Modeling Thioredoxin Reductase-Like Activity with Cyclic Selenenyl Sulfides: Participation of an NH⋅⋅⋅Se Hydrogen Bond through Stabilization of the Mixed Se−S Intermediate |
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Authors: | Dr Kenta Arai Takahiko Matsunaga Haruhito Ueno Nozomi Akahoshi Yuumi Sato Dr Gaurango Chakrabarty Prof Dr Govindasamy Mugesh Prof Dr Michio Iwaoka |
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Institution: | 1. Department of Chemistry, School of Science, Tokai University, Kitalaname, Hiratsuka-shi, Kanagawa, 259-1292 Japan;2. Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, 560012 India |
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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 (SHCys59,SHCys64]) 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 H2O2-induced oxidative stress in cultured cells, which suggests the possibility for medicinal applications to control the redox balance in cells. |
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Keywords: | antioxidants chalcogens enzyme models medicinal chemistry redox chemistry |
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