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The antimalarial drug primaquine targets Fe–S cluster proteins and yeast respiratory growth
- Source :
- Redox Biology, Redox Biology, Elsevier, 2016, 7, pp.21-29. ⟨10.1016/j.redox.2015.10.008⟩, Redox Biology, Elsevier, 2015, 7, pp.21-29. 〈10.1016/j.redox.2015.10.008〉, Redox Biology, Vol 7, Iss C, Pp 21-29 (2016), Redox Biology, 2016, 7, pp.21-29. ⟨10.1016/j.redox.2015.10.008⟩, Redox Biology, Elsevier, 2015, 7, pp.21-29. ⟨10.1016/j.redox.2015.10.008⟩
- Publication Year :
- 2016
- Publisher :
- HAL CCSD, 2016.
-
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.<br />Graphical abstract fx1<br />Highlights • The mode of action of the antimalarial drug primaquine is poorly understood. • The yeast model is used to decipher its mechanism of action. • SOD and respiratory function are key for yeast sensitivity to primaquine. • Primaquine treatment impairs Fe–S containing enzyme aconitase. • Its attack on Fe–S clusters could explain the primaquine-induced growth inhibition.
- Subjects :
- 0301 basic medicine
Saccharomyces cerevisiae Proteins
Primaquine
[SDV]Life Sciences [q-bio]
Clinical Biochemistry
SOD2
Saccharomyces cerevisiae
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Mitochondrion
Biology
Biochemistry
Aconitase
Mitochondria, Malaria, Aconitase, Sod2, Oxidative stress, Yeast model, Primaquine
Superoxide dismutase
Antimalarials
Gene Knockout Techniques
03 medical and health sciences
Gene Expression Regulation, Fungal
medicine
Respiratory function
lcsh:QH301-705.5
Yeast model
Aconitate Hydratase
lcsh:R5-920
030102 biochemistry & molecular biology
[ SDV ] Life Sciences [q-bio]
Superoxide Dismutase
Organic Chemistry
Plasmodium falciparum
Sod2
biology.organism_classification
3. Good health
Mitochondria
Malaria
030104 developmental biology
lcsh:Biology (General)
Mechanism of action
Oxidative stress
biology.protein
ATP-Binding Cassette Transporters
medicine.symptom
lcsh:Medicine (General)
Cytochrome-B(5) Reductase
Research Paper
Molecular Chaperones
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Database :
- OpenAIRE
- Journal :
- Redox Biology, Redox Biology, Elsevier, 2016, 7, pp.21-29. ⟨10.1016/j.redox.2015.10.008⟩, Redox Biology, Elsevier, 2015, 7, pp.21-29. 〈10.1016/j.redox.2015.10.008〉, Redox Biology, Vol 7, Iss C, Pp 21-29 (2016), Redox Biology, 2016, 7, pp.21-29. ⟨10.1016/j.redox.2015.10.008⟩, Redox Biology, Elsevier, 2015, 7, pp.21-29. ⟨10.1016/j.redox.2015.10.008⟩
- Accession number :
- edsair.doi.dedup.....759b19d64d5ab5d23bf13136a36bfbb1
- Full Text :
- https://doi.org/10.1016/j.redox.2015.10.008⟩