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Oxidation reactivity of zinc–cysteine clusters in metallothionein

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Abstract

Evaluating the reactivity of the metal–thiolate clusters in metallothionein (MT) is a key step in understanding the biological functions of this protein. The effects of the metal clustering and protein environment on the thiolate reactivity with hydrogen peroxide (H2O2) were investigated by performing quantum theory calculations with chemical accuracy at two levels of complexity. At the first level, the reactivity with H2O2 of a model system ([(Zn)3(MeS)9]3−, MeS is methanethiolate) of the β domain cluster of MT was evaluated using density functional theory (DFT) with the mPW1PW91 functional. At the second level of complexity, the protein environment was included in the reactant system and the calculations were performed with the hybrid ONIOM method combining the DFT–mPW1PW91 and the semiempirical PM6 levels of theory. In these conditions, the energy barrier for the oxidation of the most reactive terminal thiolate was 21.5 kcal mol−1. This is 3 kcal mol−1 higher than that calculated for the terminal thiolate in the model system [(Zn)3(MeS)9]3− and about 7 kcal mol−1 higher than that obtained for the free thiolate. In spite of this rise of the energy barrier induced by the protein environment, the thiolate oxidation by H2O2 is confirmed as a possible way for metal release from MT. On the other hand, the results suggest that the antioxidant role of MT in the living cell cannot be as important as that of glutathione (which bears a free thiol).

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Acknowledgments

Calculations were conducted largely with the supercomputer facility at the Mésocentre, a regional computational center at the University of Franche-Comté.

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Authors and Affiliations

  1. Centre de Recherche Universitaire de Djibouti, University of Djibouti, Avenue Georges Clemenceau, Djibouti, Djibouti

    Rima Kassim

  2. Laboratoire de Nanomédecine, Imagerie et Thérapeutique EA 4662, University of Franche-Comté, CHU Besançon, 25030, Besançon Cedex, France

    Christophe Ramseyer

  3. Laboratoire Chrono Environnement UMR CNRS 6249, University of Franche-Comté, 16 route de Gray, 25030, Besançon Cedex, France

    Mironel Enescu

Authors
  1. Rima Kassim
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  2. Christophe Ramseyer
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Correspondence to Mironel Enescu.

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Kassim, R., Ramseyer, C. & Enescu, M. Oxidation reactivity of zinc–cysteine clusters in metallothionein. J Biol Inorg Chem 18, 333–342 (2013). https://doi.org/10.1007/s00775-013-0977-5

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  • DOI: https://doi.org/10.1007/s00775-013-0977-5

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