Modeling Thioredoxin Reductase‐Like Activity with Cyclic Selenenyl Sulfides: Participation of an NH⋅⋅⋅Se Hydrogen Bond through Stabilization of the Mixed Se−S Intermediate

Abstract At the redox‐active center of thioredoxin reductase (TrxR), a selenenyl sulfide (Se−S) bond is formed between Cys497 and Sec498, which is activated into the thiolselenolate state ([SH,Se − ]) by reacting with a nearby dithiol motif ([SH Cys59 ,SH Cys64 ]) present in the other subunit. This process is achieved through two reversible steps: an attack of a cysteinyl thiol of Cys59 at the Se atom of the Se−S bond and a subsequent attack of a remaining thiol at the S atom of the generated mixed Se−S intermediate. However, it is not clear how the kinetically unfavorable second step progresses smoothly in the catalytic cycle. A model study that used synthetic selenenyl sulfides, which mimic the active site structure of human TrxR comprising Cys497, Sec498, and His472, suggested that His472 can play a key role by forming a hydrogen bond with the Se atom of the mixed Se−S intermediate to facilitate the second step. In addition, the selenenyl sulfides exhibited a defensive ability against H 2 O 2 ‐induced oxidative stress in cultured cells, which suggests the possibility for medicinal applications to control the redox balance in cells.