Multisite promiscuity in the processing of endogenous substrates by human carboxylesterase 1
Multisite promiscuity in the processing of endogenous substrates by human carboxylesterase 1
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DOI：
10.1016/j.jmb.2006.08.025
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发表时间：
2006-10-13
影响因子：
5.6
通讯作者：
Redinbo, Matthew R.
中科院分区：
文献类型：
--
作者：
Bencharit, Sompop;Edwards, Carol C.;Redinbo, Matthew R.
人羧酸酯酶1（Human carboxylesterase 1，hCE1）是一种药物和内源性丝氨酸水解酶，具有较宽的底物特异性。它涉及多种内源性胆固醇代谢途径，包括以下明显不同的反应：胆固醇酯水解（CEH）、脂肪酰基辅酶A水解（FACoAH）、酰基辅酶A：胆固醇酰基转移（ACAT）和脂肪酰基乙酯合成（FAEES）。hCE1执行这些涉及大底物和产物的催化作用的能力的结构基础仍然不清楚。在这里，我们提出了四种晶体结构的hCE1糖蛋白的复合物与以下的促肾上腺素底物或底物类似物：辅酶A，脂肪酸棕榈酸酯，胆汁酸胆酸盐和tatfrocholate。虽然已知hCE 1的活性位点是混杂的，并且能够与各种化学上不同的配体相互作用，但这些结构揭示了该酶含有两个额外的配体结合位点，并且每个位点也表现出相对非特异性的配体结合特性。使用这种多位点混杂，hCE1出现结构上能够组装几个催化事件，显然取决于细胞环境的生理状态。这些结果扩展了我们对酶混杂性的理解，并表明，在hCEI的情况下，采用多个非特异性位点来执行不同的催化作用。(c)2006爱思唯尔有限公司保留所有权利。
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.