Dihydropyrimidine dehydrogenase (NADP+) explained

dihydropyrimidine dehydrogenase (NADP+)
Altnames:	Dihydrothymine dehydrogenase
Ec Number:	1.3.1.2
Cas Number:	9029-01-0
Go Code:	0017113
Width:	270

In enzymology, a dihydropyrimidine dehydrogenase (NADP+) 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.^{[1] [2]} It is the initial and rate-limiting step in pyrimidine catabolism. It catalyzes the reduction of uracil and thymine. It is also involved in the degradation of the chemotherapeutic drugs 5-fluorouracil and tegafur. It also participates in beta-alanine metabolism and pantothenate and coa biosynthesis.

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,,,, and .

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.

See also

• Dihydropyrimidine dehydrogenase deficiency, a genetic disorder
• Cancer pharmacogenomics

Further reading

• Hoff PM, Royce M, Medgyesy D, Brito R, Pazdur R . Oral fluoropoyrimidines . Seminars in Oncology . 26 . 6 . 640–6 . December 1999 . 10606257 .
• Schneider HB, Becker H . Impact of dihydropyrimidine dehydrogenase on 5-fluorouracil treatment in cancer patients . European Journal of Medical Research . 8 . 5 . 226–8 . May 2003 . 12844478 .
• Omura K . 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 . June 2003 . 12851836 . 10.1007/s10147-003-0330-z . 22593228 .
• Lee W, Lockhart AC, Kim RB, Rothenberg ML . Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development . The Oncologist . 10 . 2 . 104–11 . February 2005 . 15709212 . 10.1634/theoncologist.10-2-104 .
• Lu ZH, Zhang R, Diasio RB . Purification and characterization of dihydropyrimidine dehydrogenase from human liver . The Journal of Biological Chemistry . 267 . 24 . 17102–9 . August 1992 . 10.1016/S0021-9258(18)41899-6 . 1512248 . free .
• Porter DJ, Chestnut WG, Merrill BM, Spector T . Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil . The Journal of Biological Chemistry . 267 . 8 . 5236–42 . March 1992 . 10.1016/S0021-9258(18)42757-3 . 1544906 . free .
• Dupuis A, Skehel JM, Walker JE . 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 . March 1991 . 1901022 . 10.1021/bi00225a032 .
• Eggink G, Engel H, Vriend G, Terpstra P, Witholt B . 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 . March 1990 . 2319593 . 10.1016/0022-2836(90)90310-I .
• Tuchman M, Roemeling RV, Hrushesky WA, Sothern RB, O'Dea RF . Dihydropyrimidine dehydrogenase activity in human blood mononuclear cells . Enzyme . 42 . 1 . 15–24 . 1989 . 2528450 . 10.1159/000469002.
• Diasio RB, Beavers TL, Carpenter JT . 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 . January 1988 . 3335642 . 442471 . 10.1172/JCI113308 .
• Yokota H, Fernandez-Salguero P, Furuya H, Lin K, McBride OW, Podschun B, Schnackerz KD, Gonzalez FJ . 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 . September 1994 . 10.1016/S0021-9258(17)31638-1 . 8083224 . free .
• Lu Z, Zhang R, Diasio RB . 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 . November 1993 . 8221682 .
• Vreken P, Van Kuilenburg AB, Meinsma R, Smit GP, Bakker HD, De Abreu RA, van Gennip AH . 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 . 1997 . 8892022 . 10.1007/BF01799841 . 10835574 .
• Johnson MR, Wang K, Tillmanns S, Albin N, Diasio RB . Structural organization of the human dihydropyrimidine dehydrogenase gene . Cancer Research . 57 . 9 . 1660–3 . May 1997 . 9135003 .
• Fernandez-Salguero PM, Sapone A, Wei X, Holt JR, Jones S, Idle JR, Gonzalez FJ . Lack of correlation between phenotype and genotype for the polymorphically expressed dihydropyrimidine dehydrogenase in a family of Pakistani origin . Pharmacogenetics . 7 . 2 . 161–3 . April 1997 . 9170156 . 10.1097/00008571-199704000-00012 .
• Vreken P, Van Kuilenburg AB, Meinsma R, van Gennip AH . Identification of novel point mutations in the dihydropyrimidine dehydrogenase gene . Journal of Inherited Metabolic Disease . 20 . 3 . 335–8 . July 1997 . 9266349 . 10.1023/A:1005357307122 . 3060557 .
• Vreken P, Van Kuilenburg AB, Meinsma R, van Gennip AH . Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W . Human Genetics . 101 . 3 . 333–8 . December 1997 . 9439663 . 10.1007/s004390050637 . 24362516 .
• Ogura K, Nishiyama T, Takubo H, Kato A, Okuda H, Arakawa K, Fukushima M, Nagayama S, Kawaguchi Y, Watabe T . Suicidal inactivation of human dihydropyrimidine dehydrogenase by (E)-5-(2-bromovinyl)uracil derived from the antiviral, sorivudine . Cancer Letters . 122 . 1–2 . 107–13 . January 1998 . 9464498 . 10.1016/S0304-3835(97)00377-7 .
• FRITZSON P . 1960 . Properties and assay of dihydrouracil dehydrogenase of rat liver . J. Biol. Chem. . 235 . 3 . 719 - 25 . 10.1016/S0021-9258(19)67929-9 . 13825299 . free .
• Shiotani T, Weber G . 1981 . Purification and properties of dihydrothymine dehydrogenase from rat liver . J. Biol. Chem. . 256 . 219 - 24 . 7451435 . 1 . 10.1016/S0021-9258(19)70122-7 . free .

Notes and References

1. Takai S, Fernandez-Salguero P, Kimura S, Gonzalez FJ, Yamada K . Assignment of the human dihydropyrimidine dehydrogenase gene (DPYD) to chromosome region 1p22 by fluorescence in situ hybridization . Genomics . 24 . 3 . 613–4 . December 1994 . 7713523 . 10.1006/geno.1994.1680 .
2. Web site: Entrez Gene: DPYD dihydropyrimidine dehydrogenase.