Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Acetylcholine

Chen, Xi; Fang, Lei; Liu, Junjun; Chen, Zhan

doi:10.1021/jp110709a

Cited by 41 publications

(56 citation statements)

References 56 publications

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“…These values are similar to the corresponding distances in the ES structure for BChE-catalyzed hydrolysis of ACh in our previous study. 47 This is not surprising because the only difference between ACh and ATCh is that the ester oxygen in ACh is replaced by a sulfur atom in ATCh.…”

Section: Resultsmentioning

confidence: 99%

“…40 However, a series of recent studies demonstrated that at a low substrate concentration, hydrolysis of ACh is rate-determined by the acylation reaction, 2, 41, 46 which is consistent with our recently reported study. 47 Despite extensive studies on the catalytic mechanisms of cholinesterase-catalyzed hydrolysis of ACh/ATCh, 1-2, 15, 27-30, 33-34, 36, 38, 48-50 questions remain for the mechanism of the substrate activation for BChE-catalyzed hydrolysis of ACh/ATCh. For example, what is the main factor leading to the observed substrate activation effect?…”

Section: Introductionmentioning

confidence: 99%

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Reaction Pathway and Free Energy Profiles for Butyrylcholinesterase-Catalyzed Hydrolysis of Acetylthiocholine

et al. 2012

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The catalytic mechanism for butyrylcholineserase (BChE)-catalyzed hydrolysis of acetylthiocholine (ATCh) has been studied by performing pseudobond first-principles quantum mechanical/molecular mechanical-free energy (QM/MM-FE) calculations on both acylation and deacylation of BChE. Additional quantum mechanical (QM) calculations have been carried out, along with the QM/MM-FE calculations, to understand the known substrate activation effect on the enzymatic hydrolysis of ATCh. It has been shown that the acylation of BChE with ATCh consists of two reaction steps including the nucleophilic attack on the carbonyl carbon of ATCh and the dissociation of thiocholine ester. The deacylation stage includes nucleophilic attack of a water molecule on the carboxyl carbon of substrate and dissociation between the carboxyl carbon of substrate and hydroxyl oxygen of Ser198 side chain. QM/MM-FE calculation results reveal that the acylation of BChE is rate-determining. It has also been demonstrated that an additional substrate molecule binding to the peripheral anionic site (PAS) of BChE is responsible for the substrate activation effect. In the presence of this additional substrate molecule at PAS, the calculated free energy barrier for the acylation stage (rate-determining step) is decreased by ~1.7 kcal/mol. All of our computational predictions are consistent with available experimental kinetic data. The overall free energy barriers calculated for BChE-catalyzed hydrolysis of ATCh at regular hydrolysis phase and substrate activation phase are ~13.6 and ~11.9 kcal/mol, respectively, which are in reasonable agreement with the corresponding experimentally-derived activation free energies of 14.0 kcal/mol (for regular hydrolysis phase) and 13.5 kcal/mol (for substrate activation phase). .

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reaction Pathway and Free Energy Profiles for Butyrylcholinesterase-Catalyzed Hydrolysis of Acetylthiocholine

et al. 2012

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“…In our previous theoretical studies on cholinesterases, the oxyanion hole is always identified to stabilize the transition state and play a catalytic role in the hydrolysis reaction. 4,29,31,33 Here, we also tracked the changes of the key hydrogen-bond distances between O 1 of 6-MAM and oxyanion hole. As shown in Figure 3, the distance D1 (between the hydrogen of NH group in Gly121 and O 1 of 6-MAM) is elongated from 1.95 Å in ES a to 1.97 Å in TS1 a and then shortened to 1.90 Å in INT1 a , the distance D2 (between the hydrogen of NH group in Gly122 and O 1 of 6-MAM) is elongated from 1.79 Å in ES a to 1.86 Å in TS1 a and then shortened to 1.85 Å in INT1 a , and D3 (between the hydrogen of NH group in Ala204 and O 1 of 6-MAM) is shortened from 2.41 Å in ES a to 2.22 Å in TS1 a and then to 2.12 Å in INT1 a .…”

Section: Resultsmentioning

confidence: 99%

Reaction pathways and free energy profiles for cholinesterase-catalyzed hydrolysis of 6-monoacetylmorphine

2014

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As the most active metabolite of heroin, 6-monoacetylmorphine (6-MAM) can penetrate into the brain for the rapid onset of heroin effects. The primary enzymes responsible for the metabolism of 6-MAM to the less potent morphine in humans are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The detailed reaction pathways for AChE- and BChE-catalyzed hydrolysis of 6-MAM to morphine have been explored, for the first time, in the present study by performing first-principles quantum mechanical/molecular mechanical free energy calculations. It has been demonstrated that the two enzymatic reaction processes follow the similar catalytic reaction mechanism, and the whole catalytic reaction pathway for each enzyme consists of four reaction steps. According to the calculated results, the second reaction step associated with the transition state TS2a/TS2b should be rate-determining for the AChE/BChE-catalyzed hydrolysis, and the free energy barrier calculated for the AChE-catalyzed hydrolysis (18.3 kcal/mol) is 2.5 kcal/mol lower than that for the BChE-catalyzed hydrolysis (20.8 kcal/mol). The free energy barriers calculated for the AChE- and BChE-catalyzed reactions are in good agreement with the experimentally derived activation free energies (17.5 and 20.7 kcal/mol for the AChE- and BChE-catalyzed reactions, respectively). Further structural analysis reveals that the aromatic residues Phe295 and Phe297 in the acyl pocket of AChE (corresponding to Leu286 and Val288 in BChE) contribute to the lower energy of TS2a relative to TS2b. The obtained structural and mechanistic insights could be valuable for use in future rational design of a novel therapeutic treatment of heroin abuse.

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“…42,43 In the present study, we used the modified Gaussian03 program and modified Amber8 program which were developed in our laboratory for the purpose of performing parallel computing in both the QM and MM parts of the QM/MM calculations. 45,46,47,48 …”

Section: Methodsmentioning

confidence: 99%

Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations

Huang

AbdulHameed

et al. 2014

Bioorganic & Medicinal Chemistry

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Molecular dynamics (MD) simulations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations have been perforemd to explore the dynamic behaviors of cytochrome P450 2A6 (CYP2A6) binding with nicotine analogs (that are typical inhibitors) and to calculate their binding free energies in combination with Poisson-Boltzmann surface area (PBSA) calculations. The combined MD simulations and QM/MM-PBSA calculations reveal that the most important structural parameters affecting the CYP2A6-inhibitor binding affinity are two crucial internuclear distances, i.e. the distance between the heme iron atom of CYP2A6 and the coordinating atom of the inhibitor, and the hydrogen-bonding distance between the N297 side chain of CYP2A6 and the pyridine nitrogen of the inhibitor. The combined MD simulations and QM/MM-PBSA calculations have led to dynamic CYP2A6-inhibitor binding structures that are consistent with the observed dynamic behaviors and structural features of CYP2A6-inhibitor binding, and led to the binding free energies that are in good agreement with the experimentally-derived binding free energies. The agreement between the calculated binding free energies and the experimentally-derived binding free energies suggests that the combined MD and QM/MM-PBSA approach may be used as a valuable tool to accurately predict the CYP2A6-inhibitor binding affinities in future computational design of new, potent and selective CYP2A6 inhibitors.

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Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Acetylcholine

Cited by 41 publications

References 56 publications

Reaction Pathway and Free Energy Profiles for Butyrylcholinesterase-Catalyzed Hydrolysis of Acetylthiocholine

Reaction Pathway and Free Energy Profiles for Butyrylcholinesterase-Catalyzed Hydrolysis of Acetylthiocholine

Reaction pathways and free energy profiles for cholinesterase-catalyzed hydrolysis of 6-monoacetylmorphine

Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations

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