ArticleJournal of chemical theory and computation2012
Reaction Pathway and Free Energy Profile for Cocaine Hydrolase-Catalyzed Hydrolysis of (-)-Cocaine.
Article in Journal of chemical theory and computation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 27 citations in OpenAlex.
- Catalytic Reaction Mechanism for Drug Metabolism in Human Carboxylesterase-1: Cocaine Hydrolysis Pathway.Molecular pharmaceutics · 2018Article
- Catalytic Mechanisms for Cofactor-Free Oxidase-Catalyzed Reactions: Reaction Pathways of Uricase-Catalyzed Oxidation and Hydration of Uric Acid.ACS catalysis · 2017Article
- Free energy profiles of cocaine esterase-cocaine binding process by molecular dynamics and potential of mean force simulations.Chemico-biological interactions · 2016Article
- Unexpected Reaction Pathway for butyrylcholinesterase-catalyzed inactivation of "hunger hormone" ghrelin.Scientific reports · 2016Article
- Reaction Pathway for Cocaine Hydrolase-Catalyzed Hydrolysis of (+)-Cocaine.Theoretical chemistry accounts · 2016Article
- Fundamental reaction pathway and free energy profile of proteasome inhibition by syringolin A (SylA).Organic & biomolecular chemistry · 2015Article
- Kinetic characterization of a cocaine hydrolase engineered from mouse butyrylcholinesterase.The Biochemical journal · 2015Article
- Fundamental reaction pathway for peptide metabolism by proteasome: insights from first-principles quantum mechanical/molecular mechanical free energy calculations.The journal of physical chemistry. B · 2013Article
- Fundamental reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of heroin.Biochemistry · 2013Article
- Reaction pathway and free energy profile for papain-catalyzed hydrolysis of N-acetyl-Phe-Gly 4-nitroanilide.Biochemistry · 2013Article
- Catalytic activities of a cocaine hydrolase engineered from human butyrylcholinesterase against (+)- and (-)-cocaine.Chemico-biological interactions · 2013Article
- Catalytic mechanism of cytochrome P450 for N-methylhydroxylation of nicotine: reaction pathways and regioselectivity of the enzymatic nicotine oxidation.Dalton transactions (Cambridge, England : 2003) · 2013Article
- Fundamental reaction pathway and free energy profile for inhibition of proteasome by Epoxomicin.Journal of the American Chemical Society · 2012Article
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Authors and funding
2 authors at 1 institution in 2 countries.
Funding
Abstract
Reaction pathway of (-)-cocaine hydrolysis catalyzed by our recently discovered most efficient cocaine hydrolase, which is the A199S/F227A/S287G/A328W/Y332G mutant of human butyrylcholinesterase (BChE), and the corresponding free energy profile have been studied by performing first-principles pseudobond quantum mechanical/molecular mechanical (QM/MM)-free energy (FE) calculations. Based on the QM/MM-FE results, the catalytic hydrolysis process consists of four major reaction steps, including the nucleophilic attack on carbonyl carbon of (-)-cocaine benzoyl ester by hydroxyl group of S198, dissociation of (-)-cocaine benzoyl ester, nucleophilic attack on carbonyl carbon of (-)-cocaine benzoyl ester by water, and finally the dissociation between (-)-cocaine benzoyl group and S198 of the enzyme. The second reaction step is rate-determining. The calculated free energy barrier associated with the transition state for the rate-determining step is ~15.0 kcal/mol, which is in excellent agreement with the experimentally-derived activation free energy of ~14.7 kcal/mol. The mechanistic insights obtained from the present study will be valuable for rational design of more active cocaine hydrolase against (-)-cocaine. In particular, future efforts aiming at further increasing the catalytic activity of the enzyme against (-)-cocaine should focus on stabilization of the transition state for the second reaction step in which the benzoyl ester of (-)-cocaine dissociates.
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