Purified E255L mutant SERCA1a and purified PfATP6 are sensitive to SERCA-type inhibitors but insensitive to artemisinins
Language: 
English
Abstract: 

The antimalarial drugs artemisinins have been described as inhibiting Ca(2+)-ATPase activity of PfATP6 (Plasmodium falciparum ATP6) after expression in Xenopus oocytes. Mutation of an amino acid residue in mammalian SERCA1 (Glu(255)) to the equivalent one predicted in PfATP6 (Leu) was reported to induce sensitivity to artemisinin in the oocyte system. However, in the present experiments, we found that artemisinin did not inhibit mammalian SERCA1a E255L either when expressed in COS cells or after purification of the mutant expressed in Saccharomyces cerevisiae. Moreover, we found that PfATP6 after expression and purification from S. cerevisiae was insensitive to artemisinin and significantly less sensitive to thapsigargin and 2,5-di(tert-butyl)-1,4-benzohydroquinone than rabbit SERCA1 but retained higher sensitivity to cyclopiazonic acid, another type of SERCA1 inhibitor. Although mammalian SERCA and purified PfATP6 appear to have different pharmacological profiles, their insensitivity to artemisinins suggests that the mechanism of action of this class of drugs on the calcium metabolism in the intact cell 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.

Author(s): 
Cardi, Delphine
Pozza, Alexandre
Arnou, Bertrand
Marchal, Estelle
Clausen, Johannes D.
Andersen, Jens Peter
Krishna, Sanjeev
Møller, Jesper V.
le Maire, Marc
Jaxel, Christine
Item Type: 
Journal Article
Publication Title: 
The Journal of Biological Chemistry
Journal Abbreviation: 
J. Biol. Chem.
Publication Date: 
8/20/2010
Publication Year: 
2010
Pages: 
26406-26416
Volume: 
285
Issue: 
34
ISSN: 
1083-351X
DOI: 
10.1074/jbc.M109.090340
Library Catalog: 
PubMed
Extra: 
PMID: 20530490 PMCID: PMC2924071

Turabian/Chicago Citation

Delphine Cardi, Alexandre Pozza, Bertrand Arnou, Estelle Marchal, Johannes D. Clausen, Jens Peter Andersen, Sanjeev Krishna, Jesper V. Møller, Marc le Maire and Christine Jaxel. 8/20/2010. "Purified E255L mutant SERCA1a and purified PfATP6 are sensitive to SERCA-type inhibitors but insensitive to artemisinins." The Journal of Biological Chemistry 285: 34: 26406-26416. 10.1074/jbc.M109.090340.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1074/jbc.M109.090340 | issn = 1083-351X | volume = 285 | pages = 26406-26416 | last = Cardi | first = Delphine | coauthors = Pozza, Alexandre, Arnou, Bertrand, Marchal, Estelle, Clausen, Johannes D., Andersen, Jens Peter, Krishna, Sanjeev, Møller, Jesper V., le Maire, Marc, Jaxel, Christine | title = Purified E255L mutant SERCA1a and purified PfATP6 are sensitive to SERCA-type inhibitors but insensitive to artemisinins | journal = The Journal of Biological Chemistry | date = 8/20/2010 | pmid = | pmc = }} </ref>