In enzymology, a dihydropyrimidine dehydrogenase (NADP+) (EC 1.3.1.2) is an enzyme that catalyzes the chemical reaction
- 5,6-dihydrouracil + NADP+
uracil + NADPH + H+
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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.[citation needed] It catalyzes the reduction of uracil and thymine.[3] It is also involved in the degradation of the chemotherapeutic drugs 5-fluorouracil and tegafur.[4] It also participates in beta-alanine metabolism and pantothenate and coa biosynthesis.
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+)
As of late 2007, 5 structures have been solved for this class of enzymes, with PDB accession codes 1GT8, 1GTE, 1GTH, 1H7W, and 1H7X.
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.[2]
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
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Fluorouracil (5-FU) Activity
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- 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.
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- 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.
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