Fleming_2005_J.Mol.Biol_352_165

Reference

Title : Structural insights into drug processing by human carboxylesterase 1: tamoxifen, mevastatin, and inhibition by benzil - Fleming_2005_J.Mol.Biol_352_165
Author(s) : Fleming CD , Bencharit S , Edwards CC , Hyatt JL , Tsurkan L , Bai F , Fraga C , Morton CL , Howard-Williams EL , Potter PM , Redinbo MR
Ref : Journal of Molecular Biology , 352 :165 , 2005
Abstract :

Human carboxylesterase 1 (hCE1) exhibits broad substrate specificity and is involved in xenobiotic processing and endobiotic metabolism. We present and analyze crystal structures of hCE1 in complexes with the cholesterol-lowering drug mevastatin, the breast cancer drug tamoxifen, the fatty acyl ethyl ester (FAEE) analogue ethyl acetate, and the novel hCE1 inhibitor benzil. We find that mevastatin does not appear to be a substrate for hCE1, and instead acts as a partially non-competitive inhibitor of the enzyme. Similarly, we show that tamoxifen is a low micromolar, partially non-competitive inhibitor of hCE1. Further, we describe the structural basis for the inhibition of hCE1 by the nanomolar-affinity dione benzil, which acts by forming both covalent and non-covalent complexes with the enzyme. Our results provide detailed insights into the catalytic and non-catalytic processing of small molecules by hCE1, and suggest that the efficacy of clinical drugs may be modulated by targeted hCE1 inhibitors.

PubMedSearch : Fleming_2005_J.Mol.Biol_352_165
PubMedID: 16081098
Gene_locus related to this paper: human-CES1

Related information

Inhibitor Tamoxifen    Benzil    Mevastatin
Substrate Tamoxifen    Benzil    Mevastatin    Ethylacetate
Gene_locus Tamoxifen    Benzil    Mevastatin    Ethylacetate    human-CES1
Family Tamoxifen    Benzil    Mevastatin    Ethylacetate    human-CES1    Carb_B_Chordata
Structure Tamoxifen    Benzil    Mevastatin    Ethylacetate    human-CES1    Carb_B_Chordata    1YA4    1YA8    1YAH    1YAJ

Citations formats

Fleming CD, Bencharit S, Edwards CC, Hyatt JL, Tsurkan L, Bai F, Fraga C, Morton CL, Howard-Williams EL, Potter PM, Redinbo MR (2005)
Structural insights into drug processing by human carboxylesterase 1: tamoxifen, mevastatin, and inhibition by benzil
Journal of Molecular Biology 352 :165

Fleming CD, Bencharit S, Edwards CC, Hyatt JL, Tsurkan L, Bai F, Fraga C, Morton CL, Howard-Williams EL, Potter PM, Redinbo MR (2005)
Journal of Molecular Biology 352 :165