丁丙诺啡
去甲基化
钥匙(锁)
化学
酶
组合化学
有机化学
计算机科学
生物化学
计算机安全
基因
基因表达
受体
DNA甲基化
类阿片
作者
Alexandra Carvalho,Daniel F. A. R. Dourado,Jennifer Spratt,Jill Caswell,Timofey Skvortsov,Derek J. Quinn,John Carey,Thomas S. Moody
标识
DOI:10.1021/acs.oprd.3c00417
摘要
Benzylisoquinoline alkaloids are valuable active ingredients in medicines that are typically extracted from plants and subsequently derivatized. Buprenorphine is a member of this family of compounds and is an effective analgesic and is also used for the treatment of opioid use disorder. The commercial route of synthesis for buprenorphine starts from thebaine and uses toxic reagents and harsh reaction conditions for the N- and O-demethylation steps. Here, we propose an alternative approach for buprenorphine synthesis via enzymatic N- and O-demethylation reactions. Utilizing rational enzyme design and directed evolution, we identified and engineered two oxygenase enzymes. For the N-demethylation reaction, the best variant achieved a cumulative improvement in conversion of 567-fold, while for the O-demethylation, the best variant achieved 22-fold cumulative improvement in conversion. A separate variant was able to efficiently catalyze both the N-demethylation and the O-demethylation reactions.
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