Characterization Of Plasmodium Falciparum Holo-Acp Synthase: A Potential Antimalarial Drug Target

The protozoan parasite Plasmodium falciparum is responsible for the most lethal form of malaria and kills about one million people annually, most of whom are children in sub-Saharan Africa. Fatty acid synthesis (FAS) is a validated antimalarial strategy: it occurs in a specialized parasite organelle (the apicoplast) and uses a dissociated type II FAS system similar to bacteria. Bioinformatics analysis indicates that P. falciparum encodes a single enzyme, holo-ACP synthase (PfAcpS), responsible for activating acyl carrier protein (ACP) involved in FAS. PfAcpS consists of a signal/leader peptide, a large N-terminal domain of unknown function, and a C-terminal domain (PfAcpS-C) that is highly homologous (30–50% similarity) to trimeric bacterial AcpS enzymes. We have expressed and isolated the soluble PfAcpS-C domain and shown that it catalyzes the transfer of (acyl)phosphopantetheine to PfACP from coenzyme A or from its derivatives acetyl-CoA and octanoyl CoA. PfAcpS exhibited much lower activity than E. coli AcpS and preferred higher concentrations of CoA derivatives. Several novel inhibitors of E. coli AcpS also blocked PfAcpS activity, although the degree of inhibition differed between the enzymes. The sequence similarity between PfAcpS-C and bacterial AcpS enzymes suggests that drugs targeting the latter might also inhibit P. falciparum growth and pathogenesis. (Supported by NSERC)