ArticleJournal of the American Chemical Society2009
Fundamental reaction mechanism and free energy profile for (-)-cocaine hydrolysis catalyzed by cocaine esterase.
Article in Journal of the American Chemical Society, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32 citing papers in PubMed, 55 citations in OpenAlex.
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- Characterization and engineering of a two-enzyme system for plastics depolymerization.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Catalytic Hydrolysis Mechanism of Cocaine by Human Carboxylesterase 1: An Orthoester Intermediate Slows Down the Reaction.Molecules (Basel, Switzerland) · 2019Article
- 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
- Rational design, preparation, and characterization of a therapeutic enzyme mutant with improved stability and function for cocaine detoxification.ACS chemical biology · 2014Article
- Reaction pathways and free energy profiles for cholinesterase-catalyzed hydrolysis of 6-monoacetylmorphine.Organic & biomolecular chemistry · 2014Article
- Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations.Bioorganic & medicinal chemistry · 2014Article
- A highly efficient cocaine-detoxifying enzyme obtained by computational design.Nature communications · 2014Article
- 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
- Density functional theory investigation of cocaine water complexes.Journal of molecular modeling · 2013Article
- Reaction pathway and free energy profile for papain-catalyzed hydrolysis of N-acetyl-Phe-Gly 4-nitroanilide.Biochemistry · 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
- Article
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
The fundamental reaction mechanism of cocaine esterase (CocE)-catalyzed hydrolysis of (-)-cocaine and the corresponding free energy profile have been studied by performing pseudobond first-principles quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations. On the basis of the QM/MM-FE results, the entire hydrolysis reaction consists of four reaction steps, including the nucleophilic attack on the carbonyl carbon of (-)-cocaine benzoyl ester by the hydroxyl group of Ser117, dissociation of (-)-cocaine benzoyl ester, nucleophilic attack on the carbonyl carbon of (-)-cocaine benzoyl ester by water, and finally dissociation between the (-)-cocaine benzoyl group and Ser117 of CocE. The third reaction step involving the nucleophilic attack of a water molecule was found to be rate-determining, which is remarkably different from (-)-cocaine hydrolysis catalyzed by wild-type butyrylcholinesterase (BChE; where the formation of the prereactive BChE-(-)-cocaine complex is rate-determining) or its mutants containing Tyr332Gly or Tyr332Ala mutation (where the first chemical reaction step is rate-determining). Besides, the role of Asp259 in the catalytic triad of CocE does not follow the general concept of the "charge-relay system" for all serine esterases. The free energy barrier calculated for the rate-determining step of CocE-catalyzed hydrolysis of (-)-cocaine is 17.9 kcal/mol, which is in good agreement with the experimentally derived activation free energy of 16.2 kcal/mol. In the present study, where many sodium ions are present, the effects of counterions are found to be significant in determining the free energy barrier. The finding of the significant effects of counterions on the free energy barrier may also be valuable in guiding future mechanistic studies on other charged enzymes.
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