Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase.

摘要: Dihydroorotate dehydrogenase (DHOD) is a pyrimidine biosynthetic enzyme which usually directly linked to the mitochondrial respiratory chain. Antimalarial naphthoquinones such as atovaquone (566c80) inhibit malarial DHOD by inhibiting electron transport. Since also has therapeutic activity against Pneumocystis carinii, P. carinii may be an important drug target. Organisms were obtained from immunosuppressed rats, incubated for 24 h in short-term vitro culture system, and then lysed. lysates catalyzed generation of orotate dihydroorotate at rate 852 pmol/mg protein per min. Control preparations made uninfected mice showed much less total enzymatic specific activity. As expected, was susceptible inhibitors cyanide, antimycin A, salicylhydroxamic acid (SHAM). Susceptibility SHAM suggests presence alternative oxidase. In contrast, neither pentamidine nor 5-hydroxy-6-demethylprimaquine (5H6DP), quinone metabolite primaquine, inhibited enzyme. Atovaquone 76.3% 100 microM 36.5% 10 microM. A similar degree inhibition found when organisms preincubated with drug. growth somewhat lower concentration (between 0.3 3 microM). Plasmodium falciparum are nanomolar concentrations atovaquone. Thus, while it possible that acts transport chain, possibility another target cannot excluded.