Dihydropyrimidine dehydrogenase (NADP+)

DPYD
Identifiers
Aliases	DPYD, DHP, DHPDHASE, DPD, dihydropyrimidine dehydrogenase
External IDs	OMIM: 612779 MGI: 2139667 HomoloGene: 85 GeneCards: DPYD
showGene location (Human)
Chr.	Chromosome 1 (human)
End	97,995,000 bp
showGene location (Mouse)
Chr.	Chromosome 3 (mouse)
End	119,432,924 bp
showRNA expression pattern
	More reference expression data
showGene ontology
Molecular function	• oxidoreductase activity, acting on the CH-CH group of donors; • 4 iron, 4 sulfur cluster binding; • nucleotide binding; • protein homodimerization activity; • flavin adenine dinucleotide binding; • dihydropyrimidine dehydrogenase (NADP+) activity; • iron-sulfur cluster binding; • metal ion binding; • GO:0001948 protein binding; • catalytic activity; • NADP binding; • oxidoreductase activity; • uracil binding; • NADH dehydrogenase activity; • dihydrouracil dehydrogenase (NAD+) activity;
Cellular component	• cytoplasm; • cytosol;
Biological process	• beta-alanine biosynthetic process; • uracil catabolic process; • pyrimidine nucleoside catabolic process; • pyrimidine nucleobase catabolic process; • thymidine catabolic process; • purine nucleobase catabolic process; • thymine catabolic process;
	Sources:Amigo / QuickGO
Orthologs
	1806
	99586
	ENSG00000188641
	ENSMUSG00000033308
	Q12882
	Q8CHR6
	NM_000110; NM_001160301
	NM_170778
	NP_000101; NP_001153773
	NP_740748
	Wikidata
View/Edit Human	View/Edit Mouse

showSearch
PMC	articles
PubMed	articles
NCBI	proteins

dihydropyrimidine dehydrogenase (NADP+)
dihydropyrimidine dehydrogenase (NADP+)
	Dihydroprymidine dehydrogenase dimer, Sus scrofa
Identifiers
EC no.	1.3.1.2
CAS no.	9029-01-0
Alt. names	Dihydrothymine dehydrogenase
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
PMC
showSearch
PMC	articles
PubMed	articles
NCBI	proteins

In enzymology, a dihydropyrimidine dehydrogenase (NADP+) (EC 1.3.1.2) is an enzyme that catalyzes the chemical reaction

5,6-dihydrouracil + NADP⁺

\rightleftharpoons

uracil + NADPH + H⁺

Thus, the two substrates of this enzyme are 5,6-dihydrouracil and NADP⁺, whereas its 3 products are uracil, NADPH, and H⁺.

In humans the enzyme is encoded by the DPYD gene.^[5]^[6] It is the initial and rate-limiting step in pyrimidine catabolism.^{[citation needed]} It catalyzes the reduction of uracil and thymine.^[7] It is also involved in the degradation of the chemotherapeutic drugs 5-fluorouracil and tegafur.^[8] It also participates in beta-alanine metabolism and .

Terminology[]

The systematic name of this enzyme class is 5,6-dihydrouracil:NADP+ 5-oxidoreductase.
Other names in common use include:

dihydrothymine dehydrogenase
dihydrouracil dehydrogenase (NADP+)
4,5-dihydrothymine: oxidoreductase
DPD
DHPDH
dehydrogenase, dihydrouracil (nicotinamide adenine dinucleotide, phosphate)
DHU dehydrogenase
hydropyrimidine dehydrogenase
dihydropyrimidine dehydrogenase (NADP+)

Structural studies[]

As of late 2007, 5 structures have been solved for this class of enzymes, with PDB accession codes 1GT8, 1GTE, 1GTH, 1H7W, and 1H7X.

Function[]

The protein is a pyrimidine catabolic enzyme and the initial and rate-limiting factor in the pathway of uracil and thymidine catabolism. Genetic deficiency of this enzyme results in an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy.^[6]

Interactive pathway map[]

Click on genes, proteins and metabolites below to link to respective articles.^{[§ 1]}

[[File:

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

|alt=Fluorouracil (5-FU) Activity edit]]

Fluorouracil (5-FU) Activity edit

^ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".

References[]

^ Jump up to: ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000188641 - Ensembl, May 2017
^ Jump up to: ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000033308 - Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Takai S, Fernandez-Salguero P, Kimura S, Gonzalez FJ, Yamada K (December 1994). "Assignment of the human dihydropyrimidine dehydrogenase gene (DPYD) to chromosome region 1p22 by fluorescence in situ hybridization". Genomics. 24 (3): 613–4. doi:10.1006/geno.1994.1680. PMID 7713523.
^ Jump up to: ^a ^b "Entrez Gene: DPYD dihydropyrimidine dehydrogenase".
^ Chung T, Na J, Kim YI, Chang DY, Kim YI, Kim H, Moon HE, Kang KW, Lee DS, Chung JK, Kim SS, Suh-Kim H, Paek SH, Youn H (2016). "Dihydropyrimidine Dehydrogenase Is a Prognostic Marker for Mesenchymal Stem Cell-Mediated Cytosine Deaminase Gene and 5-Fluorocytosine Prodrug Therapy for the Treatment of Recurrent Gliomas". Theranostics. 6 (10): 1477–90. doi:10.7150/thno.14158. PMC 4955049. PMID 27446484.
^ Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M (December 2013). "Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing". Clinical Pharmacology and Therapeutics. 94 (6): 640–5. doi:10.1038/clpt.2013.172. PMC 3831181. PMID 23988873.

Further reading[]

Hoff PM, Royce M, Medgyesy D, Brito R, Pazdur R (December 1999). "Oral fluoropoyrimidines". Seminars in Oncology. 26 (6): 640–6. PMID 10606257.
Schneider HB, Becker H (May 2003). "Impact of dihydropyrimidine dehydrogenase on 5-fluorouracil treatment in cancer patients". European Journal of Medical Research. 8 (5): 226–8. PMID 12844478.
Omura K (June 2003). "Clinical implications of dihydropyrimidine dehydrogenase (DPD) activity in 5-FU-based chemotherapy: mutations in the DPD gene, and DPD inhibitory fluoropyrimidines". International Journal of Clinical Oncology. 8 (3): 132–8. doi:10.1007/s10147-003-0330-z. PMID 12851836. S2CID 22593228.
Lee W, Lockhart AC, Kim RB, Rothenberg ML (February 2005). "Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development". The Oncologist. 10 (2): 104–11. doi:10.1634/theoncologist.10-2-104. PMID 15709212.
Lu ZH, Zhang R, Diasio RB (August 1992). "Purification and characterization of dihydropyrimidine dehydrogenase from human liver". The Journal of Biological Chemistry. 267 (24): 17102–9. doi:10.1016/S0021-9258(18)41899-6. PMID 1512248.
Porter DJ, Chestnut WG, Merrill BM, Spector T (March 1992). "Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil". The Journal of Biological Chemistry. 267 (8): 5236–42. doi:10.1016/S0021-9258(18)42757-3. PMID 1544906.
Dupuis A, Skehel JM, Walker JE (March 1991). "A homologue of a nuclear-coded iron-sulfur protein subunit of bovine mitochondrial complex I is encoded in chloroplast genomes". Biochemistry. 30 (11): 2954–60. doi:10.1021/bi00225a032. PMID 1901022.
Eggink G, Engel H, Vriend G, Terpstra P, Witholt B (March 1990). "Rubredoxin reductase of Pseudomonas oleovorans. Structural relationship to other flavoprotein oxidoreductases based on one NAD and two FAD fingerprints". Journal of Molecular Biology. 212 (1): 135–42. doi:10.1016/0022-2836(90)90310-I. PMID 2319593.
Tuchman M, Roemeling RV, Hrushesky WA, Sothern RB, O'Dea RF (1989). "Dihydropyrimidine dehydrogenase activity in human blood mononuclear cells". Enzyme. 42 (1): 15–24. doi:10.1159/000469002. PMID 2528450.
Diasio RB, Beavers TL, Carpenter JT (January 1988). "Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity". The Journal of Clinical Investigation. 81 (1): 47–51. doi:10.1172/JCI113308. PMC 442471. PMID 3335642.
Yokota H, Fernandez-Salguero P, Furuya H, Lin K, McBride OW, Podschun B, Schnackerz KD, Gonzalez FJ (September 1994). "cDNA cloning and chromosome mapping of human dihydropyrimidine dehydrogenase, an enzyme associated with 5-fluorouracil toxicity and congenital thymine uraciluria". The Journal of Biological Chemistry. 269 (37): 23192–6. doi:10.1016/S0021-9258(17)31638-1. PMID 8083224.
Lu Z, Zhang R, Diasio RB (November 1993). "Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy". Cancer Research. 53 (22): 5433–8. PMID 8221682.
Vreken P, Van Kuilenburg AB, Meinsma R, Smit GP, Bakker HD, De Abreu RA, van Gennip AH (1997). "A point mutation in an invariant splice donor site leads to exon skipping in two unrelated Dutch patients with dihydropyrimidine dehydrogenase deficiency". Journal of Inherited Metabolic Disease. 19 (5): 645–54. doi:10.1007/BF01799841. PMID 8892022. S2CID 10835574.
Johnson MR, Wang K, Tillmanns S, Albin N, Diasio RB (May 1997). "Structural organization of the human dihydropyrimidine dehydrogenase gene". Cancer Research. 57 (9): 1660–3. PMID 9135003.
Fernandez-Salguero PM, Sapone A, Wei X, Holt JR, Jones S, Idle JR, Gonzalez FJ (April 1997). "Lack of correlation between phenotype and genotype for the polymorphically expressed dihydropyrimidine dehydrogenase in a family of Pakistani origin". Pharmacogenetics. 7 (2): 161–3. doi:10.1097/00008571-199704000-00012. PMID 9170156.
Vreken P, Van Kuilenburg AB, Meinsma R, van Gennip AH (July 1997). "Identification of novel point mutations in the dihydropyrimidine dehydrogenase gene" (PDF). Journal of Inherited Metabolic Disease. 20 (3): 335–8. doi:10.1023/A:1005357307122. PMID 9266349. S2CID 3060557.
Vreken P, Van Kuilenburg AB, Meinsma R, van Gennip AH (December 1997). "Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W". Human Genetics. 101 (3): 333–8. doi:10.1007/s004390050637. PMID 9439663. S2CID 24362516.
Ogura K, Nishiyama T, Takubo H, Kato A, Okuda H, Arakawa K, Fukushima M, Nagayama S, Kawaguchi Y, Watabe T (January 1998). "Suicidal inactivation of human dihydropyrimidine dehydrogenase by (E)-5-(2-bromovinyl)uracil derived from the antiviral, sorivudine". Cancer Letters. 122 (1–2): 107–13. doi:10.1016/S0304-3835(97)00377-7. PMID 9464498.
FRITZSON P (1960). "Properties and assay of dihydrouracil dehydrogenase of rat liver". J. Biol. Chem. 235 (3): 719–25. doi:10.1016/S0021-9258(19)67929-9. PMID 13825299.
Shiotani T, Weber G (1981). "Purification and properties of dihydrothymine dehydrogenase from rat liver". J. Biol. Chem. 256 (1): 219–24. doi:10.1016/S0021-9258(19)70122-7. PMID 7451435.

This EC 1.3 enzyme-related article is a stub. You can help Wikipedia by .

[WikiPathways-9] The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".

[refGRCh38Ensembl-1] Jump up to: ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000188641 - Ensembl, May 2017

[refGRCm38Ensembl-2] Jump up to: ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000033308 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid7713523-5] Takai S, Fernandez-Salguero P, Kimura S, Gonzalez FJ, Yamada K (December 1994). "Assignment of the human dihydropyrimidine dehydrogenase gene (DPYD) to chromosome region 1p22 by fluorescence in situ hybridization". Genomics. 24 (3): 613–4. doi:10.1006/geno.1994.1680. PMID 7713523.

[entrez-6] Jump up to: ^a ^b "Entrez Gene: DPYD dihydropyrimidine dehydrogenase".

[Chung-7] Chung T, Na J, Kim YI, Chang DY, Kim YI, Kim H, Moon HE, Kang KW, Lee DS, Chung JK, Kim SS, Suh-Kim H, Paek SH, Youn H (2016). "Dihydropyrimidine Dehydrogenase Is a Prognostic Marker for Mesenchymal Stem Cell-Mediated Cytosine Deaminase Gene and 5-Fluorocytosine Prodrug Therapy for the Treatment of Recurrent Gliomas". Theranostics. 6 (10): 1477–90. doi:10.7150/thno.14158. PMC 4955049. PMID 27446484.

[Caudle-8] Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M (December 2013). "Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing". Clinical Pharmacology and Therapeutics. 94 (6): 640–5. doi:10.1038/clpt.2013.172. PMC 3831181. PMID 23988873.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[§ 1]

show v t Oxidoreductases: CH–CH oxidoreductases (EC 1.3)
1.3.1: NAD/NADP acceptor	Enoyl-acyl carrier protein reductase/Enoyl ACP reductase 7-Dehydrocholesterol reductase Biliverdin reductase 2,4 Dienoyl-CoA reductase Dihydroxymethyloxo-tetrahydroquinoline dehydrogenase
1.3.3: Oxygen acceptor	Dihydroorotate dehydrogenase Coproporphyrinogen III oxidase Protoporphyrinogen oxidase Bilirubin oxidase Acyl-CoA oxidase Dihydrouracil oxidase Tetrahydroberberine oxidase Secologanin synthase Tryptophan alpha,beta-oxidase Pyrroloquinoline-quinone synthase L-galactonolactone oxidase
1.3.5: Quinone	Succinate dehydrogenase SDHA SDHB SDHC SDHD
1.3.99: Other acceptors	Fumarate reductase Butyryl-CoA dehydrogenase Acyl CoA dehydrogenase ACADSB ACADS 5α-reductase SRD5A1 SRD5A2 SRD5A3 Glutaryl-CoA dehydrogenase Isovaleryl coenzyme A dehydrogenase 3-oxo-5beta-steroid 4-dehydrogenase

show v t Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)