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

Arai, K and Matsunaga, T and Ueno, H and Akahoshi, N and Sato, Y and Chakrabarty, G and Mugesh, G and Iwaoka, M (2019) Modeling Thioredoxin Reductase-Like Activity with Cyclic Selenenyl Sulfides: Participation of an NH⋅⋅⋅Se Hydrogen Bond through Stabilization of the Mixed Se−S Intermediate. In: Chemistry - A European Journal, 25 (55). pp. 12751-12760.

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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. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Item Type:	Journal Article
Publication:	Chemistry - A European Journal
Publisher:	Wiley-VCH Verlag
Additional Information:	The copyright for this article belongs to Wiley-VCH Verlag.
Keywords:	Antioxidants; Atoms; Hydrogen bonds; Redox reactions; Sulfur compounds, Active site structure; Chalcogens; Enzyme models; Medicinal applications; Medicinal chemistry; Redox chemistry; Redox-active centers; Thioredoxin reductase, Selenium
Department/Centre:	Division of Chemical Sciences > Inorganic & Physical Chemistry
Date Deposited:	05 Jan 2023 09:34
Last Modified:	05 Jan 2023 09:34
URI:	https://eprints.iisc.ac.in/id/eprint/78784

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