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|標題:||Comparison of Active Sites of Butyrylcholinesterase and Acetylcholinesterase Based on Inhibition by Geometric Isomers of Benzene-di-N-Substituted Carbamates||作者:||Chiou, S.Y.
|關鍵字:||Butyrylcholinesterase;Acetylcholinesterase;Carbamate;Conformation;Inhibitor;structure-reactivity relationships;pancreatic cholesterol esterase;cholinesterases;recognition;mechanism;lipase||Project:||Journal of Biochemical and Molecular Toxicology||期刊/報告no：:||Journal of Biochemical and Molecular Toxicology, Volume 23, Issue 5, Page(s) 303-308.||摘要:||
We have reported that benzene-1,2-,1,3-, and 1,4-di-N-substituted carbamates (1-15) are characterized as the conformationally constrained inhibitors of acetylcholinesterase and mimic gauche, eclipsed, and anti-conformations of acetylcholine, respectively (J Biochein Mol Toxicol 2007;21:348-353). We further report the inhibition of butyrylcholinesterase by these inhibitors. Carbamates 1-15 are also characterized as the pseudosubstrate inhibitors of butyrylcholinesterase as in the acetylcholinesterase catalysis. Benzene-1,4-di-N-n-hexylcarbamate (12) and benzene1,4-di-N-n-octylcarbamate (13) are the two most potent inhibitors of butyrylcholinesterase among inhibitors 1-15. These two para compounds, with the angle of 180 degrees between two C(benzene)-O bonds, mimic the preferable anti C-O/C-N conformers for the choline ethylene backbone of butyrylcholine during the butyrylcholinesterase catalysis. The second n-hexylcarbamyl or n-octylcarbamyl moiety of inhibitors 12 and 13 is proposed to bind tightly to the peripheral anionic site of butyrylcholinesterase from molecular modeling. Butyrylcholinesterase prefers para-carbamates to ortho- and meta-carbamates, whereas acetylcholinesterase prefers para- and meta-carbamates to ortho-carbamates. This result implies that the anionic site of butyrylcholinesterase is relatively smaller than that of acetylcholinesterase because meta-carbamates, which may bind to the anionic sites of both enzymes, are not potent inhibitors of butyrylcholinesterase. (C) 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:303-308, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10:1002/jbt.20286
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