Class of 2007
gustavo.afanador@jhu.edu

Research
Lipoate is an essential cofactor of key enzymes in oxidative metabolic reactions.  The transfer of this cofactor to lipoate-requiring proteins is catalyzed by a ligase.  Lipoate is attached to a specific lysine in the E2 subunit of pyruvate dehydrogenase (PDH), alpha-ketoglutarate dehydrogenase (KGDH), branched-chain alpha-ketoacid dehydrogenase (BCDH) and the H-protein of the glycine cleavage system.  In these systems, lipoate catalyzes two-electron redox reactions and serves to shuttle the reaction intermediate between active sites.  Lipoate ligases are present in eukaryotic and prokaryotic cells.  The malaria parasite, 'Plasmodium falciparum', contains a lipoate ligase (LipL1) similar to the one found in E. coli as well as a second ligase (LipL2) with little sequence homology to the 'E. coli' enzyme (14%).  Malaria parasites contain two organelles that require lipoate: the mitochondria and the apicoplast.  The apicoplast harbors a pathway capable of synthesizing lipoate, however, lipoate synthesized in the apicoplast is not trafficked to the mitochondrion.  Instead, the two lipoate ligases function in the mitochondrion to attach lipoate scavenged from outside the parasite.  The two malaria lipoate ligases have 21% of similarity, but the function of LipL2 is not well understood.  Previous results in the lab show that the growth of the parasite it can be inhibited when 8-BrO, a lipoate analogue, is supplied to the cell, interfering with the scavenging of lipoate.  Our goal is to understand why apicomplexan parasites have two divergent lipoate ligases, and what roles these proteins play in parasite biology.

Publications