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The antimalarial drug primaquine targets Fe–S cluster proteins and yeast respiratory growth

Lal�ve, Ana�s; Vallieres, Cindy; Golinelli-Cohen, Marie-Pierre; Bouton, C�cile; Song, Zehua; Pawlik, Grzegorz; Tindall, Sarah M.; Avery, Simon V.; Clain, J�r�me; Meunier, Brigitte

Authors

Ana�s Lal�ve

Cindy Vallieres

Marie-Pierre Golinelli-Cohen

C�cile Bouton

Zehua Song

Grzegorz Pawlik

Sarah M. Tindall

Simon V. Avery

J�r�me Clain

Brigitte Meunier



Abstract

Malaria is a major health burden in tropical and subtropical countries. The antimalarial drug primaquine is extremely useful for killing the transmissible gametocyte forms of Plasmodium falciparum and the hepatic quiescent forms of P. vivax. Yet its mechanism of action is still poorly understood. In this study, we used the yeast Saccharomyces cerevisiae model to help uncover the mode of action of primaquine. We found that the growth inhibitory effect of primaquine was restricted to cells that relied on respiratory function to proliferate and that deletion of SOD2 encoding the mitochondrial superoxide dismutase severely increased its effect, which can be countered by the overexpression of AIM32 and MCR1 encoding mitochondrial enzymes involved in the response to oxidative stress. This indicated that ROS produced by respiratory activity had a key role in primaquine-induced growth defect. We observed that Δsod2 cells treated with primaquine displayed a severely decreased activity of aconitase that contains a Fe–S cluster notoriously sensitive to oxidative damage. We also showed that in vitro exposure to primaquine impaired the activity of purified aconitase and accelerated the turnover of the Fe–S cluster of the essential protein Rli1. It is suggested that ROS-labile Fe–S groups are the primary targets of primaquine. Aconitase activity is known to be essential at certain life-cycle stages of the malaria parasite. Thus primaquine-induced damage of its labile Fe–S cluster – and of other ROS-sensitive enzymes – could inhibit parasite development.

Citation

Lalève, A., Vallieres, C., Golinelli-Cohen, M., Bouton, C., Song, Z., Pawlik, G., …Meunier, B. (2016). The antimalarial drug primaquine targets Fe–S cluster proteins and yeast respiratory growth. Redox Biology, 7, https://doi.org/10.1016/j.redox.2015.10.008

Journal Article Type Article
Acceptance Date Oct 22, 2015
Online Publication Date Nov 26, 2015
Publication Date Apr 1, 2016
Deposit Date Feb 6, 2017
Publicly Available Date Mar 29, 2024
Journal Redox Biology
Print ISSN 2213-2317
Electronic ISSN 2213-2317
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 7
DOI https://doi.org/10.1016/j.redox.2015.10.008
Keywords Mitochondria; Malaria; Aconitase; Sod2; Oxidative stress; Yeast model; Primaquine
Public URL https://nottingham-repository.worktribe.com/output/977392
Publisher URL http://www.sciencedirect.com/science/article/pii/S2213231715001597

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