Apicomplexa is a phylum of intracellular parasites, including pathogens of medical and veterinary importance. In contrast to pathogenic bacteria, these parasites are eukaryotes and share numerous metabolic pathways with their animal hosts, making therapeutic target development difficult. Two genera (Plasmodium and Toxoplasma), which are responsible for serious diseases in humans, have been the focus of most studies in this parasite group. Malaria caused by Plasmodium is one of the deadliest human infections, leading to 2-3 million deaths per annum. Plasmodium and Toxoplasma harbour a relict plastid, called the apicoplast, involved in unique and vital metabolic processes. Synthesis of fatty acids in the apicoplast, catalyzed by a prokaryotic type II fatty acid synthase (FASII), is a particularly interesting potential target because it is critical for the plastid biogenesis and probably required for the vital demand of cell membrane syntheses. Based on the recent development of an apicoplast purification protocol in Pr. McFadden’s group, the project aims to achieve three objectives regarding the apicoplast lipid synthesis. We will determine the lipid composition of the apicoplast and its separated membranes using conventional biochemistry as well as novel mass spectrometry lipid analysis methods. By metabolic labelling and sub-cellular fractionations, the lipids depending on the FASII pathway and their possible sub-cellular trafficking will be sought. Finally we will focus on the role of enzymes responsible for the synthesis of phosphatidic acid (ACT1 and ACT2) and predicted to be located in the apicoplast, using GFP constructs and inducible KO. Dr. Maréchal's group provides also a pharmacological screening environment: the potential of characterized enzymes as drug targets will be additionally investigated and transfered to drug development pipeline.
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