工程化亚胺还原酶在手性合成右美沙芬关键中间体中的应用。
Engineered Imine Reductase for Asymmetric Synthesis of Dextromethorphan Key Intermediate.
机构信息
School of Biotechnology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China.
Key Laboratory of Engineering Biology for Low-carbon Manufacturing, National Engineering Research Center of Industrial Enzymes, National Center of Technology Innovation for Synthetic Biology, Tianjin Engineering Research Center of Biocatalytic Technology, and Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.
出版信息
Org Lett. 2024 May 31;26(21):4463-4468. doi: 10.1021/acs.orglett.4c01079. Epub 2024 May 15.
()-1-(4-Methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (()-1-(4-methoxybenzyl)-OHIQ) is the key intermediate of the nonopioid antitussive dextromethorphan. In this study, ()-IR61-V69Y/P123A/W179G/F182I/L212V (M4) was identified with a 766-fold improvement in catalytic efficiency compared with wide-type IR61 through enzyme engineering. M4 could completely convert 200 mM of 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline into ()-1-(4-methoxybenzyl)-OHIQ in 77% isolated yield, with >99% enantiomeric excess and a high space-time yield of 542 g L day, demonstrating a great potential for the synthesis of dextromethorphan intermediate in industrial applications.
()-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉(()-1-(4-甲氧基苄基)-OHIQ)是非阿片类镇咳药右美沙芬的关键中间体。在这项研究中，通过酶工程，发现()-IR61-V69Y/P123A/W179G/F182I/L212V（M4）的催化效率比野生型 IR61 提高了 766 倍。M4 可以在 77%的分离产率下完全将 200mM 的 1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉转化为()-1-(4-甲氧基苄基)-OHIQ，对映体过量大于 99%，时空产率高达 542g L day，这表明它在工业应用中合成右美沙芬中间体具有很大的潜力。
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