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Marina Allary a Winner in Postdoctoral Fellows Poster Competition

 Name: Marina Allary
Department: Molecular Microbiology and Immunology
Mentor: Sean Prigge

Title of Project: Biosynthesis and scavenging pathways of lipoate in Plasmodium falciparum, the agent of human malaria

Abstract:
We are studying the metabolism of lipoate, a cofactor typically involved in oxidative metabolism and oxidative defense, in Plasmodium falciparum, the agent of human malaria. The parasite possesses the two enzymes necessary for lipoate biosynthesis, lipoate/octanoate transferase and lipoate synthase. The malarial genes were able to complement the appropriate gene-disrupted bacterial strains. Furthermore, recombinant lipoate synthase catalyzed in vitro the insertion of the two sulfur atoms essential for lipoate biological function. The location of these enzymes in the apicoplast, where the lipoate-requiring enzyme pyruvate dehydrogenase (PDH) is also present, suggests a link between lipoate and fatty acid biosynthesis. Moreover, PDH and at least three other proteins were labeled in parasite extracts by antiserum specific for lipoylated proteins. These other proteins are present or predicted to be in the mitochondrion, implying an additional requirement for lipoate in this compartment. Interestingly, P. falciparum possesses two paralogues (LipL1 and LipL2) of lipoate ligase, an enzyme involved in the utilization of  scavenged lipoate. Both were able to functionally complement a gene-disrupted bacterial strain. Additionally, LipL1, which is located in the mitochondrion, was enzymatically active as a recombinant protein. When added to the culture medium, radiolabeled lipoate was taken up by both the erythrocyte and the parasite, and incorporated into specific parasite proteins. Hence, lipoate biosynthesis and scavenging pathways appear to coexist in P. falciparum, but may be independent due to their compartmentalization. Lipoate analogues found to inhibit LipL1 activity are currently being used to investigate the possibility that P. falciparum is auxotrophic for lipoate.