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Lipidomic Analysis and functional study of the lipid biosynthesis of the plastid of Apicomplexa parasites

Final Report Summary - APICOLIPID (Lipidomic Analysis and functional study of the lipid biosynthesis of the plastid of Apicomplexa parasites)

Background and objectives of the Apicolipid project:
Apicomplexa is a phylum of obligate intracellular parasites, including pathogens of medical and veterinary importance such as toxoplasmosis and malaria. Toxoplasmosis affects up to one third of the world’s human population and can have dramatic consequences in immunodeprived patients and pregnant women. Malaria is one the deadliest human disease, infecting about 225 million people each year and resulting in up to 1 million deaths, predominantly children in sub saharan Africa and southeast Asia (WHO Report Dec. 2010). There is no current vaccine against malaria and current treatments are losing effectiveness due to increasing parasite drug resistance, even to front line drugs.Therefore there is a pressing need for the development of new efficient molecules against the diseases, especially malaria.
In contrast to pathogenic bacteria, Apicomplexa parasites are unicellular eukaryotes and share a wide range of metabolic pathways with their animal hosts, making therapeutic target development difficult. However, Apicomplexa harbour a relict non-photosynthetic plastid, the apicoplast, which has been acquired by the secondary endosymbiosis of a red alga (McFadden et al. 1996). The apicoplast is involved in unique and vital biological processes for the parasite (Fichera and Roos 1997). Due to its plant origin, the apicoplast thus represents a potential drug target against Apicomplexa related diseases. Beside the loss of photosynthetic capacities, the apicoplast is otherwise metabolically similar to plant and algal chloroplast and thus unique to the parasite. The apicoplast thus represents a novel potential target against Apicomplexa (Botté et al. 2011).
As a consequence of its algal origin, the apicoplast hosts a complete prokaryotic type II fatty acid synthesis pathway or FASII pathway (Waller et al. 1998). Fatty acids are the essential building blocks for the synthesis of membrane lipids. Very little is known on the exact nature and fate of the fatty acids generated by the apicoplast FASII pathway. However, previous studies indicate that the FASII pathway is essential for the parasite and may supply fatty acids for the biogenesis of the apicoplast as well as extra-plastidial membranes (Mazumdar et al. 2006, Vaughan et al. 2008, Yu et al. 2009). Beyond being able to synthesize fatty acids via its FASII, the apicoplast might be able to utilize them. Indeed, a set of acyltransferases, catalysing the synthesis of phosphatidic acid (PA), the central precursor for most membrane lipids, are predicted to be localised to the apicoplast (Ralph et al. 2004). Therefore, the apicoplast may play a central part in the lipid synthesis and homeostasis, which are crucial for the parasite division, proliferation and survival.
Our project aims to understand the apicoplast lipid metabolism and how the organelle is involved in the parasite’s vital demand for membrane syntheses. Our comprehensive study is divided in three objectives. The first objective intends to purify the apicoplast and establish the first lipidome of the organelle via a novel isolation protocol combined to metabolomic approaches. The second objective is to identify the apicoplast lipid products and assess their sub-cellular fate via metabolic labelling, using the lipid profiles obtained in the first objectives as baselines. The third objective is to characterize the enzymes responsible for the synthesis of PA, i.e. two acyltransferases homolog to plant and algal chloroplast ATS1 and ATS2. We will try to understand if the apicoplast is the site for the initial step of membrane lipid synthesis and determine if these enzymes are potential drug targets. Our investigation goes beyond understanding the apicoplast metabolism and seeks to establish the raison d’être of the organelle.