Tolrestat acts atypically as a competitive inhibitor of the thermostable aldo-keto reductase Tm1743 from Thermotogamaritima

FEBS Letters

article

Chenyun Zhang¹  Zhenzhen Min¹  Xuemeng Liu¹  Chao Wang¹  Zhiguo Wang¹  Jiejie Shen¹  Wanrong Tang¹  Xin Zhang¹  Dan Liu¹  Xiaoling Xu¹ 

[1] School of Medicine, Hangzhou Normal University;Institute of Cardiovascular Disease Research, The Affiliated Hospital of Hangzhou Normal University

关键词: aldo-ketone reductase;    competitive inhibitor;    diabetes complications;    epalrestat;    tolrestat;   

DOI  :  10.1002/1873-3468.13630

来源: John Wiley & Sons Ltd.

【 摘 要 】

Tolrestat and epalrestat have been characterized as noncompetitive inhibitors of aldo-ketone reductase 1B1 (AKR1B1), a leading drug target for the treatment of type 2 diabetes complications. However, clinical applications are limited for most AKR1B1 inhibitors due to adverse effects of cross-inhibition with other AKRs. Here, we report an atypical competitive binding and inhibitory effect of tolrestat on the thermostable AKR Tm1743 from Thermotoga maritima. Analysis of the Tm1743 crystal structure in complex with tolrestat alone and epalrestat-NADP+ shows that tolrestat, but not epalrestat, binding triggers dramatic conformational changes in the anionic site and cofactor binding pocket that prevents accommodation of NADP+ . Enzymatic and molecular dynamics simulation analyses further confirm tolrestat as a competitive inhibitor of Tm1743.

【 授权许可】

Unknown