Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 40, Pages 21959-21965Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202108559
Keywords
benzoylecgonine; CHARMM rotamer force field; cocaine detoxification; enzyme therapy; protein design
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Funding
- National Natural Science Foundation of China [82073749, 81803417]
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BZE, the major toxic metabolite of cocaine, was successfully degraded into inactive metabolites by a redesigned bacterial cocaine esterase. A new mutant, BZEease2, showed significantly improved catalytic efficiency in vivo, potentially useful for cocaine overdose treatment and environmental BZE clearance.
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.
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