title: Unexpected Reaction Pathway for butyrylcholinesterase-catalyzed inactivation of "hunger hormone" ghrelin.
abstract: Extensive computational modeling and simulations have been carried out, in the present study, to uncover the fundamental reaction pathway for butyrylcholinesterase (BChE)-catalyzed hydrolysis of ghrelin, demonstrating that the acylation process of BChE-catalyzed hydrolysis of ghrelin follows an unprecedented single-step reaction pathway and the single-step acylation process is rate-determining. The free energy barrier (18.8 kcal/mol) calculated for the rate-determining step is reasonably close to the experimentally-derived free energy barrier (~19.4 kcal/mol), suggesting that the obtained mechanistic insights are reasonable. The single-step reaction pathway for the acylation is remarkably different from the well-known two-step acylation reaction pathway for numerous ester hydrolysis reactions catalyzed by a serine esterase. This is the first time demonstrating that a single-step reaction pathway is possible for an ester hydrolysis reaction catalyzed by a serine esterase and, therefore, one no longer can simply assume that the acylation process must follow the well-known two-step reaction pathway.
authors.affiliation: Molecular Modeling and Biopharmaceutical Center and College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.|Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
authors.forename: Jianzhuang
authors.initials: J
authors.lastname: Yao
authors.affiliation: Molecular Modeling and Biopharmaceutical Center and College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.|Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
authors.forename: Yaxia
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Molecular Modeling and Biopharmaceutical Center and College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.|Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Molecular Modeling and Biopharmaceutical Center and College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.|Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
mesh_terms: D000215:Acylation; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism*; D002384:Catalysis; D054439:Ghrelin / Q000737:chemistry* / Q000378:metabolism*; D006868:Hydrolysis; D053858:Metabolic Networks and Pathways; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding
chemical_list: D054439:Ghrelin; D002091:Butyrylcholinesterase