title: The antimalarial drug primaquine targets Fe-S cluster proteins and yeast respiratory growth.
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.
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Lalève
authors.affiliation: School of Life Sciences, University Park, University of Nottingham, NG7 2RD, Nottingham, UK.
authors.forename: Cindy
authors.initials: C
authors.lastname: Vallières
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Golinelli-Cohen
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Bouton
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Song
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Pawlik
authors.affiliation: School of Life Sciences, University Park, University of Nottingham, NG7 2RD, Nottingham, UK.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Tindall
authors.affiliation: School of Life Sciences, University Park, University of Nottingham, NG7 2RD, Nottingham, UK.
authors.forename: Simon V
authors.initials: SV
authors.lastname: Avery
authors.affiliation: UMR 216, Faculté de Pharmacie de Paris, Université Paris Descartes, and Institut de Recherche pour le Développement, 75006 Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Clain
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France. Electronic address: brigitte.meunier@i2bc.paris-saclay.fr.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Meunier
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000154:Aconitate Hydratase / Q000378:metabolism; D000962:Antimalarials / Q000494:pharmacology*; D042966:Cytochrome-B(5) Reductase / Q000235:genetics; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D055786:Gene Knockout Techniques; D018832:Molecular Chaperones / Q000235:genetics; D018384:Oxidative Stress; D011319:Primaquine / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D018528:ATP-Binding Cassette Transporters; D000154:Aconitate Hydratase; D000962:Antimalarials; D042966:Cytochrome-B(5) Reductase; D018832:Molecular Chaperones; D011319:Primaquine; D029701:Saccharomyces cerevisiae Proteins; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C492990:RLI1 protein, S cerevisiae; C095735:LYS7 protein, S cerevisiae; C470363:MCR1 protein, S cerevisiae
keywords: Aconitase; Malaria; Mitochondria; Oxidative stress; Primaquine; Sod2; Yeast model