期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 25, 期 55, 页码 12751-12760出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201902230
关键词
antioxidants; chalcogens; enzyme models; medicinal chemistry; redox chemistry
资金
- JSPS-DST Special Lecture Tour Program 2014 under the Japan-India Cooperative Science Program
- JST [SAKURA Exchange Program in Science] [E20150224001]
- JSPS [KAKENHI] [17K18123]
- PMAC for Private School of Japan [The Science Research Promotion Fund]
- Tokai University
- SERB, New Delhi [J.C. Bose National Fellowship] [SB/S2/JCB-067/2015]
- Grants-in-Aid for Scientific Research [17K18123] Funding Source: KAKEN
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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