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

2015; Elsevier BV; Volume: 87; Linguagem: Inglês

10.1016/j.freeradbiomed.2015.06.011

1873-4596

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

Redox biology and oxidative stress

Glutathione peroxidases (GPxs) are enzymes working with either selenium or sulfur catalysis. They adopted diverse functions ranging from detoxification of H2O2 to redox signaling and differentiation. The relative stability of the selenoenzymes, however, remained enigmatic in view of the postulated involvement of a highly unstable selenenic acid form during catalysis. Nevertheless, density functional theory calculations obtained with a representative active site model verify the mechanistic concept of GPx catalysis and underscore its efficiency. However, they also allow that the selenenic acid, in the absence of the reducing substrate, reacts with a nitrogen in the active site. MS/MS analysis of oxidized rat GPx4 complies with the predicted structure, an 8-membered ring, in which selenium is bound as selenenylamide to the protein backbone. The intermediate can be re-integrated into the canonical GPx cycle by glutathione, whereas, under denaturing conditions, its selenium moiety undergoes β-cleavage with formation of a dehydro-alanine residue. The selenenylamide bypass prevents destruction of the redox center due to over-oxidation of the selenium or its elimination and likely allows fine-tuning of GPx activity or alternate substrate reactions for regulatory purposes.