期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 28, 期 8, 页码 1206-1213出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0891-5849(00)00239-2
关键词
dihydroorotate dehydrogenase; nitric oxide; mitochondria; cytochrome c oxidase; orotate; respiration; free radicals
Dihydroorotate dehydrogenase (DHODH) catalyzes the oxidation of dihydroorotate to orotate in the pyrimidine biosynthesis pathway. It is functionally connected to the respiratory chain, delivering electrons to ubiquinone. We report here that inhibition of cytochrome c oxidase by nitric oxide (NO) indirectly inhibits DHODH activity. In digitonin-permeabilized cells, DEA/NO, a chemical NO donor, induced a dramatic decrease in DHO-dependent O-2 consumption. The inhibition was reversible and more pronounced at low O-2 concentration; it was correlated with a decrease in orotate synthesis. Since orotate is the precursor of all pyrimidine nucleotides, indirect inhibition of DHODH by NO may significantly contribute to NO-dependent cytotoxicity. (C) 2000 Elsevier Science Inc.
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