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Phospholipid Biosynthesis in Trypanosomes

It has long been known that T. brucei parasites scavenge lipids from their host environment, via uptake of fatty acids and lyso-phospholipids, or by endocytosis of low density lipoprotein particles. More recently, studies in T. brucei procyclic (insect) and bloodstream form parasites have shown that they are also capable of de novo fatty acid and phospholipid synthesis (reviewed in Smith & Bütikofer, Mol. Biochem. Parasitol. 172: 66, 2010; Ramakrishnan et al., Prog. Lipid Res. 52: 488, 2013).

During the last decade, we have worked on the elucidation of pathways involved in lipid modifications of proteins and de novo synthesis of phospholipids in T. brucei. We have experimentally established the enzymatic reaction sequences leading to the production of phosphatidylethanolamine (PE), a major membrane phospholipid in T. brucei, and more recently, of phosphatidylglycerol (PG) and cardiolipin (CL), two signature lipids of mitochondria. Our results have demonstrated that de novo formation of PE, PG and CL is essential for growth of T. brucei procyclic (insect) and bloodstream form parasites in culture, validating the enzymes and metabolites involved in these pathways as potential drug targets.

It is well known that PE, PG and CL are required for proper function of several mitochondrial membrane proteins, in particular those belonging to the respiratory chain. In addition, they are involved in the formation and/or stability of high molecular mass protein complexes of the inner mitochondrial membrane. The availability in our laboratory of inducible knock-out and knock-down trypanosomes deficient in de novo PE, PG and CL synthesis allows us to study the roles of these phospholipids in protein function and stability in a controlled, i.e. inducible and time-dependent, and thus more detailed way than in other eukaryotic model organisms.

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