Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/68228
標題: Quantitative structure-activity relationships for the pre-steady-state inhibition of cholesterol esterase by 4-nitrophenyl-N-substituted carbamates
作者: Lin, G.
Liao, W.C.
Chiou, S.Y.
關鍵字: salt-stimulated lipase;phospholipase a(2);crystal-structure;open;conformation;binding site;absorption;mechanism;rat;acetylcholinesterase;hydrolysis
Project: Bioorganic & Medicinal Chemistry
期刊/報告no:: Bioorganic & Medicinal Chemistry, Volume 8, Issue 11, Page(s) 2601-2607.
摘要: 
4-Nitrophenyl-N-substituted carbamates (1-6) are the pseudo-substrate inhibitors of porcine pancreatic cholesterol esterase. Thus, the first step of the inhibition (K-i step) is the formation of the enzyme-inhibitor tetrahedral adduct and the second step of the inhibition (k(e)) is the formation of the carbamyl enzyme. The formation of the enzyme-inhibitor tetrahedral adduct is further divided into two steps, the formation of the enzyme-inhibitor complex with the dissociation constant. Ks, at the first step and the formation of the enzyme-inhibitor tetrahedral adduct from the complex at the second step. The two-step mechanism for the formation of the enzyme-inhibitor tetrahedral adduct is confirmed by the pre-steady-state kinetics. The results of quantitative structure-activity relationships for the pre-steady-state inhibitions of cholesterol esterase by carbamates 1-6 indicate that values of -logK(S) and logk(2)/K-2 are correlated with the Taft substituent constant, sigma*, and the rho* values from these correlations are -0.33 and 0.1, respectively. The negative rho* value for the -logK(S)-sigma*-correlation indicates that the first step of the two-step formation of the enzyme-inhibitor tetrahedral adduct (Ks step) is the formation of the positive enzyme-inhibitor complex. The positive rho* value for the logk(2)/k(-2)-sigma*-correlation indicates that the enzyme-inhibitor tetrahedral adduct is more negative than the enzyme-inhibitor complex. Finally, the two-step mechanism for the formation of the enzyme-inhibitor tetrahedral adduct is proposed according to these results. Thus, the partially positive charge is developed at nitrogen of carbamates 1-6 in the enzyme-inhibitor complex probably due to the hydrogen bonding between the lone pair of nitrogen of carbamates 1-6 and the amide hydrogen of the oxyanion hole of the enzyme. The second step of the two-step formation of the enzyme-inhibitor tetrahedral adduct is the nucleophilic attack of the serine of the enzyme to the carbonyl group of carbamates 1-6 in the enzyme-inhibitor complex and develops the negative-charged oxygen in the adduct. (C) 2000 Elsevier Science Ltd. All rights reserved.
URI: http://hdl.handle.net/11455/68228
ISSN: 0968-0896
DOI: 10.1016/s0968-0896(00)00196-6
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