The Effects of Antimalarials on the Plasmodium falciparum Dihydroorotate Dehydrogenase

Abstract

Dihydroorotate dehydrogenase (DHOD) is a key enzyme in de novo pyrimidine biosynthesis and the major source of electrons for the mitochondrial electron transport chain of intraerythrocytic malaria parasites. DHOD and the electron transport chain may also be the site of inhibition by certain antimalarial drugs. In order to test this, Plasmodium falciparum-infected erythrocytes were exposed in vitro to artemisinin or various 8-aminoquinolines, such as primaquine, WR 238605, WR 225448, and WR 255956, and then assayed for both enzyme activity and [3H]hypoxanthine incorporation, which is an indicator of viability. Atovaquone inhibits DHOD activity to a much greater extent than hypoxanthine incorporation, which is consistent with previous reports that it targets the parasite respiratory chain. However, artemisinin and the 8-aminoquinolines inhibit DHOD to the same or lesser extent than hypoxanthine incorporation, suggesting that these compounds have different modes of action.