Stochastic Protein Alkylation by Antimalarial Peroxides

Joëlle Jourdan, Annabelle Walz, Hugues Matile, Alexander Schmidt, Jianbo Wu, Xiaofang Wang, Yuxiang Dong, Jonathan L. Vennerstrom, Remo S. Schmidt, Sergio Wittlin, Pascal Mäser

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2067-2075
Number of pages9
JournalACS infectious diseases
Volume5
Issue number12
DOIs
StatePublished - Dec 13 2019

Fingerprint

Peroxides
Antimalarials
Alkylation
Plasmodium falciparum
Proteins
Heme
Parasites
Click Chemistry
Stochastic Processes
Alkynes
Phytochemicals
Proteomics
Digestion
Mass Spectrometry
Hemoglobins
Carbon
artemisinine
1,2,4-trioxane

Keywords

  • Plasmodium falciparum
  • artefenomel
  • artemisinin
  • chemical proteomics
  • malaria
  • ozonide
  • peroxide

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Jourdan, J., Walz, A., Matile, H., Schmidt, A., Wu, J., Wang, X., ... Mäser, P. (2019). Stochastic Protein Alkylation by Antimalarial Peroxides. ACS infectious diseases, 5(12), 2067-2075. https://doi.org/10.1021/acsinfecdis.9b00264

Stochastic Protein Alkylation by Antimalarial Peroxides. / Jourdan, Joëlle; Walz, Annabelle; Matile, Hugues; Schmidt, Alexander; Wu, Jianbo; Wang, Xiaofang; Dong, Yuxiang; Vennerstrom, Jonathan L.; Schmidt, Remo S.; Wittlin, Sergio; Mäser, Pascal.

In: ACS infectious diseases, Vol. 5, No. 12, 13.12.2019, p. 2067-2075.

Research output: Contribution to journalArticle

Jourdan, J, Walz, A, Matile, H, Schmidt, A, Wu, J, Wang, X, Dong, Y, Vennerstrom, JL, Schmidt, RS, Wittlin, S & Mäser, P 2019, 'Stochastic Protein Alkylation by Antimalarial Peroxides', ACS infectious diseases, vol. 5, no. 12, pp. 2067-2075. https://doi.org/10.1021/acsinfecdis.9b00264
Jourdan J, Walz A, Matile H, Schmidt A, Wu J, Wang X et al. Stochastic Protein Alkylation by Antimalarial Peroxides. ACS infectious diseases. 2019 Dec 13;5(12):2067-2075. https://doi.org/10.1021/acsinfecdis.9b00264
Jourdan, Joëlle ; Walz, Annabelle ; Matile, Hugues ; Schmidt, Alexander ; Wu, Jianbo ; Wang, Xiaofang ; Dong, Yuxiang ; Vennerstrom, Jonathan L. ; Schmidt, Remo S. ; Wittlin, Sergio ; Mäser, Pascal. / Stochastic Protein Alkylation by Antimalarial Peroxides. In: ACS infectious diseases. 2019 ; Vol. 5, No. 12. pp. 2067-2075.
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