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首页> 外文期刊>Journal of Molecular Biology >Multisite Promiscuity in the Processing of Endogenous Substrates by Human Carboxylesterase 1.
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Multisite Promiscuity in the Processing of Endogenous Substrates by Human Carboxylesterase 1.

机译：人类羧基酯酶1处理内源底物的多位混杂

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摘要

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.
机译：人羧酸酯酶1（hCE1）是一种药物和内生加工丝氨酸水解酶，具有相对广泛的底物特异性。它与多种内源性胆固醇代谢途径有关，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）和脂肪酰基乙基酯合成（FAEES）。 hCE1执行涉及大型底物和产物的这些催化作用的能力的结构基础仍不清楚。在这里，我们介绍了hCE1糖蛋白的四个晶体结构，其与以下内源性底物或底物类似物形成复合物：辅酶A，脂肪酸棕榈酸酯和胆汁酸胆酸盐和牛磺胆酸盐。虽然已知hCE1的活性位点是混杂的，并且能够与多种化学上不同的配体相互作用，但这些结构显示该酶含有两个额外的配体结合位点，并且每个位点还具有相对非特异性的配体结合特性。使用这种多位点混杂性，hCE1在结构上似乎能够组装多个催化事件，这显然取决于细胞环境的生理状态。这些结果扩大了我们对酶混杂的理解，并表明在hCE1的情况下，多个非特异性位点被用来执行不同的催化作用。

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