Lipoylation Mechanism of P. Falciparum Mitochondrial Proteins

Lipoate is an essential cofactor for the aerobic metabolism in oxidative decarboxylation reactions of 2-oxoacid complexes. Malaria parasite survival is highly dependent on scavenging this essential cofactor from the human host. Scavenged lipoate is subsequently attached to the α-ketoglutarate dehydrogenase (KDH), the branched chain α-ketoacid dehydrogenase (BCDH), and the H-protein of the Glycine cleavage system. Previous studies have shown that these three lipoylated enzymes reside in the mitochondrion. PfLipL1, the lipoate ligase, also localizes to the mitochondrion and catalyzes the lipoylation of the H-protein. However, LipL1 alone is incapable of lipoylating the BCDH and KDH. The lipoylation of these proteins occurs through a novel mechanism requiring both LipL1 and a previously uncharacterized enzyme, LipL2. Additionally, this mechanism is sensitive to redox conditions. Under strong reducing conditions BCDH and KDH are exclusively lipoylated whereas lipoylation of the H-protein requires less reducing conditions. In this work we characterize the interactions of LipL1 with the small molecules necessary for protein lipoylation. Furthermore, progress toward a structural characterization of the LipL1-LipL2 interaction will be explored.