Publication: Possible role of the Ca<sup>2+</sup>/Mn<sup>2+</sup> P-type ATPase Pmr1p on artemisinin toxicity through an induction of intracellular oxidative stress
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Issued Date
2019-03-29
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14203049
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2-s2.0-85063758806
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Mahidol University
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SCOPUS
Bibliographic Citation
Molecules. Vol.24, No.7 (2019)
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Onnicha Pongwattanakewin, The Phyu, Suchanya Suesattayapirom, Laran T. Jensen, Amornrat N. Jensen Possible role of the Ca<sup>2+</sup>/Mn<sup>2+</sup> P-type ATPase Pmr1p on artemisinin toxicity through an induction of intracellular oxidative stress. Molecules. Vol.24, No.7 (2019). doi:10.3390/molecules24071233 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/50221
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Possible role of the Ca<sup>2+</sup>/Mn<sup>2+</sup> P-type ATPase Pmr1p on artemisinin toxicity through an induction of intracellular oxidative stress
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Abstract
© 2019 by the authors. Artemisinins are widely used to treat Plasmodium infections due to their high clinical efficacy; however, the antimalarial mechanism of artemisinin remains unresolved. Mutations in P. falciparum ATPase6 (PfATP6), a sarcoplasmic endoplasmic reticulum Ca2+-transporting ATPase, are associated with increased tolerance to artemisinin. We utilized Saccharomyces cerevisiae as a model to examine the involvement of Pmr1p, a functional homolog of PfATP6, on the toxicity of artemisinin. Our analysis demonstrated that cells lacking Pmr1p are less susceptible to growth inhibition from artemisinin and its derivatives. No association between sensitivity to artemisinin and altered trafficking of the drug efflux pump Pdr5p, calcium homeostasis, or protein glycosylation was found in pmr1∆ yeast. Basal ROS levels are elevated in pmr1∆ yeast and artemisinin exposure does not enhance ROS accumulation. This is in contrast to WT cells that exhibit a significant increase in ROS production following treatment with artemisinin. Yeast deleted for PMR1 are known to accumulate excess manganese ions that can function as ROS-scavenging molecules, but no correlation between manganese content and artemisinin resistance was observed. We propose that loss of function mutations in Pmr1p in yeast cells and PfATP6 in P. falciparum are protective against artemisinin toxicity due to reduced intracellular oxidative damage.