Characterization of Plasmodium falciparum Choline Transporters
Final rept. 1 Apr 2002-31 Mar 2005
CONNECTICUT UNIV HEALTH CENTER FARMINGTON
Pagination or Media Count:
Plasmodium falciparum is the causative agent of severe human malaria. The rapid multiplication of the parasite within human red blood cells requires an active synthesis of new membranes. Choline analogs are potent antimalarial drugs. Although Choline transport has been suggested to be the target of these compounds, their exact mode of action is unknown. We identified two genes PfGAT and PfCTL1 as potential targets of these compounds. Here we report evidence that PfGAT encodes a Glycerol-3-phosphate acyltransferase enzyme responsible for the initial step of synthesis of P. falciparum membranes. Genetic data suggest that this pathway is essential for parasite survival and is a good target for development of new antimalarial drugs. We have also initiated a thorough genetic and biochemical characterization of PfCTL. Our data suggest that membrane proteins of the CTL family are not choline transporters. We generated transgenic parasites lacking PfCTL1, and showed that PfCTL is not essential for parasite intraerythrocytic development and survival. Finally we provide biochemical and genetic data suggesting that choline analogs act by specifically inhibiting phospholipid metabolism and the ability of the parasite to generate new membranes.
- Anatomy and Physiology