CLONING AND CHARACTERIZATION OF THE DIHYDROPYRIMIDINE DEHYDROGENASE CDNA AND GENE

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The dihydropyrimidine dehydrogenase (DPD) is the initial and rate- limiting enzyme in the catabolic pathway of pyrimidines. Mutations in the DPD gene are probably responsible for the metabolic disease thymine uracilurea that is responsible for neurological disorders in infants. DPD also has an important role in cancer chemotherapy that uses fluoropyrimidine drugs. It is responsible for degradation of more than 85 percent of administered 5-fluorouracil (5-FU), and the anti-cancer efficacy of 5-FU is related to DPD activity. Patients who experienced severe neurotoxicity with episodes of death were found to be deficient in DPD activity. A specific goal of this study is to clone and characterize the human DPD gene and to identify and characterize null alleles and/or alleles encoding variant enzymes, with the long-term aim of developing a convenient genotyping test for altered DPD genes for use in prenatal diagnosis and in the clinic to predict enzyme activity before cancer therapy with fluoropyrimidine drugs and to perform prenatal or postnatal diagnosis of congenital thymine uracilurea. The complete DNA and deduced protein sequence of pig and human DPD's have been determined. Structural domains were identified for NADPH, FAD, iron sulfur centers and substrate binding. The pig DPD was expressed in bacteria.