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Title: Multisite Promiscuity in the Processing of Endogenous Substrates By Human Carboxylesterase 1

Abstract

Human carboxylesterase 1 (hCE1) is a drug and endobiotic-processing serine hydrolase that exhibits relatively broad substrate specificity. It has been implicated in a variety of endogenous cholesterol metabolism pathways including the following apparently disparate reactions: cholesterol ester hydrolysis (CEH), fatty acyl Coenzyme A hydrolysis (FACoAH), acyl-Coenzyme A:cholesterol acyltransfer (ACAT), and fatty acyl ethyl ester synthesis (FAEES). The structural basis for the ability of hCE1 to perform these catalytic actions involving large substrates and products has remained unclear. Here we present four crystal structures of the hCE1 glycoprotein in complexes with the following endogenous substrates or substrate analogues: Coenzyme A, the fatty acid palmitate, and the bile acids cholate and taurocholate. While the active site of hCE1 was known to be promiscuous and capable of interacting with a variety of chemically distinct ligands, these structures reveal that the enzyme contains two additional ligand-binding sites and that each site also exhibits relatively non-specific ligand-binding properties. Using this multisite promiscuity, hCE1 appears structurally capable of assembling several catalytic events depending, apparently, on the physiological state of the cellular environment. These results expand our understanding of enzyme promiscuity and indicate that, in the case of hCE1, multiple non-specific sites are employed to perform distinctmore » catalytic actions.« less

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Stanford Linear Accelerator Center (SLAC)
Sponsoring Org.:
USDOE
OSTI Identifier:
897737
Report Number(s):
SLAC-REPRINT-2006-180
TRN: US200705%%315
DOE Contract Number:  
AC02-76SF00515
Resource Type:
Journal Article
Resource Relation:
Journal Name: J.Mol.Biol.363:201, 2006
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; BILE ACIDS; CARBOXYLESTERASES; CARBOXYLIC ACIDS; CHOLESTEROL; COENZYMES; CRYSTAL STRUCTURE; ENZYMES; ESTERS; GLYCOPROTEINS; HYDROLASES; HYDROLYSIS; METABOLISM; SERINE; SPECIFICITY; SUBSTRATES; SYNTHESIS; Other,OTHER

Citation Formats

Bencharit, S., Edwards, C.C., Morton, C.L., Howard-Williams, E.L., Kuhn, P., Potter, P.M., Redinbo, M.R., and /North Carolina U. /St. Jude Children's Hosp., Memphis /SLAC, SSRL. Multisite Promiscuity in the Processing of Endogenous Substrates By Human Carboxylesterase 1. United States: N. p., 2007. Web.
Bencharit, S., Edwards, C.C., Morton, C.L., Howard-Williams, E.L., Kuhn, P., Potter, P.M., Redinbo, M.R., & /North Carolina U. /St. Jude Children's Hosp., Memphis /SLAC, SSRL. Multisite Promiscuity in the Processing of Endogenous Substrates By Human Carboxylesterase 1. United States.
Bencharit, S., Edwards, C.C., Morton, C.L., Howard-Williams, E.L., Kuhn, P., Potter, P.M., Redinbo, M.R., and /North Carolina U. /St. Jude Children's Hosp., Memphis /SLAC, SSRL. Tue . "Multisite Promiscuity in the Processing of Endogenous Substrates By Human Carboxylesterase 1". United States. doi:.
@article{osti_897737,
title = {Multisite Promiscuity in the Processing of Endogenous Substrates By Human Carboxylesterase 1},
author = {Bencharit, S. and Edwards, C.C. and Morton, C.L. and Howard-Williams, E.L. and Kuhn, P. and Potter, P.M. and Redinbo, M.R. and /North Carolina U. /St. Jude Children's Hosp., Memphis /SLAC, SSRL},
abstractNote = {Human carboxylesterase 1 (hCE1) is a drug and endobiotic-processing serine hydrolase that exhibits relatively broad substrate specificity. It has been implicated in a variety of endogenous cholesterol metabolism pathways including the following apparently disparate reactions: cholesterol ester hydrolysis (CEH), fatty acyl Coenzyme A hydrolysis (FACoAH), acyl-Coenzyme A:cholesterol acyltransfer (ACAT), and fatty acyl ethyl ester synthesis (FAEES). The structural basis for the ability of hCE1 to perform these catalytic actions involving large substrates and products has remained unclear. Here we present four crystal structures of the hCE1 glycoprotein in complexes with the following endogenous substrates or substrate analogues: Coenzyme A, the fatty acid palmitate, and the bile acids cholate and taurocholate. While the active site of hCE1 was known to be promiscuous and capable of interacting with a variety of chemically distinct ligands, these structures reveal that the enzyme contains two additional ligand-binding sites and that each site also exhibits relatively non-specific ligand-binding properties. Using this multisite promiscuity, hCE1 appears structurally capable of assembling several catalytic events depending, apparently, on the physiological state of the cellular environment. These results expand our understanding of enzyme promiscuity and indicate that, in the case of hCE1, multiple non-specific sites are employed to perform distinct catalytic actions.},
doi = {},
journal = {J.Mol.Biol.363:201, 2006},
number = ,
volume = ,
place = {United States},
year = {Tue Jan 16 00:00:00 EST 2007},
month = {Tue Jan 16 00:00:00 EST 2007}
}