Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 363, Issue 1, Pages 201-214Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2006.08.025
Keywords
cholesterol metabolism; cholesterol esters; foam cells; atherosclerosis; heart diseases
Categories
Funding
- NCI NIH HHS [R01 CA098468] Funding Source: Medline
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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 enclogenous substrates or substrate analogues: Coenzyme A, the fatty acid palmitate, and the bile acids cholate and tatfrocholate. 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 ligandbinding 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 hCEI, multiple non-specific sites are employed to perform distinct catalytic actions. (c) 2006 Elsevier Ltd. All rights reserved.
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