Role of the Chalcogen (S, Se, Te) in the Oxidation Mechanism of the Glutathione Peroxidase Active Site

Marco Bortoli, Mauro Torsello, F. Matthias Bickelhaupt*, Laura Orian

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


The oxidation by H2O2 of the human phospholipid hydroperoxide glutathione peroxidase (GPx4), used as a model peroxidase selenoenzyme, as well as that of its cysteine (Cys) and tellurocysteine (Tec) mutants, was investigated in silico through a combined classic and quantum mechanics approach to assess the role of the different chalcogens. To perform this analysis, new parameters for selenocysteine (Sec) and tellurocysteine (Tec) were accurately derived for the AMBER ff14SB force field. The oxidation represents the initial step of the antioxidant activity of GPx, which catalyzes the reduction of H2O2 and organic hydroperoxides by glutathione (GSH). A mechanism involving a charge-separation intermediate is feasible for the Cys and Sec enzymes, leading from the initial thiol/selenol form to sulfenic/selenenic acid, whereas for the Tec mutant a direct oxidation pathway is proposed. Activation strain analyses, performed for Cys-GPx and Sec-GPx, provided insight into the rate-accelerating effect of selenium as compared to sulfur and the role of specific amino acids other than Cys/Sec that are typically conserved in the catalytic pocket.

Original languageEnglish
Pages (from-to)2990-2998
Number of pages9
Issue number21
Early online date24 Aug 2017
Publication statusPublished - 3 Nov 2017


  • activation strain analysis
  • density functional calculations
  • enzymes
  • selenium
  • tellurium


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