Impact of detergents on the activity of acetylcholinesterase and on the effectiveness of its inhibitors.
Acetylcholinesterase (AChE) plays a central role in the development of Alzheimer's disease: AChE inhibition for preventing the characteristic dwindling of acetylcholine levels constitutes the current standard treatment for the disorder. Amongst the diverse risk factors contributing to the degenerative process, high cholesterol causes a reduction in the effectiveness of the otherwise therapeutic inhibitors of AChE. Our biochemical study on the activity of AChE elucidates the effect of amphiphilic molecules on the activity and kinetics of AChE, and sheds light onto the nature of the impact of these amphiphilic molecules on enzyme-inhibitor interactions. Using kinetic studies we discovered that detergents alter the enzymatic activity of AChE through an uncompetitive mechanism. Additional experiments using AChE inhibitors (amphiphilic procaine hydrochloride, hydrophobic tetrabutylammonium bromide) in the absence or presence of detergent further illustrate the detergent-enzyme-solvent interactions. The results contribute to the understanding of the importance of hydrophobic-lipophilic interactions for the correct function of AChE and its inhibitors. We present a model system for the study of lipid-related alterations in the activity of isolated AChE in the central nervous system. This model may also be used to assess and predict the effectiveness of AChE inhibitors, which are traditionally used for the treatment of cognitive impairment, under pathological (high-cholesterol) conditions.
Zimmermann
Martina
M
Institute for the Future of the Mind, Department of Pharmacology, Mansfield Road, Oxford University, Oxford OX1 3QT, UK. martina.zimmermann@em.uni-frankfurt.de
Westwell
Martin S
MS
Greenfield
Susan A
SA
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004593:Electrophorus; D007700:Kinetics; D017830:Octoxynol / Q000494:pharmacology; D012997:Solvents / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D003902:Detergents; D012997:Solvents; D017830:Octoxynol; D000110:Acetylcholinesterase