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Efficient microbial resolution of racemic methyl 3-cyclohexene-carboxylate as chiral precursor of Edoxaban by newly identified Acinetobacter sp. JNU9335
Enzyme and Microbial Technology ( IF 3.4 ) Pub Date : 2020-09-01 , DOI: 10.1016/j.enzmictec.2020.109580
Zhe Dou 1 , Guochao Xu 1 , Ye Ni 1
Affiliation  

Optically active 3-cyclohexene-1-carboxylic acid (CHCA) derivatives are important pharmaceutical intermediates. Due to the special rotatable structure, enantioselective preparation of chiral CHCA is hard to achieve. To identify efficient and enantioselective hydrolases for the biosynthesis of CHCA from methyl 3-cyclohexene-1-carboxylate (CHCM), target-oriented screening from soil samples and gene mining from genome database were explored. All putative hydrolases attempted displayed low enantioselectivity. A hydrolase-producing strain JNU9335 was successfully identified with relatively high enantioselectivity, and was designated as a strain of Acinetobacter sp. according to 16S rDNA sequence and phylogenetic analysis. After optimization, strain JNU9335 could produce 233 U·L‒1 hydrolase with E value of 21. Isooctane/aqueous biphasic system is favorable for the enzymatic resolution of CHCM, the E value of JNU9335 could further be increased to 36. The newly identified JNU9335 could tolerate as high as 1.0 M CHCM, producing (S)-CHCM with ees of 99.6% and isolation yield of 34.7%. This study provides an efficient biocatalyst for the preparation of chiral 3-cyclohexene-1-carboxylic acid derivatives.

中文翻译:

新鉴定的不动杆菌属对作为 Edoxaban 手性前体的外消旋 3-环己烯-羧酸甲酯进行有效的微生物拆分。JNU9335

光学活性 3-环己烯-1-羧酸 (CHCA) 衍生物是重要的医药中间体。由于特殊的可旋转结构,很难实现手性CHCA的对映选择性制备。为了鉴定用于从 3-环己烯-1-羧酸甲酯 (CHCM) 生物合成 CHCA 的高效和对映选择性水解酶,探索了土壤样品的靶向筛选和基因组数据库的基因挖掘。尝试的所有推定水解酶都显示出低对映选择性。以较高的对映选择性成功鉴定出一株产水解酶菌株JNU9335,定为不动杆菌属菌株。根据16S rDNA序列和系统发育分析。优化后菌株JNU9335可产生233个U·L-1水解酶,E值为21。异辛烷/水双相体系有利于 CHCM 的酶解,JNU9335 的 E 值可进一步提高至 36。新鉴定的 JNU9335 可耐受高达 1.0 M CHCM,产生 (S)-CHCM 的 ee 为 99.6%分离收率为34.7%。该研究为制备手性3-环己烯-1-羧酸衍生物提供了一种有效的生物催化剂。
更新日期:2020-09-01
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