Protein translation as a drug target in malaria parasites

Orateur : Stuart RALPH (University of Melbourne, Australia)

Plasmodium falciparum has 3 translationally active compartments : the cytosol, the mitochondrion and a relic plastid called the apicoplast. The nuclear genome encodes 36 distinct copies of canonical aminoacyl-tRNA synthetases (aaRSs), insufficient to supply a unique enzyme for each amino acid in all three compartments. We hypothesised that the single-copy tRNA synthetases are targeted to multiple compartments, and investigated this using a combination of epitope tagging, GFP fusions and antibodies against the native proteins. We have investigated the subcellular localisation of four tRNA synthetases (AlaRS, CysRS, GlyRS and ThrRS) and we show that each of these enzymes is dually localised to the P. falciparum cytosol and the apicoplast. No mitochondrial fraction is apparent for these four enzymes, which suggests that the Plasmodiummitochondrion lacks its own tRNA synthetases. We show that a single aaRS can recognise and charge the tRNA encoded in the nucleus as well as the apicoplast genome. Plasmodium parasites overcome their deficit in aaRSs by dual targeting enzymes that are able to charge organellar and eukaryotic tRNAs. We are investigating unique tRNA synthetases as targets for possible drugs, and have used an in silico docking approach to identify potential aaRS inhibitors that inhibit Plasmodium falciparum growth in culture.

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