Indirect inhibition of mitochondrial dihydroorotate dehydrogenase activity by nitric oxide.
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.
Beuneu
C
C
Unité 8619, Centre National de la Recherche Scientifique, Université Paris-Sud, Orsay, France. claire.beuneu@bbmpc.u-psud.fr
Auger
R
R
Löffler
M
M
Guissani
A
A
Lemaire
G
G
Lepoivre
M
M
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D004072:Digitonin / Q000494:pharmacology; D000090722:Dihydroorotate Dehydrogenase; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D007939:Leukemia L1210 / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009589:Nitrogen Oxides; D009963:Orotic Acid / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000975:Antioxidants; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D006834:Hydrazines; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D011994:Recombinant Proteins; D009569:Nitric Oxide; D009963:Orotic Acid; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D003576:Electron Transport Complex IV; D004072:Digitonin; D001205:Ascorbic Acid; D010100:Oxygen