Deciphering the Plasmodium phospholipid metabolism

Theme leaderS: rachel Cerdan, Sharon WEIN, Kai Wengelnik

Phospholipids (PLs) are essential components of biological membranes. The malaria parasite Plasmodium falciparum, uses its own metabolic machinery to synthetized PLs through a complex network of metabolic pathways. The most abundant PLs in the P. falciparum infected red blood cell are phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI) and they constitute the bulk of the lipids that form parasite membranes.

1- Based on lipidomics we recently obtained a comprehensive overview of the metabolism of the main PLs in P. falciparum. Our data raised new questions about the sources of PLs, the links between the multiple pathways and the existence of some specific enzymatic steps.

Our objective is to identify the bottlenecks, the compensatory effects and the interplay between the different PL pathways by lipidomic studies using deuterium-labelled precursors. The findings will allow us to select new therapeutic targets.

We previously identified the enzyme CCT (CTP:phosphocholine cytidylyltransferase) in the PC biosynthesis pathway as promising potential target. Our team determined the 3D structures of the PfCCT catalytic domain in the absence and in the presence of its substrates and its product. Our goal is to identify and to optimize new PfCCT specific inhibitors with antimalarial activity using an integrated target-based approach combining screening of ligands and 3D structure determination.

2- Phosphoinositides (PPIs), the phosphorylated derivatives of PI, are quantitatively minor PLs with important functions in intracellular signalling and membrane identity. We identified the PPIs present in P. falciparum-infected erythrocytes and produced a catalogue of enzymes and binding proteins that are predicted in the Plasmodium proteome.

Our objective is to characterize lipid kinases, lipid phosphatases and PPI-binding proteins and to evaluate their potential as future drug targets.