Decarbamoylation of acetylcholinesterases is markedly slowed as carbamoyl groups increase in size
Document Type
Article
Publication Date
10-1-2018
Abstract
Carbamates are esters of substituted carbamic acids that react with acetylcholinesterase (AChE) by initially transferring the carbamoyl group to a serine residue in the enzyme active site accompanied by loss of the carbamate leaving group followed by hydrolysis of the carbamoyl enzyme. This hydrolysis, or decarbamoylation, is relatively slow, and half-lives of carbamoylated AChEs range from 4 min to more than 30 days. Therefore, carbamates are effective AChE inhibitors that have been developed as insecticides and as therapeutic agents. We show here, in contrast to a previous report, that decarbamoylation rate constants are independent of the leaving group for a series of carbamates with the same carbamoyl group. When the alkyl substituents on the carbamoyl group increased in size from N-monomethyl- to N,N-dimethyl-, N-ethyl-N-methyl-, or N,N-diethyl-, the decarbamoylation rate constants decreased by 4-, 70-, and 800-fold, respectively. We suggest that this relationship arises as a result of active site distortion, particularly in the acyl pocket of the active site. Furthermore, solvent deuterium oxide isotope effects for decarbamoylation decreased from 2.8 for N-monomethylcarbamoyl AChE to 1.1 for N,N-diethylcarbamoyl AChE, indicating a shift in the rate-limiting step from general acid-base catalysis to a likely conformational change in the distorted active site.
Publication Title
Archives of Biochemistry and Biophysics
Volume
655
First Page
67
Last Page
74
Digital Object Identifier (DOI)
10.1016/j.abb.2018.08.006
PubMed ID
30098983
ISSN
00039861
E-ISSN
10960384
Citation Information
Venkatasubban, Johnson, J. L., Thomas, J. L., Fauq, A., Cusack, B., & Rosenberry, T. L. (2018). Decarbamoylation of acetylcholinesterases is markedly slowed as carbamoyl groups increase in size. Archives of Biochemistry and Biophysics, 655, 67–74. https://doi.org/10.1016/j.abb.2018.08.006