Computational Design and Crystal Structure of a Highly Efficient Benzoylecgonine Hydrolase
Computational Design and Crystal Structure of a Highly Efficient Benzoylecgonine Hydrolase
复制标题
高效苯甲酰爱康宁水解酶的计算设计和晶体结构
DOI：
10.1002/anie.202108559
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发表时间：
2021-08-27
影响因子：
16.6
通讯作者：
Yao，Jianzhuang
中科院分区：
文献类型：
--
作者：
Chen，Xiabin;Deng，Xingyu;Yao，Jianzhuang
Benzoylecgonine (BZE) is the major toxic metabolite of cocaine and is responsible for the long‐term cocaine‐induced toxicity owing to its long residence time in humans. BZE is also the main contaminant following cocaine consumption. Here, we identified the bacterial cocaine esterase (CocE) as a BZE‐metabolizing enzyme (BZEase), which can degrade BZE into biological inactive metabolites (ecgonine and benzoic acid). CocE was redesigned by a reactant‐state‐based enzyme design theory. An encouraging mutant denoted as BZEase2, presented a >400‐fold improved catalytic efficiency against BZE compared with wild‐type (WT) CocE. In vivo, a single dose of BZEase2 (1 mg kg−1, IV) could eliminate nearly all BZE within only two minutes, suggesting the enzyme has the potential for cocaine overdose treatment and BZE elimination in the environment by accelerating BZE clearance. The crystal structure of a designed BZEase was also determined.
