Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 28, Issue 8, Pages 1206-1213Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0891-5849(00)00239-2
Keywords
dihydroorotate dehydrogenase; nitric oxide; mitochondria; cytochrome c oxidase; orotate; respiration; free radicals
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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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