Reaction pathway and free energy profile for butyrylcholinesterase- catalyzed hydrolysis of acetylcholine

Xi Chen, Lei Fang, Junjun Liu, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

A catalytic mechanism for the butyrylcholinesterase (BChE)-catalyzed hydrolysis of acetylcholine (ACh) has been studied by performing pseudobond first-principles quantum mechanical/molecular mechanical-free energy calculations on both acylation and deacylation of BChE. It has been shown that the acylation with ACh includes two reaction steps, including nucleophilic attack on the carbonyl carbon of ACh and dissociation of choline ester. The deacylation stage includes nucleophilic attack of a water molecule on the carboxyl carbon of the substrate and dissociation between the carboxyl carbon of the substrate and the hydroxyl oxygen of the Ser198 side chain. Notably, despite the fact that acetylcholinesterase (AChE) and BChE are very similar enzymes, the acylation of BChE with ACh is rate-determining, which is remarkably different from the AChE-catalyzed hydrolysis of ACh, in which the deacylation is rate-determining. The computational prediction is consistent with available experimental kinetic data. The overall free energy barrier calculated for BChE-catalyzed hydrolysis of ACh is 13.8 kcal/mol, which is in good agreement with the experimentally derived activation free energy of 13.3 kcal/mol.

Original languageEnglish
Pages (from-to)1315-1322
Number of pages8
JournalJournal of Physical Chemistry B
Volume115
Issue number5
DOIs
StatePublished - Feb 10 2011

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Fingerprint

Dive into the research topics of 'Reaction pathway and free energy profile for butyrylcholinesterase- catalyzed hydrolysis of acetylcholine'. Together they form a unique fingerprint.

Cite this