cDNA cloning and chromosome mapping of human dihydropyrimidine dehydrogenase, an enzyme associated with 5-fluorouracil toxicity and congenital thymine uraciluria.

摘要: The pig and human dihydropyrimidine dehydrogenase (DPD) cDNAs were cloned sequenced. enzyme, expressed in Escherichia coli, catalyzed the reduction of uracil, thymine, 5-fluorouracil with kinetics approximating those published for enzyme purified from mammalian liver. DPD could be significant quantities only when uracil was added to bacterial growth medium. enzymes contained 1025 amino acids calculated M(r) = 111,416 111,398, respectively. Conserved domains corresponding a possible NADPH binding site FAD found NH2-terminal half proteins two motifs putative [4Fe-4S] sites near carboxyl terminus enzyme. latter corresponds labile COOH-terminal fragment previously shown contain iron sulfur centers. A sequence encompassing peptide between NADPH/FAD-containing portion protein iron-sulfur COOH terminus. Thus, appears derived at least three distinct domains. DPYD gene localized centromeric region chromosome 1 1p22 q21.