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|標題:||Structure-reactivity relationships as probes for the inhibition mechanism of cholesterol esterase by aryl carbamates. I. Steady-state kinetics||作者:||Lin, G.L.
|關鍵字:||enzyme kinetics;cholesterol esterase;structure-reactivity;relationship;linear free energy relationship;salt-stimulated lipase;phospholipase a(2);para-nitrophenyl;hammett;analysis;hydrolysis;absorption;site;acid;rat;acetylcholinesterase||Project:||Journal of the Chinese Chemical Society||期刊/報告no：:||Journal of the Chinese Chemical Society, Volume 47, Issue 3, Page(s) 489-500.||摘要:||
For substituted phenyl-N-butyl carbamates(1) and 4-nitrophenyl-N-substituted carbamates (2), linear relationships between values of NH proton chemical shift (delta(NH)). pKa, and logk([OH]) and Hammett substituent constant (sigma) or Taft substituent constant (sigma*) are observed. Carbamates 1 and 2 are pseudo-substrate inhibitors of porcine pancreatic cholesterol esterase. Thus, the mechanism of the reaction necessitates that the inhibitor molecule and the enzyme form the enzyme-inhibitor tetrahedral species at the K-i step of the reaction and then form the carbamyl enzyme at the k(c) step of the reaction. Linear relationships between the logarithms of K-i and k(c) for cholesterol esterase by carbamates 1 and sigma are observed, and the reaction constants (ps) are -3.4 and -0.13, respectively. Therefore, the above reaction forms the negative-charge tetrahedral species and follows the formation of the relatively neutral carbamyl enzymes. For the inhibition of cholesterol esterase by carbamates 2 except 4-nitrophenyl-N-phenyl carbamate and 4-nitrophenyl-N-t-butyl carbamate, linear relationships of -logK(i) and logk(c) with sigma* are observed and the rho* values are -0.50 and 1.03, respectively. Since the above reaction also forms the negative-charge tetrahedral intermediate, it is possible that the K-i step of this reaction is further divided into two steps. The first K-i step is the development of the positive-charge at the carbamate nitrogen from the protonation of the carbamate nitrogen. The second K-i step is the formation of the tetrahedral intermediate with the negative-charge at the carbonyl oxygen. From Arrhenius plots of a series of inhibition reactions by carbamates 1 and 2, the isokinetic and isoequilibrium temperatures are different from the reaction temperature (25 degrees C). Therefore, the observed rho and rho* values only depend upon the electronic effects of the substituents. Taken together, the cholesterol esterase inhibition mechanism by carbamates 1 and 2 is proposed.
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