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Fundamental reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of heroin.

ABSTRACT: The pharmacological function of heroin requires an activation process that transforms heroin into 6-monoacetylmorphine (6-MAM), which is the most active form. The primary enzyme responsible for this activation process in human plasma is butyrylcholinesterase (BChE). The detailed reaction pathway of the activation process via BChE-catalyzed hydrolysis has been explored computationally, for the first time, in this study via molecular dynamics simulation and first-principles quantum mechanical/molecular mechanical free energy calculations. It has been demonstrated that the whole reaction process includes acylation and deacylation stages. The acylation consists of two reaction steps, i.e., the nucleophilic attack on the carbonyl carbon of the 3-acetyl group of heroin by the hydroxyl oxygen of the Ser198 side chain and the dissociation of 6-MAM. The deacylation also consists of two reaction steps, i.e., the nucleophilic attack on the carbonyl carbon of the acyl-enzyme intermediate by a water molecule and the dissociation of the acetic acid from Ser198. The calculated free energy profile reveals that the second transition state (TS2) should be rate-determining. The structural analysis reveals that the oxyanion hole of BChE plays an important role in the stabilization of rate-determining TS2. The free energy barrier (15.9 ± 0.2 or 16.1 ± 0.2 kcal/mol) calculated for the rate-determining step is in good agreement with the experimentally derived activation free energy (~16.2 kcal/mol), suggesting that the mechanistic insights obtained from this computational study are reliable. The obtained structural and mechanistic insights could be valuable for use in the future rational design of a novel therapeutic treatment of heroin abuse.

SUBMITTER: Qiao Y

PROVIDER: S-EPMC3812942 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Fundamental reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of heroin.

Qiao Yan Y Han Keli K Zhan Chang-Guo CG

Biochemistry 20130830 37

The pharmacological function of heroin requires an activation process that transforms heroin into 6-monoacetylmorphine (6-MAM), which is the most active form. The primary enzyme responsible for this activation process in human plasma is butyrylcholinesterase (BChE). The detailed reaction pathway of the activation process via BChE-catalyzed hydrolysis has been explored computationally, for the first time, in this study via molecular dynamics simulation and first-principles quantum mechanical/mole ...[more]

PMID: 23992153

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Project description:Butyrylcholinesterase (BChE)-cocaine binding and the fundamental pathway for BChE-catalyzed hydrolysis of cocaine have been studied by molecular modeling, molecular dynamics (MD) simulations, and ab initio calculations. Modeling and simulations indicate that the structures of the prereactive BChE/substrate complexes for (-)-cocaine and (+)-cocaine are all similar to that of the corresponding prereactive BChE/butyrylcholine (BCh) complex. The overall binding of BChE with (-)-cocaine and (+)-cocaine is also similar to that proposed with butyrylthiocholine and succinyldithiocholine, i.e., (-)- or (+)-cocaine first slides down the substrate-binding gorge to bind to Trp-82 and stands vertically in the gorge between Asp-70 and Trp-82 (nonprereactive complex) and then rotates to a position in the catalytic site within a favorable distance for nucleophilic attack and hydrolysis by Ser-198 (prereactive complex). In the prereactive complex, cocaine lies horizontally at the bottom of the gorge. The fundamental catalytic hydrolysis pathway, consisting of acylation and deacylation stages similar to those for ester hydrolysis by other serine hydrolases, was proposed on the basis of the simulated prereactive complex and confirmed theoretically by ab initio reaction coordinate calculations. Both the acylation and deacylation follow a double-proton-transfer mechanism. The calculated energetic results show that within the chemical reaction process the highest energy barrier and Gibbs free energy barrier are all associated with the first step of deacylation. The calculated ratio of the rate constant (k(cat)) for the catalytic hydrolysis to that (k(0)) for the spontaneous hydrolysis is approximately 9.0 x 10(7). The estimated k(cat)/k(0) value of approximately 9.0 x 10(7) is in excellent agreement with the experimentally derived k(cat)/k(0) value of approximately 7.2 x 10(7) for (+)-cocaine, whereas it is approximately 2000 times larger than the experimentally derived k(cat)/k(0) value of approximately 4.4 x 10(4) for (-)-cocaine. All of the results suggest that the rate-determining step of the BChE-catalyzed hydrolysis of (+)-cocaine is the first step of deacylation, whereas for (-)-cocaine the change from the nonprereactive complex to the prereactive complex is rate-determining and has a Gibbs free energy barrier higher than that for the first step of deacylation by approximately 4 kcal/mol. A further analysis of the structural changes from the nonprereactive complex to the prereactive complex reveals specific amino acid residues hindering the structural changes, providing initial clues for the rational design of BChE mutants with improved catalytic activity for (-)-cocaine.

Dataset Information

Fundamental reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of heroin.

Publications

Fundamental reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of heroin.

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