Abstract
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 language | English |
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Article number | 15 |
Pages (from-to) | 1-9 |
Number of pages | 9 |
Journal | Theoretical Chemistry Accounts |
Volume | 135 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1 2016 |
Bibliographical note
Publisher Copyright:© 2015, Springer-Verlag Berlin Heidelberg.
Keywords
- Catalytic mechanism
- Cocaine
- Enzymatic hydrolysis
ASJC Scopus subject areas
- Physical and Theoretical Chemistry