Lipoic Acid Acquisition and Glutathione Biosynthesis in Apicomplexan Parasites

The thiols lipoic acid and glutathione (GSH) are cofactors of enzymatic reactions crucial to the metabolism of most organisms, and play a vital role in maintaining redox homeostasis. The dithiol-containing fatty acid derivative lipoic acid can be acquired through de novo biosynthesis and salvage. In apicomplexans, salvage is confined to the mitochondrion, while biosynthesis occurs solely in the apicoplast. Lipoic acid biosynthesis depends on the supply of octanoyl-acyl carrier protein, an intermediate of type II fatty acid biosynthesis (FASII). This links the occurrence of lipoic acid biosynthesis directly to that of FASII, suggesting that the biosynthesis of lipoic acid is essential for the exo-erythrocytic development of Plasmodium and growth of Toxoplasma gondii tachyzoites, as described for FASII. Lipoic acid salvage is important for the intra-erythrocytic and sexual development of Plasmodium, and inhibition of the respective lipoic acid protein ligase 1 and 2 of malarial parasites might offer potential for interfering with these stages of parasite development. The suitability of the glutathione biosynthesis pathway for the development of new antimalarials is also discussed. Plasmodium parasites synthesize GSH de novo, and it was shown that the deletion of the gene encoding g-glutamylcysteine synthetase (γGCS), the first enzyme of GSH biosynthesis, only marginally affects the intraerythrocytic development of Plasmodium berghei. This is in contrast to the lethal effects of the specific inhibition of this enzyme by L-buthionine sulfoximine on the human malarial parasite Plasmodium falciparum in vitro. In addition, a knockout of the gene in P. falciparum has, so far, proved impossible. These observations suggest differences in the requirements forGSHbiosynthesis in murine and human malaria species during intra-erythrocytic development, which need to be considered when validating this pathway for future drug development.