Research Projects

Plasmodium falciparum, severe Malaria causing organism, has been central to many vaccine and drug development strategies, however, the pathogen has been parallely evolving to counter any therapeutics used against it. The orgenelle dynamics also plays a critical role during its pathogenesis and surivival, thereby making them attractive targets for detailed investigation and hence, drug designing. The parasites require a large amount of lipids to generate new membrane-bound compartments for the assembly of future daughter cells, for cell signalling event, as well as to generate storage lipids, triacylglycerol (TAG), and cholesteryl-esters. Phospholipids synthesis occurs mainly in the endoplasmic reticulum (ER) membrane and the mitochondrial inner membrane (MIM), before their distribution to other cellular membranes. Mitochondrial membrane biogenesis and lipid homeostasis presents divergent pathways in this parasite, significantly different from its human host. Some phospholipids are common in all cellular membranes, such as phosphatidylethanolamine (PE) or phosphatidylcholine (PC), but some are exclusive to the mechanism of mitochondrial membrane biogenesis, such as Cardiolipin (CL). CL is a unique and essential component of the MIM, known for stabilizing respiratory complexes and maintaining mitochondrial architecture. Researchers have successfully chalked out CL biosynthesis in prokaryotes and some eukaryotes, however, its mechanistic groundwork remains largely elusive in P. falciparum. Two types of CL synthase (CLS) are known to function, respectively, each one for prokaryotes and eukaryotes. Prokaryotic and some parasite CLS harbours two Phospholipase domains, while the eukaryotic enzymes contains CDP-alcohol phosphatidyltransferase domain, with different substrate specificity. We want to exploit this potential as a promising drug target due to a evolutionary divergence between the Plasmodium and host enzymes. This proposal aims to investigate the biosynthetic and transport machinery responsible for CL production in P. falciparum, focusing on prokaryotic-type Cardiolipin Synthase (CLS) and the associated lipid transport machinery, particularly the PRELI-domain protein (PRELID) and MDM2/TRIAP1 homolog complex involved in phosphatidic acid (PA) trafficking. In parallel, the presence of PRELID and MDM2-like factors hints at a conserved yet divergent lipid transport system, facilitating PA movement from the ER to the MIM or MOM, a step necessary for initiating CL biosynthesis. Phospholipid biosynthesis and inter-organelle lipid transport, particularly involving the mitochondrial inner membrane (MIM), plays pivotal role in sustaining mitochondrial function and morphology. Till date, there are no matching structure is present the Protein Data Bank corresponding any similarity with Plasmodium homologues. Therefore, understanding their mechanism of action and revealing key structural details would pave a way towards designing targeted antimalarials.