Selective inhibition of apicoplast tryptophanyl-tRNA synthetase causes delayed death in Plasmodium falciparum

CFA Pasaje; V Cheung; K Kennedy; EE Lim; JB Baell; MDW Griffin; SA Ralph

Journal article

Selective inhibition of apicoplast tryptophanyl-tRNA synthetase causes delayed death in Plasmodium falciparum

CFA Pasaje, V Cheung, K Kennedy, EE Lim, JB Baell, MDW Griffin, SA Ralph

Scientific Reports | NATURE PORTFOLIO | Published : 2016

DOI: 10.1038/srep27531

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Abstract

The malaria parasite Plasmodium falciparum relies on efficient protein translation. An essential component of translation is the tryptophanyl-tRNA synthetase (TrpRS) that charges tRNAtrp. Here we characterise two isoforms of TrpRS in Plasmodium; one eukaryotic type localises to the cytosol and a bacterial type localises to the remnant plastid (apicoplast). We show that the apicoplast TrpRS aminoacylates bacterial tRNA trp while the cytosolic TrpRS charges eukaryotic tRNAtrp. An inhibitor of bacterial TrpRSs, indolmycin, specifically inhibits aminoacylation by the apicoplast TrpRS in vitro, and inhibits ex vivo Plasmodium parasite growth, killing parasites with a delayed death effect characte..

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Michael Griffin Author

Stuart Ralph Author

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Grants

Awarded by Australian Research Council

Funding Acknowledgements

This work was supported by an Australian National Health and Medical Research Council grant (628704). M.D.W.G is a recipient of the C.R. Roper Fellowship and an Australian Research Council Future Fellowship (project number FT140100544). S.A.R is supported by an NHMRC RD Wright Biomedical fellowship (APP1062504). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. We thank Geoffrey McFadden at the University of Melbourne for the ACP-DsRed/CS-eYFP 3D7 P. falciparum. The E. coli mutant KY4040 was obtained from The E. coli Genetic Stock Center at Yale University. We thank Wim G. Hol at the SSGCID and Wes Van Voorhis at the CERID for providing the cytosolic TrpRS plasmid used in determining enzyme kinetics. The Australian Red Cross Blood Service kindly supplied blood.