Reaction pathway for cocaine hydrolase-catalyzed hydrolysis of (+)-cocaine

Yuan Yao, Junjun Liu, Fang Zheng, Chang Guo Zhan

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2 Scopus citations


A recently designed and discovered cocaine hydrolase (CocH), engineered from human butyrylcholinesterase, has been proven promising as a novel enzyme therapy for treatment of cocaine overdose and addiction because it is highly efficient in catalyzing hydrolysis of naturally occurring (−)-cocaine. It has been known that the CocH also has a high catalytic efficiency against (+)-cocaine, a synthetic enantiomer of cocaine. Reaction pathway and the corresponding free energy profile for the CocH-catalyzed hydrolysis of (+)-cocaine have been determined, in the present study, by performing first-principles pseudobond quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations. According to the QM/MM-FE results, the catalytic hydrolysis process is initiated by the nucleophilic attack on carbonyl carbon of (−)-cocaine benzoyl ester via hydroxyl oxygen of S198 side chain, and the second reaction step (i.e., dissociation of benzoyl ester) is rate-determining. This finding for CocH-catalyzed hydrolysis of (+)-cocaine is remarkably different from that for the (+)-cocaine hydrolysis catalyzed by bacterial cocaine esterase in which the first reaction step of the deacylation is associated with the highest free energy barrier (~17.9 kcal/mol). The overall free energy barrier (~16.0 kcal/mol) calculated for the acylation stage of CocH-catalyzed hydrolysis of (+)-cocaine is in good agreement with the experimental free energy barrier of ~14.5 kcal/mol derived from the experimental kinetic data.

Original languageEnglish
Article number15
Pages (from-to)1-9
Number of pages9
JournalTheoretical Chemistry Accounts
Issue number1
StatePublished - Jan 1 2016

Bibliographical note

Publisher Copyright:
© 2015, Springer-Verlag Berlin Heidelberg.


  • Catalytic mechanism
  • Cocaine
  • Enzymatic hydrolysis

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry


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