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Multisite promiscuity in the processing of endogenous substrates by human carboxylesterase 1

Academic Article
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Overview

authors

  • Bencharit, S.
  • Edwards, C. C.
  • Morton, C. L.
  • Howard-Williams, E. L.
  • Kuhn, Peter
  • Potter, P. M.
  • Redinbo, M. R.

publication date

  • October 2006

journal

  • Journal of Molecular Biology  Journal

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.

subject areas

  • Binding Sites
  • Carboxylic Ester Hydrolases
  • Crystallography, X-Ray
  • Humans
  • Protein Processing, Post-Translational
  • Substrate Specificity
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Research

keywords

  • atherosclerosis
  • cholesterol esters
  • cholesterol metabolism
  • foam cells
  • heart diseases
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Identity

PubMed Central ID

  • PMC1762004

International Standard Serial Number (ISSN)

  • 0022-2836

Digital Object Identifier (DOI)

  • 10.1016/j.jmb.2006.08.025

PubMed ID

  • 16962139
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Additional Document Info

start page

  • 201

end page

  • 214

volume

  • 363

issue

  • 1

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