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Reappraising the effects of artemisinin on the ATPase activity of PfATP6 and SERCA1a E255L expressed in Xenopus laevis oocytes

Nature Structural & Molecular Biology volume 23, pages 1–2 (2016)Cite this article

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An Erratum to this article was published on 05 April 2016

This article has been updated

To the Editor

Artemisinin is a widely used antimalarial drug, and understanding its molecular mechanism of action is fundamental to improving malaria diagnosis and drug administration and development. A decrease in artemisinin sensitivity, mainly in Southeast Asia, has recently been reported, thus underlining the need for further knowledge of artemisinin's molecular mechanism of action. Among other possibilities, PfATP6, the sarcoplasmic-endoplasmic Ca2+ ATPase (SERCA) encoded by Plasmodium falciparum, has been proposed as the target of artemisinin1. PfATP6 is homologous to SERCA1a from animal skeletal muscle, both in its amino acid sequence and function2. Eckstein-Ludwig et al. have reported that in membranes samples prepared from Xenopus laevis oocytes injected with PfATP6 or rabbit SERCA1a mRNA, the ATPase activity of the expressed PfATP6 is inhibited by artemisinin, whereas the drug has no effect on SERCA1a1. A single residue in PfATP6, Leu263, which is not conserved in SERCA1a, has been reported to be critical for artemisinin sensitivity, and an L263E substitution renders PfATP6 artemisinin insensitive2. Conversely, the reverse substitution in rabbit SERCA1a, E255L, has been reported to confer artemisinin sensitivity to the mammalian ATPase2. In contrast, we have found that artemisinin (and derivatives) have no effect on the ATPase activities of PfATP6 and SERCA1a E255L expressed and purified in active form from Saccharomyces cerevisae3. Similarly, artemisinin has no effect on the activity of SERCA1a E255L expressed in microsomes of COS-1 cells3. A number of studies have found no association between previously described PfATP6 mutations and artemisinin resistance4,5 (Supplementary Note). Although several studies have reported some association (e.g., ref. 6) and a single field study has reported a PfATP6 mutation in L263 associated with artemisinin resistance7, the experimental data presented in these studies are not conclusive, and further studies in this area would be welcome. Nonetheless, PfATP6 is still believed by some authors to be a target of artemisinin8,9,10,11. As a direct consequence of this view, substantial human and economic resources have been spent on large-scale sequencing of the PfATP6-encoding gene in world regions with artemisinin resistance (Supplementary Note and references therein).

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Figure 1: ATPase activities in P2 membrane fractions prepared from oocytes expressing SERCA1a, SERCA1a E255L or PfATP6.

Change history

  • 13 January 2016

    In the version of this article initially published, the position of the mutation reported in ref. 7 was incorrectly described as L236; it should be L263. In addition, in the HTML version of this article originally published, the concentration of artemisinin was given incorrectly as 50 mM instead of 50 μM; the PDF version and the legend text were correct. The errors have been corrected in the PDF and HTML versions of the article.

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Acknowledgements

The authors are very grateful to C. Jaxel (UMR 9198, Gif sur Yvette) for invaluable help throughout this study; to I. Florent (UMR 7245, Paris) for the direct test of artemisinin on live parasites; to C. Montigny (UMR 9198, Gif sur Yvette) for complementary experiments and fruitful discussions; to D. Cardi (UMR 9198, Gif sur Yvette), who initiated the work on PfATP6; to B. Arnou (Aarhus University) for preliminary work on the oocyte system; to B. Gasnier and C. Jouffret (UMR 8192, Paris) for the gift of control oocytes; to B. Miroux (UMR 7099, Paris) for continuous support; and to G. Lenoir, P. Champeil and J.L. Vazquez-Ibar (UMR 9198, Gif sur Yvette) for fruitful discussions.

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Authors and Affiliations

  1. Laboratoire des Protéines et Systèmes Membranaires, Institute for Integrative Biology of the Cell (I2BC) UMR 9198, Commissariat à l'Energie Atomique (CEA), Gif-sur-Yvette, France, Université Paris-Sud, Orsay, France

    Stéphanie David-Bosne & Marc le Maire

  2. Centre National de la Recherche Scientifique (CNRS) Gif-sur-Yvette, France

    Stéphanie David-Bosne & Marc le Maire

  3. Centre for Membrane Pumps in Cells and Disease (PUMPKIN), Danish National Research Foundation, Aarhus University, Aarhus, Denmark

    Michael Voldsgaard Clausen, Hanne Poulsen, Jesper Vuust Møller & Poul Nissen

  4. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

    Michael Voldsgaard Clausen, Hanne Poulsen & Poul Nissen

  5. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Jesper Vuust Møller

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  1. Stéphanie David-Bosne
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Correspondence to Poul Nissen or Marc le Maire.

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David-Bosne, S., Clausen, M., Poulsen, H. et al. Reappraising the effects of artemisinin on the ATPase activity of PfATP6 and SERCA1a E255L expressed in Xenopus laevis oocytes. Nat Struct Mol Biol 23, 1–2 (2016). https://doi.org/10.1038/nsmb.3156

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