id: Q14117
gene_symbol: DPYS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DPYS encodes dihydropyrimidinase (DHP/DHPase; EC 3.5.2.2), the second enzyme of the
  reductive pyrimidine catabolic pathway. Acting downstream of dihydropyrimidine
  dehydrogenase (DPYD) and upstream of beta-ureidopropionase (UPB1), it catalyzes the
  reversible, Zn2+-dependent hydrolytic ring opening of 5,6-dihydrouracil to
  N-carbamoyl-beta-alanine (3-ureidopropanoate) and of 5,6-dihydrothymine to
  N-carbamoyl-beta-aminoisobutyrate. It is a binuclear zinc metalloenzyme of the
  metallo-dependent (cyclic amidohydrolase / amidohydrolase) hydrolase superfamily,
  hydantoinase/dihydropyrimidinase family, and forms a homotetramer with two Zn2+ ions
  bridged by a carbamylated lysine per subunit. The enzyme is cytosolic and most highly
  expressed in liver and kidney. Loss-of-function variants cause dihydropyrimidinase
  deficiency (dihydropyrimidinuria), an autosomal recessive disorder with a variable
  neurological phenotype, and impaired dihydropyrimidinase activity increases the risk of
  fluoropyrimidine (5-fluorouracil) toxicity.
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetically inferred cytosolic localization. DHP is a soluble cytosolic
      metabolic enzyme, consistent with the ISS and Reactome (TAS) cytosol annotations.
    action: ACCEPT
    reason: >-
      Correct and precise cellular-component annotation for a soluble cytosolic
      pyrimidine-catabolic enzyme; represents the site where DHP acts.
- term:
    id: GO:0006208
    label: pyrimidine nucleobase catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred participation in pyrimidine nucleobase catabolism. DHP
      catalyzes the second step of reductive pyrimidine degradation, matching this process.
    action: ACCEPT
    reason: >-
      Core biological-process annotation, directly consistent with the enzyme's role in
      dihydropyrimidine ring opening within pyrimidine catabolism.
    supported_by:
      - reference_id: file:human/DPYS/DPYS-uniprot.txt
        supporting_text: Catalyzes the second step of the reductive pyrimidine
- term:
    id: GO:0004157
    label: dihydropyrimidinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred dihydropyrimidinase activity across orthologs. This is the
      defining, experimentally supported molecular function of the gene product.
    action: ACCEPT
    reason: >-
      Core molecular function; agrees with direct experimental (IDA/IMP) evidence in human
      and the conserved family activity.
    supported_by:
      - reference_id: file:human/DPYS/DPYS-uniprot.txt
        supporting_text: Can catalyze the ring opening of 5,6-dihydrouracil
- term:
    id: GO:0004157
    label: dihydropyrimidinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation from the RHEA:16121 / EC 3.5.2.2 mapping. This correctly maps
      to dihydropyrimidinase activity and matches the curated catalytic activity.
    action: ACCEPT
    reason: >-
      Accurate EC/RHEA-based inference of the core molecular function.
    supported_by:
      - reference_id: file:human/DPYS/DPYS-uniprot.txt
        supporting_text: EC=3.5.2.2
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      InterPro-based electronic localization to the cytoplasm. True but less precise than
      the cytosol annotations from IBA/ISS/TAS evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct but a broader parent of cytosol; the more specific GO:0005829 (cytosol)
      annotations better capture the localization.
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro (Amidohydro_1) electronic annotation to the broad hydrolase parent. Correct
      but far less informative than the specific dihydropyrimidinase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-level parent of GO:0004157; uninformative given the well-established specific
      activity.
- term:
    id: GO:0016810
    label: hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based electronic annotation to an intermediate hydrolase parent. DHP does
      hydrolyze a C-N bond, but this is a parent of the specific activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct branch but a general parent of GO:0004157 dihydropyrimidinase activity; the
      specific term is preferred.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare protein-binding IPI from the HuRI all-by-all binary (Y2H) interactome
      (interaction with APPBP2/Q92624). Uninformative regarding molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput binary-interactome datapoint that does not convey an informative
      molecular function; kept per curation policy (not removed) but flagged as
      over-annotation.
    supported_by:
      - reference_id: PMID:32296183
        supporting_text: a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      Bare protein-binding IPI from a neurodegenerative-disease-focused yeast two-hybrid
      interactome (multiple IntAct partners). Uninformative regarding molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput Y2H interactome datapoint; not an informative molecular function.
      Retained per curation policy but flagged as over-annotation.
    supported_by:
      - reference_id: PMID:32814053
        supporting_text: systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins
- term:
    id: GO:0051219
    label: phosphoprotein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Electronic annotation transferred from a mouse ortholog via Ensembl Compara. There
      is no functional evidence that DHP binds phosphoproteins; nothing in the enzyme's
      structure or biochemistry supports a phosphoprotein-binding role.
    action: REMOVE
    reason: >-
      Over-propagated electronic inference with no supporting biology for human DPYS; the
      protein is a cytosolic metabolic hydrolase, not a phosphoprotein-binding adaptor.
- term:
    id: GO:0004157
    label: dihydropyrimidinase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity transfer of dihydropyrimidinase activity from an ortholog
      (UniProtKB:Q55DL0). Consistent with the direct experimental and IBA evidence.
    action: ACCEPT
    reason: >-
      Redundant with the experimentally supported core molecular function; correctly
      assigned.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Self-association inferred by similarity (from rat ortholog Q63150). Consistent with
      the homotetrameric quaternary structure of the human enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the oligomeric (homotetramer) assembly rather than the catalytic core
      function; biologically plausible but ancillary.
    supported_by:
      - reference_id: file:human/DPYS/DPYS-uniprot.txt
        supporting_text: Homotetramer.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: >-
      Detected by high-throughput mass spectrometry in the human urinary exosome proteome.
      DHP is highly expressed in kidney epithelium, so its presence in urinary exosomes is
      a real detection but does not represent the site of its catalytic function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Proteomic detection in secreted exosomes; peripheral to the enzyme's cytosolic
      metabolic role rather than a functional localization.
    supported_by:
      - reference_id: PMID:19056867
        supporting_text: LC-MS/MS to profile the proteome of human urinary exosomes
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73589
  qualifier: located_in
  review:
    summary: >-
      Reactome-asserted cytosolic localization for the conversion of 5,6-dihydrouracil to
      3-ureidopropionate. Matches the enzyme's soluble cytosolic nature.
    action: ACCEPT
    reason: >-
      Correct, specific localization consistent with IBA/ISS cytosol annotations and the
      known reaction context.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73618
  qualifier: located_in
  review:
    summary: >-
      Reactome-asserted cytosolic localization for the conversion of 5,6-dihydrothymine to
      3-ureidoisobutyrate. Matches the enzyme's soluble cytosolic nature.
    action: ACCEPT
    reason: >-
      Correct, specific localization consistent with the other cytosol annotations.
- term:
    id: GO:0004157
    label: dihydropyrimidinase activity
  evidence_type: IDA
  original_reference_id: PMID:10410956
  qualifier: enables
  review:
    summary: >-
      Direct assay of dihydropyrimidinase activity in human liver homogenates using a
      radiochemical method that separates dihydrouracil from its ring-opened product
      N-carbamyl-beta-alanine.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for the enzyme's core catalytic activity in human
      tissue.
    supported_by:
      - reference_id: PMID:10410956
        supporting_text: separation of radiolabeled dihydrouracil from N-carbamyl-beta-alanine by HPLC
- term:
    id: GO:0004157
    label: dihydropyrimidinase activity
  evidence_type: IMP
  original_reference_id: PMID:18075467
  qualifier: enables
  review:
    summary: >-
      Site-directed mutagenesis and expression of DPYS sequence variants showed that
      inactivating mutations reduce DHP enzyme activity, supporting that DPYS enables this
      activity.
    action: ACCEPT
    reason: >-
      Mutation/expression evidence directly linking the gene product to dihydropyrimidinase
      activity.
    supported_by:
      - reference_id: PMID:18075467
        supporting_text: inactivating mutations in
- term:
    id: GO:0004157
    label: dihydropyrimidinase activity
  evidence_type: IDA
  original_reference_id: PMID:9718352
  qualifier: enables
  review:
    summary: >-
      Expression of the human gene and disease-causing variants in a eukaryotic system
      demonstrated dihydropyrimidinase activity, with all deficiency mutations reducing it.
    action: ACCEPT
    reason: >-
      Direct experimental support for the core catalytic function of human DPYS.
    supported_by:
      - reference_id: PMID:9718352
        supporting_text: we showed that all mutations reduced
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity transfer of cytosolic localization (from rat ortholog Q63150).
      Consistent with all other cytosol/cytoplasm evidence.
    action: ACCEPT
    reason: >-
      Correct, specific localization consistent with the IBA/TAS cytosol annotations.
- term:
    id: GO:0006208
    label: pyrimidine nucleobase catabolic process
  evidence_type: IDA
  original_reference_id: PMID:9718352
  qualifier: involved_in
  review:
    summary: >-
      DHP-deficiency work characterizing the human gene and its variants supports
      participation in pyrimidine nucleobase catabolism (the deficiency causes
      dihydropyrimidinuria, an accumulation of pathway intermediates).
    action: ACCEPT
    reason: >-
      Core biological-process annotation supported by disease biochemistry and the
      enzyme's position in the reductive pyrimidine degradation pathway.
    supported_by:
      - reference_id: PMID:9718352
        supporting_text: Dihydropyrimidinase (DHP) deficiency (MIM 222748) is characterized by
- term:
    id: GO:0006210
    label: thymine catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer of participation in thymine catabolism. DHP acts on
      5,6-dihydrothymine (from thymine reduction), so the thymine-degradation branch is a
      genuine physiological role.
    action: ACCEPT
    reason: >-
      Consistent with the enzyme's demonstrated ring opening of 5,6-dihydrothymine within
      pyrimidine (thymine) catabolism.
    supported_by:
      - reference_id: file:human/DPYS/DPYS-uniprot.txt
        supporting_text: Can catalyze the ring opening of 5,6-dihydrouracil
- term:
    id: GO:0006212
    label: uracil catabolic process
  evidence_type: IDA
  original_reference_id: PMID:10410956
  qualifier: involved_in
  review:
    summary: >-
      Direct assay of DHP activity on dihydrouracil (the reduced form of uracil) in human
      liver supports involvement in uracil catabolism.
    action: ACCEPT
    reason: >-
      Core biological-process annotation; DHP performs the second committed step of uracil
      degradation.
    supported_by:
      - reference_id: PMID:10410956
        supporting_text: separation of radiolabeled dihydrouracil from N-carbamyl-beta-alanine by HPLC
- term:
    id: GO:0006212
    label: uracil catabolic process
  evidence_type: IMP
  original_reference_id: PMID:18075467
  qualifier: involved_in
  review:
    summary: >-
      Genetic/expression analysis linking inactivating DPYS mutations to altered uracil
      catabolism (measured by uracil/dihydrouracil breath tests) supports involvement in
      uracil catabolism.
    action: ACCEPT
    reason: >-
      Mutation-based evidence tying DPYS function to in-vivo uracil catabolism.
    supported_by:
      - reference_id: PMID:18075467
        supporting_text: inactivating mutations in
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: NAS
  original_reference_id: PMID:9718352
  qualifier: enables
  review:
    summary: >-
      DHP is a binuclear zinc metalloenzyme; the human crystal structure (PDB 2VR2)
      confirms two Zn2+ ions per subunit bridged by a carbamylated lysine, corroborating
      zinc ion binding as an integral part of the catalytic mechanism.
    action: ACCEPT
    reason: >-
      Zinc binding is a defining, structurally confirmed feature of DHP catalysis; correct
      molecular-function annotation.
    supported_by:
      - reference_id: file:human/DPYS/DPYS-uniprot.txt
        supporting_text: Binds 2 Zn(2+) ions per subunit.
core_functions:
- description: >-
    Zn2+-dependent hydrolytic ring opening of 5,6-dihydrouracil to N-carbamoyl-beta-alanine
    (and 5,6-dihydrothymine to N-carbamoyl-beta-aminoisobutyrate), the second step of
    reductive pyrimidine catabolism.
  molecular_function:
    id: GO:0004157
    label: dihydropyrimidinase activity
  directly_involved_in:
    - id: GO:0006212
      label: uracil catabolic process
  locations:
    - id: GO:0005829
      label: cytosol
  supported_by:
    - reference_id: file:human/DPYS/DPYS-uniprot.txt
      supporting_text: Catalyzes the second step of the reductive pyrimidine
    - reference_id: PMID:10410956
      supporting_text: separation of radiolabeled dihydrouracil from N-carbamyl-beta-alanine by HPLC
- description: >-
    Dihydropyrimidinase activity within the broader pyrimidine nucleobase catabolic
    pathway, using a binuclear zinc center for catalysis.
  molecular_function:
    id: GO:0004157
    label: dihydropyrimidinase activity
  directly_involved_in:
    - id: GO:0006208
      label: pyrimidine nucleobase catabolic process
  locations:
    - id: GO:0005829
      label: cytosol
  supported_by:
    - reference_id: file:human/DPYS/DPYS-uniprot.txt
      supporting_text: Binds 2 Zn(2+) ions per subunit.
    - reference_id: PMID:9718352
      supporting_text: we showed that all mutations reduced
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:10410956
  title: Radiochemical assay for determination of dihydropyrimidinase activity using
    reversed-phase high-performance liquid chromatography.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Radiochemical HPLC assay of dihydropyrimidinase activity in human
      liver, separating dihydrouracil from N-carbamyl-beta-alanine; directly supports the
      core catalytic activity and uracil catabolic role.
- id: PMID:18075467
  title: Genetic regulation of dihydropyrimidinase and its possible implication in
    altered uracil catabolism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Site-directed mutagenesis/expression of DPYS variants shows
      inactivating mutations reduce DHP activity and impair uracil catabolism; supports MF
      and BP annotations.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Mass-spec detection of DHP among urinary exosome proteins; supports
      the extracellular-exosome localization only as a peripheral, non-core observation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified HuRI binary interactome. Source of a bare protein-binding IPI; a
      high-throughput datapoint that is not functionally informative for DHP.
- 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: >-
      PubMed-verified neurodegenerative-disease Y2H interactome. Source of a bare
      protein-binding IPI; high-throughput and not functionally informative for DHP.
- id: PMID:9718352
  title: 'Dihydropyrimidinase deficiency: structural organization, chromosomal localization,
    and mutation analysis of the human dihydropyrimidinase gene.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Characterizes the human DPYS gene and the first DHP-deficiency
      mutations; eukaryotic expression shows all mutations reduce enzyme activity.
      Supports MF, BP, zinc-binding (NAS), and disease context.
- id: Reactome:R-HSA-73589
  title: conversion of 5,6-dihydrouracil to 3-ureidopropionate
  findings: []
- id: Reactome:R-HSA-73618
  title: conversion of 5,6-Dihydrothymine to 3-Ureidoisobutyrate
  findings: []
- id: file:human/DPYS/DPYS-uniprot.txt
  title: UniProtKB Q14117 DPYS (dihydropyrimidinase) record
  findings: []