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

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Ittarat I, Asawamahasakda W, Bartlett MS, Smith JW, Meshnick SR

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

Antimicrob Agents Chemother. 1995 Feb;39(2):325-8.

PubMed ID

7726490 [ View in PubMed

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Abstract

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

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Atovaquone	Dihydroorotate dehydrogenase (quinone), mitochondrial	Protein	Humans	Unknown	Inhibitor	Details
Atovaquone	Dihydroorotate dehydrogenase (quinone), mitochondrial	Protein	Plasmodium falciparum (isolate 3D7)	Yes	Inhibitor	Details