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7143-09-1Relevant articles and documents
Reaction mechanism for cocaine esterase-catalyzed hydrolyses of (+)- and (-)-cocaine: Unexpected common rate-determining step
Liu, Junjun,Zhao, Xinyun,Yang, Wenchao,Zhan, Chang-Guo
experimental part, p. 5017 - 5025 (2011/06/19)
First-principles quantum mechanical/molecular mechanical free energy calculations have been performed to examine the catalytic mechanism for cocaine esterase (CocE)-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (-)-cocaine. It has been shown that the acylation of (+)-cocaine consists of nucleophilic attack of the hydroxyl group of Ser117 on the carbonyl carbon of (+)-cocaine benzoyl ester and the dissociation of (+)-cocaine benzoyl ester. The first reaction step of deacylation of (+)-cocaine, which is identical to that of (-)-cocaine, is rate-determining, indicating that CocE-catalyzed hydrolyses of (+)- and (-)-cocaine have a common rate-determining step. The computational results predict that the catalytic rate constant of CocE against (+)-cocaine should be the same as that of CocE against (-)-cocaine, in contrast with the remarkable difference between human butyrylcholinesterase-catalyzed hydrolyses of (+)- and (-)-cocaine. The prediction has been confirmed by experimental kinetic analysis on CocE-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (-)-cocaine. The determined common rate-determining step indicates that rational design of a high-activity mutant of CocE should be focused on the first reaction step of the deacylation. Furthermore, the obtained mechanistic insights into the detailed differences in the acylation between the (+)- and (-)-cocaine hydrolyses provide indirect clues for rational design of amino acid mutations that could more favorably stabilize the rate-determining transition state in the deacylation and, thus, improve the catalytic activity of CocE. This study provides a valuable mechanistic base for rational design of an improved esterase for therapeutic treatment of cocaine abuse.
Cocaine catalytic antibodies: The primary importance of linker effects
Matsushita, Masayuki,Hoffman, Timothy Z.,Ashley, Jon A.,Zhou, Bin,Wirsching, Peter,Janda, Kim D.
, p. 87 - 90 (2007/10/03)
Current treatments for cocaine addiction are not effective. The development of a catalytic monoclonal antibody (mAb) provides a strategy for not only binding, but also degrading cocaine, which offers a broad-based therapy. Hapten design is the central element for programming antibody catalysis. The characteristics of the linker used in classic transition-state analogue phosphonate haptens were shown to be important for obtaining mAbs that hydrolyze the benzoate ester of cocaine.
An improved cocaine hydrolase: The A328Y mutant of human butyrylcholinesterase is 4-fold more efficient
Xie, Weihua,Altamirano, Cibby Varkey,Bartels, Cynthia F.,Speirs, Robert J.,Cashman, John R.,Lockridge, Oksana
, p. 83 - 91 (2007/10/03)
Butyrylcholinesterase (BChE) has a major role in cocaine detoxication. The rate at which human BChE hydrolyzes cocaine is slow, with ak(cat) of 3.9 min-1 and K(m) of 14 μM. Our goal was to improve cocaine hydrolase activity by mutating residues near the active site. The mutant A328Y had a k(cat) of 10.2 min-1 and K(m) of 9 μM for a 4-fold improvement in catalytic efficiency (k(cat)/Km). Since benzoylcholine (k(cat) 15,000 min- 1) and cocaine form the same acyl-enzyme intermediate but are hydrolyzed at 4000-fold different rates, it was concluded that a step leading to formation of the acyl-enzyme intermediate was rate-limiting. BChE purified from plasma of cat, horse, and chicken was tested for cocaine hydrolase activity. Compared with human BChE, horse BChE had a 2-fold higher k(cat) but a lower binding affinity, cat BChE was similar to human, and chicken BChE had only 10% of the catalytic efficiency. Naturally occurring genetic variants of human BChE were tested for cocane hydrolase activity. The J and K variants (E497V and A539T) had k(cat) and K(m) values similar to wild type, but because these variants are reduced to 66 and 33% of normal levelsin human blood respectively, people with these variants may be at risk for cocaine toxicity. The atypical variant (D70G) had a 10 fold lower binding affinity for cocaine, suggesting that persons with the atypical variant of BChE may experience severe or fatal cocaine intoxication when administered a dose of cocaine that is not harmful to others.