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Etude du mutant E255L de l'ATPase Ca2+ SERCA1a de lapin et de l'ATPase Ca2+ PfATP6 de Plasmodium falciparum

Abstract : Heterologous expression in yeast (S. cerevisiae), purification, characterization and inhibition assays by artemisinin, a powerful antimalaria The antimalarial drugs artemisinins have been described as inhibitors of the ATPase activity of PfATP6, the only sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) of the parasite responsible for malaria, Plasmodium falciparum, after its expression in Xenopus laevis oocytes. Mutation of an amino acid residue in mammalian SERCA1 (E255) to the equivalent one predicted in PfATP6 (L) was reported to induce sensitivity to artemisinin in the oocyte system. However, after purification of PfATP6 and of mammalian SERCA1a E255L expressed in Saccharomyces cerevisiae, it is shown that artemisinins do not inhibit their ATPase activities whereas PfATP6 is somewhat less sensitive to thapsigargin than to rabbit SERCA1 and retains full sensitivity to SERCA1 inhibitors. The insensitivity of purified PfATP6 to artemisinins suggests that the mechanism of action of this class of drugs is complex and cannot be ascribed to direct inhibition of PfATP6. Furthermore, the successful purification of PfATP6 affords the opportunity to develop new antimalarials by screening for inhibitors against PfATP6. Mots clés: PfATP6, ATPase-Ca2+, protéines membranaires, expression hétérologue, purification, artémisinine, paludisme
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https://tel.archives-ouvertes.fr/tel-00447184
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Submitted on : Thursday, January 14, 2010 - 3:02:22 PM
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Delphine Cardi. Etude du mutant E255L de l'ATPase Ca2+ SERCA1a de lapin et de l'ATPase Ca2+ PfATP6 de Plasmodium falciparum. Sciences du Vivant [q-bio]. Université Paris Sud - Paris XI, 2009. Français. ⟨tel-00447184⟩

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