id: Q12882
gene_symbol: DPYD
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DPYD encodes dihydropyrimidine dehydrogenase [NADP(+)] (DPD; EC 1.3.1.2), the initial
  and rate-limiting enzyme of the reductive catabolism of the pyrimidine bases uracil and
  thymine. It reduces uracil to 5,6-dihydrouracil and thymine to 5,6-dihydrothymine using
  NADPH as the electron donor. DPD is a large cytosolic homodimeric flavoprotein; each
  subunit binds two FAD, two FMN and four [4Fe-4S] clusters that shuttle electrons from
  NADPH to the pyrimidine substrate. It is the principal enzyme that catabolises the
  fluoropyrimidine chemotherapeutic 5-fluorouracil (5-FU), and the dihydrouracil it
  produces is further processed (by dihydropyrimidinase and beta-ureidopropionase) toward
  beta-alanine. Deficiency of DPD (DPYD deficiency) causes severe, potentially
  life-threatening toxicity from 5-FU/capecitabine, and more complete deficiency produces
  thymine-uraciluria with a variable neurological phenotype (seizures, motor and
  intellectual disability). DPYD is a major pharmacogenetic gene, and DPYD genotyping is
  used clinically to guide fluoropyrimidine dosing.
alternative_products:
- name: '1'
  id: Q12882-1
- name: '2'
  id: Q12882-2
  sequence_note: VSP_044929, VSP_044930
existing_annotations:
- term:
    id: GO:0006210
    label: thymine catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation that DPYD is involved in thymine catabolism. This is a
      core biological process for DPD: it reduces thymine to 5,6-dihydrothymine as the
      first step of thymine degradation. Concordant with the IDA annotations from
      PMID:1512248 and PMID:10410956 and with the UniProt catalytic activity.
    action: ACCEPT
    reason: >-
      Correct, well-supported core process. DPD catalyzes the committed first step of
      thymine catabolism.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "Reaction=5,6-dihydrothymine + NADP(+) = thymine + NADPH + H(+);"
- term:
    id: GO:0006212
    label: uracil catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation that DPYD is involved in uracil catabolism. Core
      process: DPD reduces uracil to 5,6-dihydrouracil as the committed first step of
      uracil degradation, consistent with the IDA annotations and UniProt.
    action: ACCEPT
    reason: >-
      Correct, well-supported core process representing the first committed step of uracil
      catabolism.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "Reaction=5,6-dihydrouracil + NADP(+) = uracil + NADPH + H(+);"
- term:
    id: GO:0017113
    label: dihydropyrimidine dehydrogenase (NADP+) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation of the diagnostic molecular function of DPD. This is
      the central catalytic activity of the gene product (EC 1.3.1.2) and is independently
      supported by multiple experimental (IDA/IMP) annotations.
    action: ACCEPT
    reason: >-
      This is the core molecular function of DPYD and is strongly supported by direct
      experimental characterization of the purified human enzyme.
    supported_by:
    - reference_id: PMID:1512248
      supporting_text: >-
        Kinetic studies with uracil, thymine, 5-fluorouracil, and NADPH were carried out.
- term:
    id: GO:0050661
    label: NADP binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      DPD uses NADPH as the electron donor for pyrimidine reduction and has a defined
      NADP(+)-binding site; NADP binding is an integral part of its catalytic mechanism.
    action: ACCEPT
    reason: >-
      Supported by the enzyme's use of NADPH (kinetic KM values for NADPH) and the
      UniProt NADP(+)-binding site features.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "F:NADP binding; ISS:UniProtKB."
- term:
    id: GO:0002058
    label: uracil binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      DPD binds its substrate uracil; a defined uracil-binding site is present in the
      protein. This substrate-binding activity is part of the enzyme's function.
    action: ACCEPT
    reason: >-
      Uracil is a physiological substrate of DPD (KM 4.9 uM) and a discrete uracil-binding
      region has been identified in the enzyme.
    supported_by:
    - reference_id: PMID:8083224
      supporting_text: >-
        A sequence encompassing a peptide corresponding to the uracil binding site was
        found between the NADPH/FAD-containing NH2-terminal portion of the protein and the
        iron-sulfur binding sites near to the COOH terminus.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      DPD is a cytosolic enzyme. The phylogenetic localization is concordant with the IDA
      (PMID:1512248), UniProt subcellular location, and Reactome, which all describe a
      cytosolic activity.
    action: ACCEPT
    reason: DPD is a soluble cytosolic protein; this is the well-established location.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      InterPro-based electronic annotation to cytoplasm. Correct but less specific than
      the cytosol annotations; retained as an accurate broader localization.
    action: ACCEPT
    reason: >-
      Consistent with the more specific cytosol annotations; a correct broader parent
      localization.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt Subcellular Location keyword mapping to cytosol. Concordant with all other
      localization evidence.
    action: ACCEPT
    reason: Correct cytosolic localization, agreeing with IDA and IBA evidence.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm."
- term:
    id: GO:0006208
    label: pyrimidine nucleobase catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to pyrimidine nucleobase catabolic process, the general
      parent process encompassing both uracil and thymine catabolism. Accurate for DPD as
      the initiating enzyme of pyrimidine base degradation.
    action: ACCEPT
    reason: >-
      Correct parent process. DPD catalyzes the first committed step of pyrimidine
      (uracil and thymine) base catabolism.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "Catalyzes the reduction of uracil and thymine (PubMed:1512248)."
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based electronic annotation to the very general term oxidoreductase
      activity. DPD is an oxidoreductase, but this term is far less informative than the
      specific GO:0017113 already annotated.
    action: MODIFY
    reason: >-
      Too general; the specific activity dihydropyrimidine dehydrogenase (NADP+) activity
      (GO:0017113) is established experimentally and should be preferred.
    proposed_replacement_terms:
    - id: GO:0017113
      label: dihydropyrimidine dehydrogenase (NADP+) activity
- term:
    id: GO:0016627
    label: oxidoreductase activity, acting on the CH-CH group of donors
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based electronic annotation to a more specific oxidoreductase parent (DPD
      reduces the C5=C6 double bond of the pyrimidine ring). Accurate as an ancestor of
      GO:0017113 but still more general than the specific, experimentally supported term.
    action: MODIFY
    reason: >-
      Correct branch but intermediate specificity; the leaf term GO:0017113 is
      experimentally established and should be used.
    proposed_replacement_terms:
    - id: GO:0017113
      label: dihydropyrimidine dehydrogenase (NADP+) activity
- term:
    id: GO:0017113
    label: dihydropyrimidine dehydrogenase (NADP+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (RHEA/EC-based) electronic annotation of the diagnostic DPD activity.
      Matches the RHEA reactions and EC 1.3.1.2 in the UniProt record and duplicates the
      experimentally supported molecular function.
    action: ACCEPT
    reason: >-
      Correct EC/RHEA-based mapping to the enzyme's core molecular function; concordant
      with experimental evidence.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "Reaction=5,6-dihydrouracil + NADP(+) = uracil + NADPH + H(+);"
- term:
    id: GO:0051536
    label: iron-sulfur cluster binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based annotation for iron-sulfur cluster binding. Well supported: each DPD
      subunit binds four [4Fe-4S] clusters that mediate electron transfer between the FAD
      and FMN sites.
    action: ACCEPT
    reason: >-
      DPD is an iron-sulfur flavoprotein; [4Fe-4S] binding is documented biochemically and
      structurally.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "Note=Binds 4 [4Fe-4S] clusters. Contains approximately 16 iron atoms"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Two IPI protein-binding annotations from a high-throughput yeast two-hybrid
      interactome screen (partners LXN, Q9BS40; GOPC, Q9HD26). The generic term "protein
      binding" is uninformative about DPD's function, and these binary interactome hits
      have no established biological role for DPD.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare "protein binding" from a proteome-scale Y2H screen provides no functional
      insight; DPD acts as a soluble homodimeric enzyme and no functional consequence of
      the LXN or GOPC interactions is established.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: we more than doubled the number of high-quality binary PPIs
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "Q12882; Q9BS40: LXN; NbExp=3; IntAct=EBI-2839838, EBI-1044504;"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:1512248
  qualifier: located_in
  review:
    summary: >-
      Direct assay: DPD was purified as a soluble enzyme from human liver, consistent with
      a cytosolic localization.
    action: ACCEPT
    reason: DPD is a cytosolic enzyme; supported by purification of the soluble protein.
    supported_by:
    - reference_id: PMID:1512248
      supporting_text: >-
        this enzyme was purified 7800-fold to homogeneity from human liver
- term:
    id: GO:0006210
    label: thymine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:1512248
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental evidence: the purified human enzyme reduces thymine, the first
      step of thymine catabolism.
    action: ACCEPT
    reason: Core process; directly demonstrated with the purified human enzyme.
    supported_by:
    - reference_id: PMID:1512248
      supporting_text: >-
        Kinetic studies with uracil, thymine, 5-fluorouracil, and NADPH were carried out.
- term:
    id: GO:0019483
    label: beta-alanine biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-based annotation reflecting that pyrimidine (uracil) catabolism ultimately
      yields beta-alanine. DPD catalyzes only the first step; ring opening and
      beta-alanine release are performed by the downstream enzymes DPYS and UPB1. This is
      a pathway-membership annotation rather than DPD's core molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate at the pathway level (uracil catabolism feeds beta-alanine biosynthesis)
      but downstream of DPD's direct reaction; retained as a non-core process.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "Amino-acid biosynthesis; beta-alanine biosynthesis."
- term:
    id: GO:0042178
    label: xenobiotic catabolic process
  evidence_type: IDA
  original_reference_id: PMID:8083224
  qualifier: involved_in
  review:
    summary: >-
      Captures DPD's role in catabolising the fluoropyrimidine drug 5-fluorouracil, a
      xenobiotic. This is well established (>80% of administered 5-FU is inactivated by
      DPD) but represents a drug-metabolism/pharmacological context rather than DPD's
      endogenous core function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real and clinically important (5-FU degradation), but a xenobiotic/drug-metabolism
      role that is secondary to the enzyme's endogenous pyrimidine-catabolic function.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "involved the degradation of the chemotherapeutic drug 5-fluorouracil"
- term:
    id: GO:0046045
    label: TMP catabolic process
  evidence_type: IDA
  original_reference_id: PMID:8083224
  qualifier: involved_in
  review:
    summary: >-
      DPD acts on the free pyrimidine base thymine, not on the nucleotide dTMP/TMP. TMP
      catabolic process is upstream of and more specific than DPD's actual reaction and is
      an over-specific/mis-leveled annotation for this enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      DPD's substrate is the thymine base; TMP catabolism requires prior
      dephosphorylation/nucleosidase steps not catalyzed by DPD. Better captured by
      thymine catabolic process (GO:0006210).
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "Catalyzes the reduction of uracil and thymine (PubMed:1512248)."
- term:
    id: GO:0046050
    label: UMP catabolic process
  evidence_type: IDA
  original_reference_id: PMID:8083224
  qualifier: involved_in
  review:
    summary: >-
      DPD acts on the free base uracil, not on the nucleotide UMP. UMP catabolic process
      is upstream of DPD's reaction and is an over-specific/mis-leveled annotation for this
      enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      DPD's substrate is the uracil base; UMP catabolism requires prior
      dephosphorylation/nucleosidase steps not catalyzed by DPD. Better captured by uracil
      catabolic process (GO:0006212).
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "Catalyzes the reduction of uracil and thymine (PubMed:1512248)."
- term:
    id: GO:0017113
    label: dihydropyrimidine dehydrogenase (NADP+) activity
  evidence_type: IDA
  original_reference_id: PMID:8083224
  qualifier: enables
  review:
    summary: >-
      Direct evidence: the cloned DPD enzyme reduces uracil, thymine and 5-fluorouracil,
      demonstrating dihydropyrimidine dehydrogenase (NADP+) activity.
    action: ACCEPT
    reason: Core molecular function, directly demonstrated for the recombinant enzyme.
    supported_by:
    - reference_id: PMID:8083224
      supporting_text: >-
        catalyzed the reduction of uracil, thymine, and 5-fluorouracil with kinetics
        approximating those published for the enzyme purified from mammalian liver
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73585
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localization of the uracil-reducing reaction to the cytosol. Concordant
      with all other localization evidence.
    action: ACCEPT
    reason: Correct cytosolic localization; Reactome describes cytosolic DPD.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73616
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localization of the thymine-reducing reaction to the cytosol.
      Concordant with all other localization evidence.
    action: ACCEPT
    reason: Correct cytosolic localization; Reactome describes cytosolic DPD.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm."
- term:
    id: GO:0006212
    label: uracil catabolic process
  evidence_type: IDA
  original_reference_id: PMID:18075467
  qualifier: involved_in
  review:
    summary: >-
      Uracil catabolic process is a correct core process for DPD. The cited reference
      (Thomas et al. 2007) primarily concerns dihydropyrimidinase (DHP, gene DPYS), the
      SECOND enzyme in the pathway, and uses a uracil breath test that reports overall
      uracil catabolism (in which DPD catalyzes the first step). The process term is
      appropriate for DPD even though this particular reference is centered on the
      downstream enzyme.
    action: ACCEPT
    reason: >-
      Correct process for DPD; independently supported by PMID:1512248 and the IBA
      annotation. Not removed despite the reference being centered on DPYS, since the
      process assignment for DPD is accurate (see reference_review for the citation caveat).
    supported_by:
    - reference_id: PMID:18075467
      supporting_text: >-
        alterations of uracil catabolism are not limited to DPD deficiency
- term:
    id: GO:0017113
    label: dihydropyrimidine dehydrogenase (NADP+) activity
  evidence_type: IDA
  original_reference_id: PMID:18075467
  qualifier: enables
  review:
    summary: >-
      This IDA links DPD activity (GO:0017113) to PMID:18075467, but the cached abstract of
      that paper is about dihydropyrimidinase (DHP, gene DPYS) and a uracil breath test,
      not a direct assay of DPD (NADP+) dehydrogenase activity. The molecular function
      itself is correct and definitively established for DPD by PMID:1512248 and
      PMID:8083224; the concern is only that this particular reference is a poor citation
      for the DPD activity (recorded in reference_review as MISCITED).
    action: ACCEPT
    reason: >-
      The DPD molecular function is correct and amply supported; the annotation is retained
      (experimental; full text not read) with the reference-quality caveat captured in
      reference_review rather than removing the annotation.
    supported_by:
    - reference_id: PMID:18075467
      supporting_text: >-
        This study investigates the role of DPYS sequence variations in individuals with
        unexplained molecular basis of altered uracil catabolism.
- term:
    id: GO:0006210
    label: thymine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:10410956
  qualifier: involved_in
  review:
    summary: >-
      Thymine catabolic process for DPD. The cited method paper describes a radiochemical
      assay for the pathway (dihydropyrimidinase step), consistent with DPD's role in
      pyrimidine base degradation. The process assignment is correct for DPD.
    action: ACCEPT
    reason: >-
      Correct core process; supported redundantly by PMID:1512248 and the IBA annotation.
    supported_by:
    - reference_id: PMID:10410956
      supporting_text: >-
        A radiochemical assay was developed to measure the activity of
        dihydropyrimidinase (DHP) in human liver homogenates.
- term:
    id: GO:0017113
    label: dihydropyrimidine dehydrogenase (NADP+) activity
  evidence_type: IDA
  original_reference_id: PMID:10410956
  qualifier: enables
  review:
    summary: >-
      This IDA links DPD activity to a methods paper (Van Kuilenburg et al. 1999) whose
      cached abstract describes a radiochemical assay for dihydropyrimidinase (DHP), the
      downstream enzyme, in liver homogenates. The DPD molecular function is correct but
      this reference does not itself demonstrate DPD (NADP+) dehydrogenase activity; the
      citation caveat is recorded in reference_review as MISCITED.
    action: ACCEPT
    reason: >-
      Molecular function is correct for DPD and well supported by PMID:1512248 and
      PMID:8083224; annotation retained with the reference-quality caveat noted rather than
      removed (experimental; full text not read).
    supported_by:
    - reference_id: PMID:10410956
      supporting_text: >-
        A radiochemical assay was developed to measure the activity of
        dihydropyrimidinase (DHP) in human liver homogenates.
- term:
    id: GO:0006145
    label: purine nucleobase catabolic process
  evidence_type: IMP
  original_reference_id: PMID:11988088
  qualifier: involved_in
  review:
    summary: >-
      Annotation to PURINE nucleobase catabolic process. DPD is a PYRIMIDINE catabolic
      enzyme, and the cited paper (van Kuilenburg et al. 2002) concerns DPD deficiency and
      thymine-uraciluria (pyrimidine metabolism), not purine catabolism. This is almost
      certainly a term-selection/data-entry error (purine vs pyrimidine); the intended term
      is the pyrimidine one (GO:0006208), which is separately annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      DPD has no role in purine catabolism; the reference is entirely about pyrimidine
      (uracil/thymine) metabolism. Flagged as an over-annotation/likely mis-selection
      rather than removed, per the policy of not deleting experimental annotations whose
      full text has not been read; the correct process is GO:0006208.
    supported_by:
    - reference_id: PMID:11988088
      supporting_text: >-
        Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease
        characterized by thymine-uraciluria in homozygous deficient patients.
- term:
    id: GO:0006208
    label: pyrimidine nucleobase catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity annotation to pyrimidine nucleobase catabolic process, the
      correct parent process for DPD. Concordant with experimental and phylogenetic
      evidence.
    action: ACCEPT
    reason: >-
      Correct parent process; DPD initiates pyrimidine base catabolism.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "Catalyzes the reduction of uracil and thymine (PubMed:1512248)."
- term:
    id: GO:0006208
    label: pyrimidine nucleobase catabolic process
  evidence_type: IMP
  original_reference_id: PMID:11988088
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IMP) evidence linking DPD variants to impaired pyrimidine base
      catabolism (DPD deficiency with thymine-uraciluria). This is the correct core process
      for the enzyme.
    action: ACCEPT
    reason: >-
      Loss-of-function DPD variants cause thymine-uraciluria, directly implicating DPD in
      pyrimidine nucleobase catabolism.
    supported_by:
    - reference_id: PMID:11988088
      supporting_text: >-
        Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease
        characterized by thymine-uraciluria in homozygous deficient patients.
- term:
    id: GO:0017113
    label: dihydropyrimidine dehydrogenase (NADP+) activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity annotation of the diagnostic DPD molecular function. Redundant
      with the experimentally supported activity.
    action: ACCEPT
    reason: Correct core molecular function; supported experimentally and phylogenetically.
    supported_by:
    - reference_id: PMID:1512248
      supporting_text: >-
        Kinetic studies with uracil, thymine, 5-fluorouracil, and NADPH were carried out.
- term:
    id: GO:0017113
    label: dihydropyrimidine dehydrogenase (NADP+) activity
  evidence_type: IMP
  original_reference_id: PMID:11988088
  qualifier: enables
  review:
    summary: >-
      IMP evidence: disease-causing DPD missense variants reduce or abolish DPD activity
      (interpreted via the 3D structure as disrupting cofactor binding/electron transport),
      supporting the assignment of dihydropyrimidine dehydrogenase (NADP+) activity to
      DPYD.
    action: ACCEPT
    reason: >-
      Loss-of-function variants map onto cofactor/electron-transfer sites and reduce DPD
      activity, confirming the molecular function.
    supported_by:
    - reference_id: PMID:11988088
      supporting_text: >-
        interfered directly or indirectly with cofactor binding or electron transport
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      DPD is a homodimer; homodimerization activity is supported by sequence similarity and
      by direct biochemical evidence that the human enzyme is composed of two subunits.
    action: ACCEPT
    reason: >-
      The functional enzyme is an obligate homodimer, documented biochemically and in
      UniProt (SUBUNIT: Homodimer).
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer."
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:1512248
  qualifier: enables
  review:
    summary: >-
      Direct evidence: the purified ~210 kDa human enzyme is composed of two subunits,
      demonstrating homodimerization.
    action: ACCEPT
    reason: The purified native enzyme is a two-subunit homodimer.
    supported_by:
    - reference_id: PMID:1512248
      supporting_text: >-
        Purified human enzyme has  a molecular mass of 210 +/- 5 kDa and appears to be
        composed of two subunits.
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      DPD is a flavoprotein binding two FAD per subunit; FAD accepts electrons from NADPH
      at the N-terminal FAD/NADPH domain. Supported by sequence similarity and biochemical
      flavin content.
    action: ACCEPT
    reason: >-
      FAD is an essential cofactor of DPD; the purified enzyme contains FAD and a defined
      FAD-binding site.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "Binds 2 FAD"
- term:
    id: GO:0050661
    label: NADP binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      NADP(+)/NADPH binding by DPD, supported by sequence similarity and the defined
      NADP(+)-binding site; NADPH is the electron donor for pyrimidine reduction.
    action: ACCEPT
    reason: >-
      NADPH is the physiological electron donor and DPD has a defined NADP(+)-binding site.
    supported_by:
    - reference_id: file:human/DPYD/DPYD-uniprot.txt
      supporting_text: "F:NADP binding; ISS:UniProtKB."
- term:
    id: GO:0006212
    label: uracil catabolic process
  evidence_type: IDA
  original_reference_id: PMID:1512248
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental evidence: the purified human enzyme reduces uracil, the first
      step of uracil catabolism.
    action: ACCEPT
    reason: Core process; directly demonstrated with the purified human enzyme.
    supported_by:
    - reference_id: PMID:1512248
      supporting_text: >-
        Kinetic studies with uracil, thymine, 5-fluorouracil, and NADPH were carried out.
- term:
    id: GO:0017113
    label: dihydropyrimidine dehydrogenase (NADP+) activity
  evidence_type: IDA
  original_reference_id: PMID:1512248
  qualifier: enables
  review:
    summary: >-
      Direct experimental characterization of the purified human enzyme establishing
      dihydropyrimidine dehydrogenase (NADP+) activity, with kinetics on uracil, thymine,
      5-FU and NADPH. This is the definitive experimental support for the core molecular
      function.
    action: ACCEPT
    reason: >-
      Gold-standard IDA on the purified human enzyme; the defining molecular function of
      DPYD.
    supported_by:
    - reference_id: PMID:1512248
      supporting_text: >-
        Kinetic studies with uracil, thymine, 5-fluorouracil, and NADPH were carried out.
core_functions:
- description: >-
    Dihydropyrimidine dehydrogenase (NADP+) activity: DPD is a cytosolic homodimeric
    flavoprotein that catalyzes the NADPH-dependent reduction of the pyrimidine bases
    uracil and thymine to 5,6-dihydrouracil and 5,6-dihydrothymine (EC 1.3.1.2), the
    initial and rate-limiting step of reductive pyrimidine base catabolism. Catalysis
    relies on bound FAD, FMN and four [4Fe-4S] clusters per subunit that transfer electrons
    from NADPH to the substrate, and on binding of NADP and the uracil/thymine substrate.
  molecular_function:
    id: GO:0017113
    label: dihydropyrimidine dehydrogenase (NADP+) activity
  directly_involved_in:
  - id: GO:0006212
    label: uracil catabolic process
  - id: GO:0006210
    label: thymine catabolic process
  - id: GO:0006208
    label: pyrimidine nucleobase catabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:1512248
    supporting_text: >-
      Kinetic studies with uracil, thymine, 5-fluorouracil, and NADPH were carried out.
  - reference_id: PMID:8083224
    supporting_text: >-
      catalyzed the reduction of uracil, thymine, and 5-fluorouracil with kinetics
      approximating those published for the enzyme purified from mammalian liver
  - reference_id: file:human/DPYD/DPYD-uniprot.txt
    supporting_text: "Catalyzes the reduction of uracil and thymine (PubMed:1512248)."
proposed_new_terms: []
suggested_questions:
- question: >-
    Which DPYD interacting partners identified in high-throughput screens (e.g. LXN, GOPC)
    have a demonstrable effect on DPD activity, stability or localization?
- question: >-
    Do the two GO:0017113 IDA annotations attributed to PMID:18075467 and PMID:10410956
    (both centered on the downstream enzyme dihydropyrimidinase / DPYS) reflect the full
    text, or are they mis-attributed to DPYD?
suggested_experiments:
- description: >-
    Reconstitute recombinant human DPD and measure steady-state kinetics for uracil,
    thymine and 5-fluorouracil across clinically relevant DPYD variants to correlate
    genotype with residual activity.
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF: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:10410956
  title: Radiochemical assay for determination of dihydropyrimidinase activity using
    reversed-phase high-performance liquid chromatography.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      Methods paper describing a radiochemical assay for dihydropyrimidinase (DHP, the
      downstream enzyme), not a direct DPD assay. Poor support for the GO:0017113 IDA it is
      attached to; process (thymine catabolism) assignment is acceptable.
- id: PMID:11988088
  title: Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene
    interpreted by analysis of the three-dimensional protein structure.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Directly about DPYD/DPD deficiency; disease-causing missense variants disrupt
      cofactor binding/electron transport, supporting the DPD molecular function and
      pyrimidine catabolic process. The purine-catabolism annotation attached to this
      reference is a mis-selection.
- id: PMID:1512248
  title: Purification and characterization of dihydropyrimidine dehydrogenase from
    human liver.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Purification and kinetic characterization of the human enzyme; primary support for
      DPD (NADP+) activity, FAD/FMN/iron content, homodimeric structure, and cytosolic
      localization.
- id: PMID:18075467
  title: Genetic regulation of dihydropyrimidinase and its possible implication in
    altered uracil catabolism.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      Paper is about dihydropyrimidinase (DHP, gene DPYS) and a uracil breath test, not a
      direct DPD assay. The GO:0017113 IDA on this reference is a mis-fit; the uracil
      catabolic process assignment for DPD is acceptable.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput Y2H interactome map; source of the two bare "protein binding" IPIs
      (LXN, GOPC) with no established functional relevance for DPD.
- id: PMID:8083224
  title: cDNA cloning and chromosome mapping of human dihydropyrimidine dehydrogenase,
    an enzyme associated with 5-fluorouracil toxicity and congenital thymine uraciluria.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cloning of human/pig DPD; recombinant enzyme reduces uracil, thymine and 5-FU;
      defines NADPH/FAD and [4Fe-4S] domains and the uracil-binding region.
- id: Reactome:R-HSA-73585
  title: reduction of uracil to form dihydrouracil
  findings: []
- id: Reactome:R-HSA-73616
  title: reduction of thymine to form 5,6-Dihydrothymine
  findings: []
- id: file:human/DPYD/DPYD-uniprot.txt
  title: UniProt text export for DPYD (Q12882)
  findings: []