Stereoselectivity of enoyl-CoA hydratase results from preferential activation of one of two bound substrate conformers
Stereoselectivity of enoyl-CoA hydratase results from preferential activation of one of two bound substrate conformers
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DOI：
10.1016/s1074-5521(02)00263-6
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发表时间：
2002-11-01
影响因子：
--
通讯作者：
Tonge, PJ
中科院分区：
文献类型：
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作者：
Bell, AF;Feng, YG;Tonge, PJ
Enoyl-CoA水合酶催化反式-2-巴豆酰辅酶A水合生成3(S)-和3(R)-羟基丁酰辅酶A，立体选择性(3(S)/3(R))为400,000：1。重要的是，拉曼光谱显示底物类似物己二烯基辅酶A的S-顺和S-反式构象都与酶结合，但只有S-顺式构象被极化。这种选择性极化是基态应变的一个例子，表明存在催化相关的基态不稳定，这是由于酶向过渡态而不是基态的选择性互补引起的。因此，酶催化反应的立体选择性来自两个结合底物构象中的一个的选择性激活，而不是单个构象的选择性结合。这些发现对抑制剂的设计和基态相互作用在酶催化中的作用具有重要的意义。
Enoyl-CoA hydratase catalyzes the hydration of trans-2-crotonyl-CoA to 3(S)- and 3(R)-hydroxybutyryl-CoA with a stereoselectivity (3(S)/3(R)) of 400,000 to 1. Importantly, Raman spectroscopy reveals that both the s-cis and s-trans conformers of the substrate analog hexadienoyl-CoA are bound to the enzyme, but that only the s-cis conformer is polarized. This selective polarization is an example of ground state strain, indicating the existence of catalytically relevant ground state destabilization arising from the selective complementarity of the enzyme toward the transition state rather than the ground state. Consequently, the stereoselectivity of the enzyme-catalyzed reaction results from the selective activation of one of two bound substrate conformers rather than from selective binding of a single conformer. These findings have important implications for inhibitor design and the role of ground state interactions in enzyme catalysis.