増田 涼介

Although much attention has been paid to chemical elucidation of the catalytic cycle of glutathione peroxidase (GPx), it has been hampered by instability of selenocysteine selenenic acid (Sec–SeOH) intermediates. In this study, not only chemical processes of the canonical catalytic cycle but also those involved in the bypass mechanism, including the intramolecular cyclization of a Sec–SeOH to the corresponding five-membered ring selenenyl amide were demonstrated experimentally by utilizing selenopeptide model systems in which reactive intermediates can be stabilized by a nano-sized molecular cradle. The resulting cyclic selenenyl amide exhibited higher durability under oxidative conditions than in the state of a Sec–SeOH, corroborating its role as the protective form of GPx. The cyclization of Sec–SeOHs of the Sec-Gly-Thr and Sec-Gly-Lys models, which mimic the catalytic site of isozymes GPx1 and GPx4, respectively, was found to proceed at lower temperature than in the Sec-Gly-Gly model, which corresponds to the generalized form of the tripeptides in the catalytic site of GPx. The role of the hydrogen-bond accepting moieties in the cyclization process was elucidated by DFT calculation. It was indicated that, if the selenocysteine centers are incorporated in appropriate microenvironments, the bypass mechanism can function efficiently.