Modeling Thioredoxin Reductase‐Like Activity with Cyclic Selenenyl Sulfides: Participation of an NH⋅⋅⋅Se Hydrogen Bond through Stabilization of the Mixed Se−S Intermediate. Issue 55 (7th August 2019)

• Record Type: Journal Article
• Authors: Arai, Kenta; Matsunaga, Takahiko; Ueno, Haruhito; Akahoshi, Nozomi; Sato, Yuumi; Chakrabarty, Gaurango; Mugesh, Govindasamy; Iwaoka, Michio
• Is Part Of: Chemistry. Volume 25:Issue 55(2019)
• Page Start: 12751
• Page End: 12760
• Publication Date: 2019-08-07
• Subjects: antioxidants -- chalcogens -- enzyme models -- medicinal chemistry -- redox chemistry; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201902230
• Languages: English
• ISSNs: 0947-6539

Abstract

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 H2 O2 ‐induced oxidative stress in cultured cells, which suggests the possibility for medicinal applications to control the redox balance in cells. Abstract : Thioredoxin reductase (TrxR) model : This model study that uses synthetic selenenyl sulfides as a mimic of the TrxR active site comprising C497, U498, and H472 suggests that the basic H472 would accelerate the reduction of the Se−S bond in the catalytic cycle (see scheme). Furthermore, the compounds exhibit a defensive ability against H2 O2 ‐induced oxidative stress in cultured cells, which suggests the possibility for medicinal applications to control a redox balance in cells.