School of Science, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8551, Japan.
Chemistry. 2023 Dec 19;29(71):e202302615. doi: 10.1002/chem.202302615. Epub 2023 Oct 31.
Selenocysteine (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.
硒代半胱氨酸（Sec）衍生的环硒代酰胺，由 Sec 亚硒酸（Sec-SeOH）的分子内环化形成，被假定为谷胱甘肽过氧化物酶（GPx）旁路机制中的保护形式。然而，它们在蛋白质或小分子系统中的化学性质尚未通过实验阐明。最近，我们使用包含在分子摇篮中的硒肽模型系统，首次通过核磁共振观察到 Sec-SeOH 及其环化成相应的环硒代酰胺。在此，我们阐明了 Sec 衍生的环硒代酰胺的结构和反应性。晶体结构和对半胱氨酸巯基或 1,3-二酮型化学探针的反应表明，环硒代酰胺具有高亲电性。这表明它们不仅可以作为保护形式来抑制 GPx 中 Sec-SeOH 的失活，而且可以作为硒蛋白反应中的高亲电性中间体。
