Highly Electrophilic Intermediates in the Bypass Mechanism of Glutathione Peroxidase: Synthesis, Reactivity, and Structures of Selenocysteine‐Derived Cyclic Selenenyl Amides

Abstract

AbstractSelenocysteine (Sec)‐derived cyclic selenenyl amides, formed by the intramolecular cyclization of Sec selenenic acids (Sec–SeOHs), have been postulated to function as protective forms in the bypass mechanism of glutathione peroxidase (GPx). However, their chemical properties have not been experimentally elucidated in proteins or small‐molecule systems. Recently, we reported the first nuclear magnetic resonance observation of Sec–SeOHs and their cyclization to the corresponding cyclic selenenyl amides by using selenopeptide model systems incorporated in a molecular cradle. Herein, we elucidate the structures and reactivities of Sec‐derived cyclic selenenyl amides. The crystal structures and reactions toward a cysteine thiol or a 1,3‐diketone‐type chemical probe indicated the highly electrophilic character of cyclic selenenyl amides. This suggests that they can serve not only as protective forms to suppress the inactivation of Sec–SeOHs in GPx but also as highly electrophilic intermediates in the reactions of selenoproteins.