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Probing stereoselective inhibition of the acyl binding site of cholesterol esterase with four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol

BACKGROUND: Recently there has been increased interest in pancreatic cholesterol esterase due to correlation between enzymatic activity in vivo and absorption of dietary cholesterol. Cholesterol esterase plays a role in digestive lipid absorption in the upper intestinal tract, though its role in cho...

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Autores principales: Chiou, Shyh-Ying, Lai, Cheng-Yue, Lin, Long-Yau, Lin, Gialih
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2005
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1262691/
https://www.ncbi.nlm.nih.gov/pubmed/16176589
http://dx.doi.org/10.1186/1471-2091-6-17
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author Chiou, Shyh-Ying
Lai, Cheng-Yue
Lin, Long-Yau
Lin, Gialih
author_facet Chiou, Shyh-Ying
Lai, Cheng-Yue
Lin, Long-Yau
Lin, Gialih
author_sort Chiou, Shyh-Ying
collection PubMed
description BACKGROUND: Recently there has been increased interest in pancreatic cholesterol esterase due to correlation between enzymatic activity in vivo and absorption of dietary cholesterol. Cholesterol esterase plays a role in digestive lipid absorption in the upper intestinal tract, though its role in cholesterol absorption in particular is controversial. Serine lipases, acetylcholinesterase, butyrylcholinesterase, and cholesterol esterase belong to a large family of proteins called the α/β-hydrolase fold, and they share the same catalytic machinery as serine proteases in that they have an active site serine residue which, with a histidine and an aspartic or glutamic acid, forms a catalytic triad. The aim of this work is to study the stereoselectivity of the acyl chain binding site of the enzyme for four diastereomers of an inhibitor. RESULTS: Four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol (1) are synthesized from the condensation of R-(+)- or S-(-)-1, 1'-bi-2-naphthanol with R-(+)- or S-(-)-α-methylbenzyl isocyanate in the presence of a catalytic amount of pyridine in CH(2)Cl(2). The [α](25)(D )values for (1R, αR)-1, (1R, αS)-1, (1S, αR)-1, and (1S, αS)-1 are +40, +21, -21, and -41°, respectively. All four diastereomers of inhibitors are characterized as pseudo substrate inhibitors of pancreatic cholesterol esterase. Values of the inhibition constant (K(i)), the carbamylation constant (k(2)), and the bimolecular rate constant (k(i)) for these four diastereomeric inhibitors are investigated. The inhibitory potencies for these four diastereomers are in the descending order of (1R, αR)-1, (1R, αS)-1, (1S, αR)-1, and (1S, αS)-1. The k(2 )values for these four diastereomers are about the same. The enzyme stereoselectivity for the 1, 1'-bi-2-naphthyl moiety of the inhibitors (R > S, ca. 10 times) is the same as that for 2'-N-butylcarbamyl-1, 1'-bi-2-naphthol (2). The enzyme stereoselectivity for the α-methylbenzylcarbamyl moiety of the inhibitors is also R > S (2–3 times) due to the constraints in the acyl binding site. CONCLUSION: We are the first to report that the acyl chain binding site of cholesterol esterase shows stereoselectivity for the four diastereomers of 1.
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spelling pubmed-12626912005-10-22 Probing stereoselective inhibition of the acyl binding site of cholesterol esterase with four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol Chiou, Shyh-Ying Lai, Cheng-Yue Lin, Long-Yau Lin, Gialih BMC Biochem Research Article BACKGROUND: Recently there has been increased interest in pancreatic cholesterol esterase due to correlation between enzymatic activity in vivo and absorption of dietary cholesterol. Cholesterol esterase plays a role in digestive lipid absorption in the upper intestinal tract, though its role in cholesterol absorption in particular is controversial. Serine lipases, acetylcholinesterase, butyrylcholinesterase, and cholesterol esterase belong to a large family of proteins called the α/β-hydrolase fold, and they share the same catalytic machinery as serine proteases in that they have an active site serine residue which, with a histidine and an aspartic or glutamic acid, forms a catalytic triad. The aim of this work is to study the stereoselectivity of the acyl chain binding site of the enzyme for four diastereomers of an inhibitor. RESULTS: Four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol (1) are synthesized from the condensation of R-(+)- or S-(-)-1, 1'-bi-2-naphthanol with R-(+)- or S-(-)-α-methylbenzyl isocyanate in the presence of a catalytic amount of pyridine in CH(2)Cl(2). The [α](25)(D )values for (1R, αR)-1, (1R, αS)-1, (1S, αR)-1, and (1S, αS)-1 are +40, +21, -21, and -41°, respectively. All four diastereomers of inhibitors are characterized as pseudo substrate inhibitors of pancreatic cholesterol esterase. Values of the inhibition constant (K(i)), the carbamylation constant (k(2)), and the bimolecular rate constant (k(i)) for these four diastereomeric inhibitors are investigated. The inhibitory potencies for these four diastereomers are in the descending order of (1R, αR)-1, (1R, αS)-1, (1S, αR)-1, and (1S, αS)-1. The k(2 )values for these four diastereomers are about the same. The enzyme stereoselectivity for the 1, 1'-bi-2-naphthyl moiety of the inhibitors (R > S, ca. 10 times) is the same as that for 2'-N-butylcarbamyl-1, 1'-bi-2-naphthol (2). The enzyme stereoselectivity for the α-methylbenzylcarbamyl moiety of the inhibitors is also R > S (2–3 times) due to the constraints in the acyl binding site. CONCLUSION: We are the first to report that the acyl chain binding site of cholesterol esterase shows stereoselectivity for the four diastereomers of 1. BioMed Central 2005-09-22 /pmc/articles/PMC1262691/ /pubmed/16176589 http://dx.doi.org/10.1186/1471-2091-6-17 Text en Copyright © 2005 Chiou et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Chiou, Shyh-Ying
Lai, Cheng-Yue
Lin, Long-Yau
Lin, Gialih
Probing stereoselective inhibition of the acyl binding site of cholesterol esterase with four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol
title Probing stereoselective inhibition of the acyl binding site of cholesterol esterase with four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol
title_full Probing stereoselective inhibition of the acyl binding site of cholesterol esterase with four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol
title_fullStr Probing stereoselective inhibition of the acyl binding site of cholesterol esterase with four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol
title_full_unstemmed Probing stereoselective inhibition of the acyl binding site of cholesterol esterase with four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol
title_short Probing stereoselective inhibition of the acyl binding site of cholesterol esterase with four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol
title_sort probing stereoselective inhibition of the acyl binding site of cholesterol esterase with four diastereomers of 2'-n-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1262691/
https://www.ncbi.nlm.nih.gov/pubmed/16176589
http://dx.doi.org/10.1186/1471-2091-6-17
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