Bencharit_2006_J.Mol.Biol_363_201

Reference

Title : Multisite promiscuity in the processing of endogenous substrates by human carboxylesterase 1 - Bencharit_2006_J.Mol.Biol_363_201
Author(s) : Bencharit S , Edwards CC , Morton CL , Howard-Williams EL , Kuhn P , Potter PM , Redinbo MR
Ref : Journal of Molecular Biology , 363 :201 , 2006
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 distinct catalytic actions.

PubMedSearch : Bencharit_2006_J.Mol.Biol_363_201
PubMedID: 16962139
Gene_locus related to this paper: human-CES1

Related information

Inhibitor Palmitate
Substrate Palmitate    Homatropine
Gene_locus Palmitate    Homatropine    human-CES1
Family Palmitate    Homatropine    human-CES1    Carb_B_Chordata
Structure Palmitate    Homatropine    human-CES1    Carb_B_Chordata    2DQY    2DQZ    2DR0    2H7C
Chemical Palmitate    Homatropine    human-CES1    Carb_B_Chordata    2DQY    2DQZ    2DR0    2H7C    Palmitate

Citations formats

Bencharit S, Edwards CC, Morton CL, Howard-Williams EL, Kuhn P, Potter PM, Redinbo MR (2006)
Multisite promiscuity in the processing of endogenous substrates by human carboxylesterase 1
Journal of Molecular Biology 363 :201

Bencharit S, Edwards CC, Morton CL, Howard-Williams EL, Kuhn P, Potter PM, Redinbo MR (2006)
Journal of Molecular Biology 363 :201