Dual targeting of aminoacyl-tRNA synthetases to the apicoplast and cytosol in Plasmodium falciparum.
The causative agent of malaria, Plasmodium, possesses three translationally active compartments: the cytosol, the mitochondrion and a relic plastid called the apicoplast. Aminoacyl-tRNA synthetases to charge tRNA are thus required for all three compartments. However, the Plasmodiumfalciparum genome encodes too few tRNA synthetases to supply a unique enzyme for each amino acid in all three compartments. We have investigated the subcellular localisation of three tRNA synthetases (AlaRS, GlyRS and ThrRS), which occur only once in the nuclear genome, 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 three enzymes, which suggests that the Plasmodium mitochondrion lacks at least these three tRNA synthetases. The unique Plasmodium ThrRS is the presumed target of the antimalarial compound borrelidin. Borrelidin kills P. falciparum parasites quickly without the delayed death effect typical of apicoplast translation inhibitors and without an observable effect on apicoplast morphology. By contrast, mupirocin, an inhibitor of the apicoplast IleRS, kills with a delayed death effect that inhibits apicoplast growth and division. Because inhibition of dual targeted tRNA synthetases should arrest translation in all compartments of the parasite, these enzymes deserve further investigation as potential targets for antimalarial drug development.
Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
Katherine E
KE
Jackson
James S
JS
Pham
Michelle
M
Kwek
Nilushi S
NS
De Silva
Stacey M
SM
Allen
Christopher D
CD
Goodman
Geoffrey I
GI
McFadden
Lluis
L
Ribas de Pouplana
Stuart A
SA
Ralph
D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism*; D000962:Antimalarials / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology*; D005233:Fatty Alcohols / Q000494:pharmacology; D016712:Mupirocin / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000378:metabolism / Q000502:physiology*; D018087:Plastids / Q000201:enzymology*; D021381:Protein Transport
D000962:Antimalarials; D005233:Fatty Alcohols; C005066:borrelidin; D016712:Mupirocin; D000604:Amino Acyl-tRNA Synthetases