Structural insights into drug processing by human carboxylesterase 1: Tamoxifen, mevastatin, and inhibition by benzil
Structural insights into drug processing by human carboxylesterase 1: Tamoxifen, mevastatin, and inhibition by benzil
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DOI：
10.1016/j.jmb.2005.07.016
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发表时间：
2005-09-09
影响因子：
5.6
通讯作者：
Redinbo, MR
中科院分区：
文献类型：
--
作者：
Fleming, CD;Bencharit, S;Redinbo, MR
人羧酸酯酶1(HCE1)具有广泛的底物特异性，参与异种加工和内生代谢。我们介绍并分析了hCE1与降胆固醇药物美伐他汀、乳腺癌药物他莫昔芬、脂肪酰乙酯(自由)类似物乙酸乙酯和新型hCE1抑制剂苯并苯的络合物的晶体结构。我们发现，美伐他汀似乎不是hCE1的底物，而是该酶的部分非竞争性抑制剂。类似地，我们证明他莫昔芬是hCE1的低微摩尔、部分非竞争性抑制剂。此外，我们描述了纳米摩尔亲和力二酮苯对hCE1抑制的结构基础，它通过与酶形成共价和非共价复合体来发挥作用。我们的结果为hCE1对小分子的催化和非催化处理提供了详细的见解，并提示临床药物的疗效可能受到靶向hCE1抑制剂的调节。(C)2005爱思唯尔有限公司。保留所有权利。
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 (FREE) 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 noncatalytic processing of small molecules by hCE1, and suggest that the efficacy of clinical drugs may be modulated by targeted hCE1 inhibitors. (c) 2005 Elsevier Ltd. All rights reserved.