Dihydrouracil dehydrogenase

Ho DH, Townsend L, Luna MA et al. Distribution and inhibition of dihydrouracil dehydrogenase activities in human tissues using 5-fluorouracil as a substrate. Anticancer Res 1986 6 781-784. 

In other studies it was found that 5-alkyluracils inhibited the degradation of uracil and thymine by rat tissue supernatants. It is believed that these compounds are competitors for dihydrouracil dehydrogenase, which catalyses the reduction of uracil and thymine [278]. 

Dihydrouracil dehydrogenase (NAD+) [EC 1.3.1.1] catalyzes the reaction of 5,6-dihydrouracil with NAD+ to produce uracil and NADH. Dihydrouracil dehydrogenase (NADP+) [EC 1.3.1.2], also called dihydropyrimidine dehydrogenase (NADP+) and dihydrothymine dehydrogenase, catalyzes the reaction of 5,6-dihydrouracil with NADP+ to produce uracil and NADPH. The enzyme can also use dihydrothymine as a substrate. 

DIHYDROOROTATE DEHYDROGENASE DIHYDROOROTATE OXIDASE DIHYDROPTERIDINE REDUCTASE DIHYDROPTEROATE SYNTHASE DIHYDROPYRIMIDINASE DIHYDROURACIL DEHYDROGENASE Dihydroxyacetone kinase,... 

DIHYDROLIROAMIDE DEHYDROGENASE DIHYDROURACIL DEHYDROGENASE DIIODORHENYLPYRUVATE REDUCTASE DNA LIGASES... 

In the first step, the pyrimidine is hydrogenated at the double bond by dihydrouracil dehydrogenase (EC 1.3.1.2) to a dihydropyrimidine (Scheme 1.6.2). The enzymes obtained from rat [4] and human [5] liver have been purified and characterized. They were later subjected to molecular cloning [6], The hydrogens are added to the double bond at the Si face of C5 and C6 in an anti-addition reaction. This was deduced from NMR spectra recorded from the isolated degradation products after administration of [5-2H]- and [6-2H]uracil and 2H20 to a mammalian enzyme system [7]. 

Uracil and thymine are converted to their end products, /3-alanine and /3-aminoisobutyrate, respectively, in parallel pathways. In the first step, uracil and thymine are reduced by dihydrouracil dehydrogenase to their corresponding dihydro derivatives. As these latter molecules are hydrolyzed, the rings open, yielding /3-ureidopropionate and /3-ureidoisobutyrate, respectively. Finally, /3-alanine and /3-aminoisobutyrate are produced in deamination reactions catalyzed by /3-ureidopropionase. 

The response to 5-FU correlates significantly with low levels of the degradative enzymes dihydrouracil dehydrogenase and thymidine phosphorylase, and a low level of expression ofTS. 

Cytosine deaminase 2 dihydrouracil dehydrogenase 3 dihydropyrimidinase 4 /5-ureidopropionase 5 uracil dehydrogenase 6 barbiturase (barbituric acid amino hydrolase)... 

Uracil degradation in mice is controlled by one allelic pair of the Pd locus. It was suggested that this locus regulates the activity of all three enzymes of the pyrimidine-degradation system dihydrouracil dehydrogenase, dihydropyrimidinase, and 3-ureidopropionase (Dagg et al., 1964). This was corroborated for 3-ureido-propionase by Sannaet al., 0970). 

After intravenous administration, about 80-90% of the dose is catabolized in the liver by dihydropyrimidine dehydrogenase (DPD) [38] (Figure 14.3). The formation of the inactive 5-fluoro-5,6-dihydrouracil (5-FUH2) by DPD is the rate-limiting step of 5-FU catabolism [39]. DPD is widely distributed among tissues, with the highest levels found in the liver. Once 5-FU entered tumor cells, its antitumor effect is mainly dependent on the extent of 5-FU anabolism. After two sequential anabolic steps involving thymidine phosphorylase (TP) and thymidine kinase... 

Jiang H, Lu J, Ji J. Circadian rhythm of dihydrouracil/uracil ratios in biological fluids a potential biomarker for dihydropyrimidine dehydrogenase levels. Br J Pharmacol 2004 141 616-623. van Kuilenburg AB, Haasjes J, Riehel DJ et al. Clinieal implieations of dihydropyrimidine dehydrogenase (DPD) defleieney in patients with severe 5-fluorouraeil-assoeiated toxicity identification of new mutations in the DPD gene. Clin Cancer Res 2000 6 4705 712. 

Mattison LK, Fourie J, Hirao Y et al. The uracil breath test in the assessment of dihydropyrimidine dehydrogenase activity pharmacokinetic relationship between expired 13C02 and plasma [2-13C]dihydrouracil. Clin Cancer Pes 2006 12 549-555. 

Studies on isolated enzymes have revealed some differences between various systems. For example, the first step in uracil catabolism by Clostridium uraeUicum involved a DPNH-dependent conversion of uracil to dihydrouracil 432), while the corresponding reductions of uracil and thymine to dihydropyrimidines in acetone powder extracts of rat liver were TPNH-dependent reactions 416). Dihydropyrimidine dehydrogenase and dihydrouracil hydrases have been purified from animal 421, 433) and bacterial sources 432, 434). It was found that the hydrase enzyme from... 

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