Selenocysteine oxidation in glutathione peroxidase catalysis: an MS-supported quantum mechanics study

Orian, Laura; Mauri, Pierluigi; Roveri, Antonella; Toppo, Stefano; Benazzi, Louise; Bosello-Travain, Valentina; Palma, Antonella De; Maiorino, Matilde; Miotto, Giovanni; Zaccarin, Mattia; Polimeno, Antonino; Flohé, Leopold; Ursini, Fulvio

doi:10.1016/j.freeradbiomed.2015.06.011

Cited by 113 publications

(125 citation statements)

References 69 publications

(102 reference statements)

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“…An analogous mechanism (Scheme ) can be postulated for the sulfur mutant (Cys‐GPx), the antioxidant activity of which is lower than that of Sec‐GPx . Recent mechanistic studies, based on DFT calculations on a cluster of seven amino acids forming the catalytic site of GPx, revealed that an identical mechanism could indeed be invoked to explain the enzymatic activities of Cys‐GPx and Sec‐GPx, and the different energetics (barriers and stabilities of intermediates) along the reaction path showed that the presence of selenium was rate accelerating . Pioneering mechanistic investigations of Sec‐GPx were conducted by Morokuma and co‐workers, who used pure quantum mechanical methods on a simplified model cluster based on human GPx3 and used a hybrid quantum mechanics/molecular mechanics (QM/MM) scheme on the whole enzyme .…”

Section: Introductionmentioning

confidence: 99%

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

Bortoli

Torsello²,

Bickelhaupt

et al. 2017

ChemPhysChem

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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.

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Section: Introductionmentioning

confidence: 99%

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

Bortoli

Torsello²,

Bickelhaupt

et al. 2017

ChemPhysChem

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“…Related chemistry occurs with selenocysteine-containing glutathione peroxidases, where the selenocysteine takes the place of one of the Cys residues, and is particularly reactive as it is present in its ionized (RSe − ) form due to the much lower pK a of Sec (~ 4.8; [22]) compared to 8-9 for most thiols. The catalytic activity of this enzyme has been thoroughly investigated, with the reaction of the active site RSe − (or RS − , in the case of Cys-containing species) with ROOH, occurring simultaneously with the protonation of the leaving group by a neighboring, proton-donating amino acid [23] as in reaction 1. The rate constant for this enzymatically catalyzed first step is ~ 10 7 M −1 s −1 or approximately a million times faster than for the thiolate of free Cys at pH 7.…”

Section: Reversible Cysteine Oxidation In Redox Signaling In Cellsmentioning

confidence: 99%

Protein cysteine oxidation in redox signaling: Caveats on sulfenic acid detection and quantification

Forman

Davies

Krämer

et al. 2017

Archives of Biochemistry and Biophysics

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Oxidation of critical signaling protein cysteines regulated by H2O2 has been considered to involve sulfenic acid (RSOH) formation. RSOH may subsequently form either a sulfenyl amide (RSNHR’) with a neighboring amide, or a mixed disulfide (RSSR’) with another protein cysteine or glutathione. Previous studies have claimed that RSOH can be detected as an adduct (e.g., with 5,5-dimethylcyclohexane-1,3-dione; dimedone). Here, kinetic data are discussed which indicate that few proteins can form RSOH under physiological signaling conditions. We also present experimental evidence that indicates that (1) dimedone reacts rapidly with sulfenyl amides, and more rapidly than with sulfenic acids, and (2) that disulfides can react reversibly with amides to form sulfenyl amides. As some proteins are more stable as the sulfenyl amide than as a glutathionylated species, the former may account for some of the species previously identified as the “sulfenome” - the cellular complement of reversibly-oxidized thiol proteins generated via sulfenic acids.

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“…This accounts for a much higher reaction rate with electrophiles, which in selenoproteins can reach a 10 7 times faster rate than that of free cysteine and also makes a thiol (selenol)/disulfide (selenylsulfide) exchange extremely fast (8). Of course, this pronounced nucleophilicity of Sec predisposes selenoproteins for redox reactions, which, as meanwhile amply exemplified, are not always meant to cope with oxidative stress.…”

Section: What Makes Selenoproteins So Unique?mentioning

confidence: 99%

“…In this respect, the evolving versatility of selenium catalysis reminds of the name-giving goddess, Selene, who loved to surprise with her mysterious abilities (4). The most recent surprise was the discovery of selenium taking an out time from catalytic cycling in GPx (8). In the absence of reducing substrate, the selenium adopts a resting position in the form of a selenenylamide bond and keeps sleeping until it is woken up by a prince's kiss: by its favored thiol substrate.…”

Section: What Makes Selenoproteins So Unique?mentioning

confidence: 99%

The Evolving Versatility of Selenium in Biology

Brigelius‐Flohé

2015

Antioxidants & Redox Signaling

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This editorial shortly summarizes the highlights described in the Forum, novelties about selenoproteins. Two articles describe the selenoprotein biosynthesis and the role of so far identified proteins involved, including that of selenocysteine-β-lyase, which also may link selenoproteins to energy metabolism. Novel and, in part, unexpected functions are reviewed. Thioredoxin reductase 1 (TrxR1) can change from an anti- to a pro-oxidant and appears to be involved in the regulation of the Nrf2/Keap1 system. Methionine sulfoxide reductase B1 (MsrB1) catalyzes a novel posttranslational protein modification. The membrane proteins, Sel K,S,T,N, and I, form selenylsulfide bonds leading to the formation and stabilization of protein complexes required for protein trafficking. By this mechanism, selenoprotein K (SelK) supports palmitoylation of membrane-associated proteins. Thus, selenium and selenoproteins obviously have functions by far exceeding that of counteracting oxidative stress and even also catalyzing oxidoreductive processes.

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Selenocysteine oxidation in glutathione peroxidase catalysis: an MS-supported quantum mechanics study

Cited by 113 publications

References 69 publications

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

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

Protein cysteine oxidation in redox signaling: Caveats on sulfenic acid detection and quantification

The Evolving Versatility of Selenium in Biology

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