Roles of lipoate pathways in Plasmodium survival

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Plasmodium parasites are responsible for over half a billion malaria cases annually. During the asexual stages of development in red blood cells, malaria parasites acquire certain nutrients from human serum while retaining the ability to synthesize others. We are studying an essential enzyme cofactor called lipoate and its metabolism in Plasmodium falciparum. Our recent studies demonstrate that erythrocytic stage parasites are auxotrophic for lipoate, even though they contain a metabolic pathway to synthesize this cofactor. Proteins in the apicoplast organelle rely on lipoate synthesis while proteins in the parasite mitochondrion rely on scavenging and cannot obtain lipoate synthesized in the apicoplast. The proposed studies are focused on two aspects of lipoate scavenging and employ a combination of biochemical, cell biology and genetic approaches. Our first aim is to define how lipoate is taken up from the external environment and attached to specific proteins in the parasite mitochondrion. These experiments will identify rate limiting steps in the uptake of lipoate and they will forge a detailed link between the lipoate attachment enzymes and their protein substrates. Our second aim is to identify the lipoate-dependent mitochondrial proteins that are essential for parasite survival and determine the roles of these proteins in parasite biology. In other organisms, these proteins form large multi-enzyme complexes which can have a variety of metabolic and non-metabolic roles. Our experiments will dissect the domain structure of these proteins, determine their activities, and identify their binding partners in protein complexes. Genetic approaches will define the roles of lipoate metabolism proteins in the survival of blood stage parasites. By virtue of relying on a host nutrient, these proteins represent a vulnerable aspect of parasite biology which could be targeted at several levels.