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

Abstract

The oxidation by H O 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 H O 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.

Major Depressive Disorder and Oxidative Stress: In Silico Investigation of Fluoxetine Activity against ROS

“…Computational methodologies are nowadays largely employed to rationalize chemical and biochemical phenomena. Particularly, accurate mechanistic studies on the control of oxidative stress by endogenous defenses, including enzymes such as glutathione peroxidase [30][31][32], and molecular drugs that act as mimics of these enzymes [33][34][35][36][37] or as radical scavengers [38] have been reported by some of us. In this work, we investigate in silico the antioxidant activity of fluoxetine via HAT (hydrogen atom transfer) and RAF (radical adduct formation) mechanisms.…”

Organodiselenides: Organic Catalysis and Drug Design Learning from Glutathione Peroxidase

“…This suggests that in the GPx catalytic site, selenium is protected by the surrounding residues which prevent the attack of the second GSH as well as the formation of a bulky three-center intermediate; (iii) notably, when comparing S -+ SSe and S -+ STe, both proceeding via S N 2 mechanism in water, the activation energy slightly increases by around 1.5 kcal mol -1 , a result which is not promising for the design and employment of Tec-GPx. Other disadvantages of the Te mutant in the oxidative step of the GPx cycle have been very recently reported [17]. In this context, it is worth to mention the computational study by Bayse about the GPx-like mechanism of phenylselenol [203].…”

“…In contrast, tellurium, which has no biological role, is neatly different being actually a metalloid. Some of us have recently assessed that indeed the presence of Tec in the GPx implies a different mechanism for the reduction of a hydroperoxide [17]. The study of small organochalcogenides is fundamental because they might have direct application in pharmacology.…”

Rongalite‐Promoted on Water Synthesis of Functionalised Tellurides and Ditellurides

“…In addition, the promising catalytic and pharmacological properties of O‐ and N‐containing organochalcogenides have prompted researchers to design and synthesise novel functionalised organochalcogenides . Suitably substituted β‐hydroxy‐ and β‐amino‐ tellurides were demonstrated to be excellent mimics of GPx and also exhibited remarkable activity as carbonic anhydrase activators and inhibitors…”