DPYS

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred cytosolic localization. DHP is a soluble cytosolic metabolic enzyme, consistent with the ISS and Reactome (TAS) cytosol annotations. Reason: Correct and precise cellular-component annotation for a soluble cytosolic pyrimidine-catabolic enzyme; represents the site where DHP acts.
GO:0006208 pyrimidine nucleobase catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred participation in pyrimidine nucleobase catabolism. DHP catalyzes the second step of reductive pyrimidine degradation, matching this process. Reason: Core biological-process annotation, directly consistent with the enzyme's role in dihydropyrimidine ring opening within pyrimidine catabolism. Supporting Evidence: file:human/DPYS/DPYS-uniprot.txt Catalyzes the second step of the reductive pyrimidine
GO:0004157 dihydropyrimidinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred dihydropyrimidinase activity across orthologs. This is the defining, experimentally supported molecular function of the gene product. Reason: Core molecular function; agrees with direct experimental (IDA/IMP) evidence in human and the conserved family activity. Supporting Evidence: file:human/DPYS/DPYS-uniprot.txt Can catalyze the ring opening of 5,6-dihydrouracil
GO:0004157 dihydropyrimidinase activity	IEA GO_REF:0000120	ACCEPT	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. Reason: Accurate EC/RHEA-based inference of the core molecular function. Supporting Evidence: file:human/DPYS/DPYS-uniprot.txt EC=3.5.2.2
GO:0005737 cytoplasm	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro-based electronic localization to the cytoplasm. True but less precise than the cytosol annotations from IBA/ISS/TAS evidence. Reason: Correct but a broader parent of cytosol; the more specific GO:0005829 (cytosol) annotations better capture the localization.
GO:0016787 hydrolase activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro (Amidohydro_1) electronic annotation to the broad hydrolase parent. Correct but far less informative than the specific dihydropyrimidinase activity. Reason: High-level parent of GO:0004157; uninformative given the well-established specific activity.
GO:0016810 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	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. Reason: Correct branch but a general parent of GO:0004157 dihydropyrimidinase activity; the specific term is preferred.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare protein-binding IPI from the HuRI all-by-all binary (Y2H) interactome (interaction with APPBP2/Q92624). Uninformative regarding molecular function. 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. Supporting Evidence: PMID:32296183 a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Bare protein-binding IPI from a neurodegenerative-disease-focused yeast two-hybrid interactome (multiple IntAct partners). Uninformative regarding molecular function. Reason: High-throughput Y2H interactome datapoint; not an informative molecular function. Retained per curation policy but flagged as over-annotation. Supporting Evidence: PMID:32814053 systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins
GO:0051219 phosphoprotein binding	IEA GO_REF:0000107	REMOVE	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. Reason: Over-propagated electronic inference with no supporting biology for human DPYS; the protein is a cytosolic metabolic hydrolase, not a phosphoprotein-binding adaptor.
GO:0004157 dihydropyrimidinase activity	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of dihydropyrimidinase activity from an ortholog (UniProtKB:Q55DL0). Consistent with the direct experimental and IBA evidence. Reason: Redundant with the experimentally supported core molecular function; correctly assigned.
GO:0042802 identical protein binding	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Self-association inferred by similarity (from rat ortholog Q63150). Consistent with the homotetrameric quaternary structure of the human enzyme. Reason: Reflects the oligomeric (homotetramer) assembly rather than the catalytic core function; biologically plausible but ancillary. Supporting Evidence: file:human/DPYS/DPYS-uniprot.txt Homotetramer.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	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. Reason: Proteomic detection in secreted exosomes; peripheral to the enzyme's cytosolic metabolic role rather than a functional localization. Supporting Evidence: PMID:19056867 LC-MS/MS to profile the proteome of human urinary exosomes
GO:0005829 cytosol	TAS Reactome:R-HSA-73589	ACCEPT	Summary: Reactome-asserted cytosolic localization for the conversion of 5,6-dihydrouracil to 3-ureidopropionate. Matches the enzyme's soluble cytosolic nature. Reason: Correct, specific localization consistent with IBA/ISS cytosol annotations and the known reaction context.
GO:0005829 cytosol	TAS Reactome:R-HSA-73618	ACCEPT	Summary: Reactome-asserted cytosolic localization for the conversion of 5,6-dihydrothymine to 3-ureidoisobutyrate. Matches the enzyme's soluble cytosolic nature. Reason: Correct, specific localization consistent with the other cytosol annotations.
GO:0004157 dihydropyrimidinase activity	IDA PMID:10410956 Radiochemical assay for determination of dihydropyrimidinase...	ACCEPT	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. Reason: Direct experimental evidence for the enzyme's core catalytic activity in human tissue. Supporting Evidence: PMID:10410956 separation of radiolabeled dihydrouracil from N-carbamyl-beta-alanine by HPLC
GO:0004157 dihydropyrimidinase activity	IMP PMID:18075467 Genetic regulation of dihydropyrimidinase and its possible i...	ACCEPT	Summary: Site-directed mutagenesis and expression of DPYS sequence variants showed that inactivating mutations reduce DHP enzyme activity, supporting that DPYS enables this activity. Reason: Mutation/expression evidence directly linking the gene product to dihydropyrimidinase activity. Supporting Evidence: PMID:18075467 inactivating mutations in
GO:0004157 dihydropyrimidinase activity	IDA PMID:9718352 Dihydropyrimidinase deficiency: structural organization, chr...	ACCEPT	Summary: Expression of the human gene and disease-causing variants in a eukaryotic system demonstrated dihydropyrimidinase activity, with all deficiency mutations reducing it. Reason: Direct experimental support for the core catalytic function of human DPYS. Supporting Evidence: PMID:9718352 we showed that all mutations reduced
GO:0005829 cytosol	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of cytosolic localization (from rat ortholog Q63150). Consistent with all other cytosol/cytoplasm evidence. Reason: Correct, specific localization consistent with the IBA/TAS cytosol annotations.
GO:0006208 pyrimidine nucleobase catabolic process	IDA PMID:9718352 Dihydropyrimidinase deficiency: structural organization, chr...	ACCEPT	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). Reason: Core biological-process annotation supported by disease biochemistry and the enzyme's position in the reductive pyrimidine degradation pathway. Supporting Evidence: PMID:9718352 Dihydropyrimidinase (DHP) deficiency (MIM 222748) is characterized by
GO:0006210 thymine catabolic process	ISS GO_REF:0000024	ACCEPT	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. Reason: Consistent with the enzyme's demonstrated ring opening of 5,6-dihydrothymine within pyrimidine (thymine) catabolism. Supporting Evidence: file:human/DPYS/DPYS-uniprot.txt Can catalyze the ring opening of 5,6-dihydrouracil
GO:0006212 uracil catabolic process	IDA PMID:10410956 Radiochemical assay for determination of dihydropyrimidinase...	ACCEPT	Summary: Direct assay of DHP activity on dihydrouracil (the reduced form of uracil) in human liver supports involvement in uracil catabolism. Reason: Core biological-process annotation; DHP performs the second committed step of uracil degradation. Supporting Evidence: PMID:10410956 separation of radiolabeled dihydrouracil from N-carbamyl-beta-alanine by HPLC
GO:0006212 uracil catabolic process	IMP PMID:18075467 Genetic regulation of dihydropyrimidinase and its possible i...	ACCEPT	Summary: Genetic/expression analysis linking inactivating DPYS mutations to altered uracil catabolism (measured by uracil/dihydrouracil breath tests) supports involvement in uracil catabolism. Reason: Mutation-based evidence tying DPYS function to in-vivo uracil catabolism. Supporting Evidence: PMID:18075467 inactivating mutations in
GO:0008270 zinc ion binding	NAS PMID:9718352 Dihydropyrimidinase deficiency: structural organization, chr...	ACCEPT	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. Reason: Zinc binding is a defining, structurally confirmed feature of DHP catalysis; correct molecular-function annotation. Supporting Evidence: file:human/DPYS/DPYS-uniprot.txt Binds 2 Zn(2+) ions per subunit.

Gene Description

Existing Annotations Review

Core Functions

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.

Dihydropyrimidinase activity within the broader pyrimidine nucleobase catabolic pathway, using a binuclear zinc center for catalysis.

References

📚 Additional Documentation

Notes

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