
      providing mutant-phenotype evidence that PRPS1 participates in purine nucleotide
      biosynthesis.
    action: ACCEPT
    reason: Directly supported; disease variant increases purine nucleotide and uric
      acid production.
    supported_by:
    - reference_id: PMID:12847698
      supporting_text: "accelerated purine nucleotide and uric acid production"
- term:
    id: GO:0006221
    label: pyrimidine nucleotide biosynthetic process
  evidence_type: NAS
  original_reference_id: PMID:17701896
  qualifier: involved_in
  review:
    summary: Author statement that PRPS1 is critical for nucleotide biosynthesis. PRPP
      is the obligatory ribose-phosphate substrate used by orotate phosphoribosyltransferase
      in de novo pyrimidine synthesis, so PRPS1 supplies pyrimidine as well as purine
      pathways.
    action: ACCEPT
    reason: Biologically correct; PRPP feeds de novo pyrimidine nucleotide synthesis,
      making PRPS1 an upstream contributor to this process.
    supported_by:
    - reference_id: PMID:16939420
      supporting_text: "important metabolite essential for"
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: IMP
  original_reference_id: PMID:17701900
  qualifier: involved_in
  review:
    summary: Loss-of-function PRPS1 mutations cause CMTX5, a hereditary peripheral neuropathy
      with hearing loss and optic neuropathy. This reflects a pleiotropic disease consequence
      of reduced nucleotide supply in the nervous system rather than a neuron-specific
      developmental function of the housekeeping enzyme.
    action: KEEP_AS_NON_CORE
    reason: The neuropathy phenotype is a downstream, tissue-vulnerability consequence
      of impaired PRPP/nucleotide metabolism, not the enzyme's core molecular role;
      retain as a non-core, disease-associated process.
    supported_by:
    - reference_id: PMID:17701900
      supporting_text: "The enzyme mediates the biochemical step critical"
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: IMP
  original_reference_id: PMID:8253776
  qualifier: involved_in
  review:
    summary: PRPS1 superactivity is associated in some families with neurodevelopmental
      impairment, again reflecting a systemic metabolic effect on the nervous system
      rather than a dedicated developmental function.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic disease association; retain as non-core rather than a core function
      of this ubiquitous metabolic enzyme.
    supported_by:
    - reference_id: PMID:8253776
      supporting_text: "in some families, neurodevelopmental impairment"
- term:
    id: GO:0034418
    label: urate biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:12847698
  qualifier: involved_in
  review:
    summary: Gain-of-function PRPS1 overactivity drives uric acid overproduction. Urate
      is a distal catabolic product of the purine nucleotides whose synthesis PRPS1
      accelerates, so this is a downstream metabolic consequence rather than a direct
      enzymatic role.
    action: KEEP_AS_NON_CORE
    reason: Biologically valid as a disease phenotype but several steps removed from
      the PRPP synthetase reaction; retain as non-core.
    supported_by:
    - reference_id: PMID:12847698
      supporting_text: "uric acid \noverproduction"
- term:
    id: GO:0046101
    label: hypoxanthine biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:17701896
  qualifier: involved_in
  review:
    summary: In PRPS1 loss-of-function (Arts syndrome) hypoxanthine is undetectable
      in urine, indicating altered purine catabolite levels. This reflects downstream
      consequences of reduced PRPP/purine metabolism rather than a direct PRPS1 catalytic
      role in hypoxanthine synthesis.
    action: KEEP_AS_NON_CORE
    reason: Downstream metabolic consequence of the enzyme's activity, not its core
      molecular function; retain as non-core.
    supported_by:
    - reference_id: PMID:17701896
      supporting_text: "undetectable hypoxanthine in urine"
- term:
    id: GO:0004749
    label: ribose phosphate diphosphokinase activity
  evidence_type: IDA
  original_reference_id: PMID:16939420
  qualifier: enables
  review:
    summary: Direct assay of recombinant human PRS1, whose crystal structure was solved
      in complex with ATP/AMP and metal ion, confirming the PRPP synthetase catalytic
      activity and defining the active and allosteric sites.
    action: ACCEPT
    reason: Direct experimental evidence for the core catalytic activity of the human
      enzyme.
    supported_by:
    - reference_id: PMID:16939420
      supporting_text: "PRS (PRPP synthetase) catalyses synthesis of PRPP from"
- term:
    id: GO:0004749
    label: ribose phosphate diphosphokinase activity
  evidence_type: IDA
  original_reference_id: PMID:17701900
  qualifier: enables
  review:
    summary: Direct measurement showing decreased PRPP synthetase enzyme activity in
      cells from CMTX5 patients carrying the M115T variant, confirming that PRPS1 carries
      this catalytic activity.
    action: ACCEPT
    reason: Direct experimental support for the core catalytic activity, including reduced
      activity for a disease variant.
    supported_by:
    - reference_id: PMID:17701900
      supporting_text: "showed decreased enzyme activity in patients with M115T"
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IDA
  original_reference_id: PMID:16939420
  qualifier: enables
  review:
    summary: The crystal structure of human PRS1 was solved in complex with the AMP
      moiety of ATP bound at the ATP-binding site, directly demonstrating ATP binding.
    action: ACCEPT
    reason: Direct structural evidence for ATP binding, a required substrate-binding
      activity for the enzyme.
    supported_by:
    - reference_id: PMID:16939420
      supporting_text: "The AMP moiety of ATP \nbinds at the ATP-binding site"
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:16939420
  qualifier: enables
  review:
    summary: The crystal structure demonstrates that human PRS1 forms a homodimer that
      is the building block of the higher-order oligomer, directly supporting homodimerization
      activity.
    action: ACCEPT
    reason: Structurally demonstrated homodimerization; the homodimer is the functional
      building block of the active hexamer.
    supported_by:
    - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer. The active form is probably a hexamer composed of 3"
core_functions:
- description: Catalyzes the Mg2+-dependent transfer of the beta,gamma-diphosphoryl
    group of ATP to D-ribose 5-phosphate, producing 5-phospho-alpha-D-ribose 1-diphosphate
    (PRPP) plus AMP, the committed step that generates the activated ribose-phosphate
    donor for nucleotide biosynthesis and salvage.
  molecular_function:
    id: GO:0004749
    label: ribose phosphate diphosphokinase activity
  directly_involved_in:
  - id: GO:0006015
    label: 5-phosphoribose 1-diphosphate biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:16939420
    supporting_text: "catalyses synthesis of PRPP from"
  - reference_id: file:human/PRPS1/PRPS1-uniprot.txt
    supporting_text: "D-ribose 5-phosphate + ATP = 5-phospho-alpha-D-ribose 1-"
- description: Provides PRPP as the essential ribose-phosphate precursor for de novo
    and salvage purine nucleotide biosynthesis, bridging the pentose phosphate pathway
    to purine metabolism.
  molecular_function:
    id: GO:0004749
    label: ribose phosphate diphosphokinase activity
  directly_involved_in:
  - id: GO:0006164
    label: purine nucleotide biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:17701896
    supporting_text: "likely result in impaired purine biosynthesis"
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:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  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: file:human/PRPS1/PRPS1-uniprot.txt
  title: UniProtKB entry P60891 (PRPS1_HUMAN), Ribose-phosphate pyrophosphokinase 1
  findings: []
- id: PMID:12847698
  title: Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid
    overproduction in a young woman.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified case report; supports gain-of-function superactivity
      driving purine nucleotide and uric acid overproduction.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput two-hybrid interactome; source of generic protein-binding
      and PRPS1 self-interaction calls.
- id: PMID:16939420
  title: Crystal structure of human phosphoribosylpyrophosphate synthetase 1 reveals
    a novel allosteric site.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural/biochemical characterization of human PRS1; directly supports
      catalytic activity, ATP binding, metal binding, and homodimer assembly.
- id: PMID:17701896
  title: Arts syndrome is caused by loss-of-function mutations in PRPS1.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Demonstrates loss-of-function PRPS1 variants reduce enzyme activity
      and impair purine biosynthesis.
- id: PMID:17701900
  title: Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase
    enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy
    with hearing loss and optic neuropathy (cmtx5).
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: CMTX5 loss-of-function study; shows decreased PRPP synthetase activity
      for a disease variant.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of generic and self-interaction
      calls.
- id: PMID:25502805
  title: A massively parallel pipeline to clone DNA variants and examine molecular
    phenotypes of human disease mutations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput variant molecular-phenotyping pipeline; source of
      a PRPS1 self-interaction call.
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome-perturbation study.
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Quantitative interactome study; generic protein-binding call.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Interactome-architecture study; generic protein-binding call.
- id: PMID:29892012
  title: An interactome perturbation framework prioritizes damaging missense mutations
    for developmental disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Interactome-perturbation framework; generic protein-binding call.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Population-scale variant interactome; generic and self-interaction
      calls.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Reference binary interactome; source of generic and self-interaction
      calls.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large high-throughput neurodegeneration interactome screen; dozens
      of unvalidated PRPS1 partners, hence over-annotation of generic protein binding.
- 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: Proteome-scale cell-specific interactome; generic protein-binding
      call.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; generic protein-binding call.
- id: PMID:7593598
  title: The genetic and functional basis of purine nucleotide feedback-resistant
    phosphoribosylpyrophosphate synthetase superactivity.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Kinetic characterization of recombinant human PRS1 wild-type and
      superactivity variants; supports catalytic activity and allosteric regulation.
- id: PMID:8253776
  title: Human X-linked phosphoribosylpyrophosphate synthetase superactivity is associated
    with distinct point mutations in the PRPS1 gene.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Identifies PRPS1 superactivity point mutations; X-linked purine metabolic
      disorder with neurodevelopmental impairment.
- id: Reactome:R-HSA-111215
  title: PRPS1 dimer pyrophosphorylates R5P using dATP
  findings: []
- id: Reactome:R-HSA-73580
  title: PRPS dimers pyrophosphorylate R5P using ATP
  findings: []