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標題: Structure-reactivity relationships as probes to acetylcholinesterase inhibition mechanisms by aryl carbarnates. I. Steady-state kinetics
作者: Lin, G.L.
Lai, C.Y.
Liao, W.C.
關鍵字: acetylcholinesterase inhibition;LFER;QSAR;aryl carbarnates;enzyme;mechanism;pancreatic cholesterol esterase;active-site gorge;molecular;recognition;alzheimer-type;binding;butyrylcholinesterase;cholinesterases;carbamate;substrate;dementia
Project: Journal of the Chinese Chemical Society
期刊/報告no:: Journal of the Chinese Chemical Society, Volume 50, Issue 6, Page(s) 1259-1265.
From enzyme kinetics, 4-nitrophenyl-N-substituted carbamates 1 are characterized as pseudo-substrate inhibitors of acetylcholinesterase. However, the activity of the carbamyl enzyme does not recover in the presence of a competitive inhibitor, edrophonium. Therefore, carbamates 1 should be called as the "pseudo-pseudo-substrate" inhibitors of the enzyme. Moreover, the -logK(i), logk(c), and logk(i) values are linearly correlated with Taft-Ingold equation, log (k/k(o)) = rho*sigma* + delta E-s. A three-step AChE inhibition mechanism by carbamates 1 is proposed. The first step is the pre-equilibrium protonations of carbamates 1 with rho* value of -1.4 from pK(a)-sigma*-correlation. The second step is the enzyme-carbamates 1 tetrahedral intermediate formation from nucleophilic attack of the active site Ser200 on the protonated carbamates 1. The rho* value for the -logK(i)-sigma*-E-s-correlation indicates that the true rho* value for the second step is 0.5 [= -0.9 - (-1.4)]. The delta value of 0.56 for the -logK(i)-sigma*-E-s-correlation indicates that carbamates 1 with bulky substituents retarded the formation of enzyme-inhibitor tetrahedral intermediates. The third step (k(c) step) is the carbamylation step and is the carbamyl enzyme conjugate formation from the enzyme-carbamates 1 tetrahedral intermediate. The rho* value of 0.21 for the logk(c)-correlation indicates that the transition state for the carbamylation step is more negative charge than the enzyme-carbamates 1 tetrahedral intermediate. Moreover, the k(c) step is insensitive to substituent effects since there is a cancellation of electronic demands for bond-making and bond-breaking components, like S(N)2 reactions. The delta value of 0.00 for the logk(c)-correlation indicates that the k(c) step is independent of substituent steric effect. Therefore, the product of this step carbamyl enzyme conjugate is as crowded as the enzyme-carbamates 1 tetrahedral intermediate and is likely bound to the leaving group, p-nitrophenol.
ISSN: 0009-4536
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