Affiliation:
1. Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences Tianjin 300308 P.R. China
2. University of Chinese Academy of Sciences 19 A Yuquan Road Beijing 100049 P.R. China
3. School of Pharmacy North Sichuan Medical College Nanchong 637100 P.R. China
4. National Center of Technology Innovation for Synthetic Biology National Engineering Research Center of Industrial Enzymes and Key Laboratory of Engineering Biology for Low-Carbon Manufacturing Tianjin 300308 P.R. China
Abstract
AbstractStrictosidine synthase (STR) catalyzes the Pictet–Spengler (PS) reaction of tryptamine and secologanin to produce strictosidine. Recent studies demonstrated that the enzyme can also catalyze the reaction of non‐natural substrates to form new alkaloid skeletons. For example, the PS condensation of 1H‐indole‐4‐ethanamine with secologanin could be promoted by the STR from Rauvolfia serpentina (RsSTR) to generate a rare class of skeletons with a seven‐membered ring, namely azepino‐[3,4,5‐cd]‐indoles, which are precursors for the synthesis of new compounds displaying antimalarial activity. In the present study, the detailed reaction mechanism of RsSTR‐catalyzed formation of the rare seven‐membered azepino‐indole skeleton through the PS reaction was revealed at the atomic level by quantum chemical calculations. The structures of the transition states and intermediates involved in the reaction pathway were optimized, and the energetics of the complete reaction were analyzed. Based on our calculation results, the most likely pathway of the enzyme‐catalyzed reaction was determined, and the rate‐determining step of the reaction was clarified. The mechanistic details obtained in the present study are important in understanding the promiscuous activity of RsSTR in the formation of the rare azepino‐indole skeleton molecule and are also helpful in designing STR enzymes for the synthesis of other new alkaloid skeleton molecules.
Funder
National Key Research and Development Program of China
Office of Innovation and Improvement
Cited by
1 articles.
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