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Stochastic protein alkylation by antimalarial peroxides

Jourdan, Joëlle and Walz, Annabelle and Matile, Hugues and Schmidt, Alexander and Wu, Jianbo and Wang, Xiaofang and Dong, Yuxiang and Vennerstrom, Jonathan L. and Schmidt, Remo S. and Wittlin, Sergio and Mäser, Pascal. (2019) Stochastic protein alkylation by antimalarial peroxides. ACS infectious diseases, 5 (12). pp. 2067-2075.

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Official URL: https://edoc.unibas.ch/73645/

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Abstract

Antimalarial peroxides such as the phytochemical artemisinin or the synthetic ozonides arterolane and artefenomel undergo reductive cleavage of the pharmacophoric peroxide bond by ferrous heme, released by parasite hemoglobin digestion. The generated carbon-centered radicals alkylate heme in an intramolecular reaction and proteins in an intermolecular reaction. Here, we determine the proteinaceous alkylation signatures of artemisinin and synthetic ozonides in; Plasmodium falciparum; using alkyne click chemistry probes to identify target proteins by affinity purification and mass spectrometry-based proteomics. Using stringent controls and purification procedures, we identified 25; P. falciparum; proteins that were alkylated by the antimalarial peroxides in a peroxide-dependent manner, but the alkylation patterns were more random than we had anticipated. Moreover, there was little overlap in the alkylation signatures identified in this work and those disclosed in previous studies. Our findings suggest that alkylation of parasite proteins by antimalarial peroxides is likely to be a nonspecific, stochastic process.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Jourdan, Joëlle and Walz, Annabelle and Schmidt, Remo and Wittlin, Sergio and Mäser, Pascal
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:ACS Publications
ISSN:2373-8227
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:03 Mar 2020 16:07
Deposited On:03 Mar 2020 16:07

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