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

Charisse Flerida A Pasaje, Vanessa Cheung, Kit Kennedy, Erin E. Lim, Jonathan B. Baell, Michael D. W. Griffin, Stuart A. Ralph

Research output: Contribution to journalArticleResearchpeer-review

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 characteristic of apicoplast inhibitors. Indolmycin treatment ablates apicoplast inheritance and is rescuable by addition of the apicoplast metabolite isopentenyl pyrophosphate (IPP). These data establish that inhibition of an apicoplast housekeeping enzyme leads to loss of the apicoplast and this is sufficient for delayed death. Apicoplast TrpRS is essential for protein translation and is a promising, specific antimalarial target.

Original languageEnglish
Article number27531
Number of pages13
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 9 Jun 2016

Cite this

Pasaje, Charisse Flerida A ; Cheung, Vanessa ; Kennedy, Kit ; Lim, Erin E. ; Baell, Jonathan B. ; Griffin, Michael D. W. ; Ralph, Stuart A. / Selective inhibition of apicoplast tryptophanyl-tRNA synthetase causes delayed death in Plasmodium falciparum. In: Scientific Reports. 2016 ; Vol. 6.
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Selective inhibition of apicoplast tryptophanyl-tRNA synthetase causes delayed death in Plasmodium falciparum. / Pasaje, Charisse Flerida A; Cheung, Vanessa; Kennedy, Kit; Lim, Erin E.; Baell, Jonathan B.; Griffin, Michael D. W.; Ralph, Stuart A.

In: Scientific Reports, Vol. 6, 27531, 09.06.2016.

Research output: Contribution to journalArticleResearchpeer-review

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