請用此 Handle URI 來引用此文件: http://hdl.handle.net/11455/68175
標題: Enantiomeric inhibitors of cholesterol esterase and acetylcholinesterase
作者: Lin, G.
Tsai, Y.C.
Liu, H.C.
Liao, W.C.
Chang, C.H.
關鍵字: enantiomeric inhibitor
inhibition of cholesterol esterase and
acetylcholinesterase
catalyzed transacylation reaction
hydrolysis
enantioselection
substrate
期刊/報告no:: Biochimica Et Biophysica Acta-Protein Structure and Molecular Enzymology, Volume 1388, Issue 1, Page(s) 161-174.
摘要: Enantiomers of N-methyl-N,alpha-methylbenzylbutyramide (1), 1-butyl-3-methyl-3'-alpha-methylbenzylurea (2), 1,2,3,4-tetrahydro-1-naphthyl-N-butylcarbamate (3), 1,1'-bi-2-naphthyl-2,2'-di-N-butylcarbamate (4), 1,1'-bi-2-naphthyl-2-ol-2'-N-butylcarbamate (5), and 1,1'-bi-2-naphthyl-2-butyrate-2'-N-butylcarbamate (6) are inhibitors of porcine pancreatic cholesterol esterase-catalyzed hydrolysis of 4-nitrophenyl butyrate and of electric eel acetylcholinesterase-catalyzed hydrolysis of acetylthiocholine in the presence of 5,5'-dithiobis-2-nitrobenzoate. For competitive inhibitors, values of the inhibition constant (K-i) and the enantiomeric ratio (E-comp.) are investigated. For active site-directed irreversible inhibitors, values of the inhibition constant (K-i), the carbamylation constant (k(2)), the bimolecular rate constant (k(i)), and the enantiomeric ratio (E) are investigated. Toward both enzymes, compounds 1 are poor competitive inhibitors (K-i = 10(2)-10(4) mu M) but have good enantioselectivities (E-comp. = 10-50, the preference for R). R-2 and S-2 are competitive inhibitors of acetylcholinesterase with K-i = 26 and 80 mu M, respectively (the preference for R) but are active site-directed irreversible inhibitors of cholesterol esterase with k(i) = 4 and 16 M-1 sec(-1), respectively (the preference for S). For those competitive inhibitions, both leaving group hydrophilic and hydrophobic binding sites of cholesterol esterase or both anionic substrate binding site and peripheral anionic binding site of acetylcholinesterase bind to N,N-methyl-alpha-methylbenzyl disubstituted amide parts of these inhibitors and the enzyme does not catalyze the hydrolysis of these inhibitors. The opposite stereopreference (S) for the inhibition of cholesterol esterase by compounds 2 may be due to the fact that N,N-methyl-alpha-methylbenzyl disubstituted amide parts of these inhibitors bind to the alkyl chain binding site of the enzyme. Compounds 3-6 are active site-directed irreversible inhibitors of cholesterol esterase (k(i) = 1-13 000 M-1 s(-1)) and peripheral anionic binding site-directed irreversible inhibitors of acetylcholinesterase (k(i) = 1.7-1300 M-1 s(-1)). Compounds 3 have low enantioselectivities (E = 1.3-1.4) for both enzymes. The stereopreference for atropisomers 4 and 6 is S-form toward both enzymes (E = 2-30) and is identical to that of cholesterol esterase-catalyzed hydrolysis of 1,1'-bi-2-naphthyl-2,2'-diacylace. This stereopreference (S) may be due to the fact that the butyryl group or one of two butylcarbamate groups of S-atropisomers binds more effectively to the leaving group hydrophobic binding site of cholesterol esterase or the peripheral anionic binding site of acetylcholinesterase than that of R-atropisomers. The opposite stereopreference (R) for atropisomers 5 toward both enzymes may be due to a favorable interaction between the hydroxyl group of the inhibitors and the leaving group hydrophilic binding site of cholesterol esterase or the peripheral anionic binding site of acetylcholinesterase. (C) 1998 Elsevier Science B.V. All rights reserved.
URI: http://hdl.handle.net/11455/68175
ISSN: 0167-4838
文章連結: http://dx.doi.org/10.1016/s0167-4838(98)00184-8
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