Houk Ronald J T, Monzingo Arthur, Anslyn Eric V
Sandia National Laboratories, 7011 East Avenue, Mail Stop 9291, Livermore, California 94550-0969, USA.
Acc Chem Res. 2008 Mar;41(3):401-10. doi: 10.1021/ar700127n. Epub 2008 Jan 30.
One of the most common, and yet least well understood, enzymatic transformations is proton abstraction from activated carbon acids such as carbonyls. Understanding the mechanism for these proton abstractions is basic to a good understanding of enzyme function. Significant controversy has arisen over the means by which a given enzyme might facilitate these deprotonations. Creating small molecule mimics of enzymes and physical organic studies that model enzymes are good approaches to probing mechanistic enzymology. This Account details a number of molecular recognition and physical organic studies, both from our laboratory and others, dealing with the elucidation of this quandary. Our analysis launches from an examination of the active sites and proposed mechanism of several enzyme-catalyzed deprotonations of carbon acids. This analysis highlights the geometries of the hydrogen bonds found at the enzyme active sites. We find evidence to support pi-oriented hydrogen bonding, rather than lone pair oriented hydrogen bonding. Our observations prompted us to study the stereochemistry of hydrogen bonding that activates carbonyl alpha-carbons to deprotonation. The results from our own thermodynamic, kinetics, and computational studies, all of which are reviewed herein, suggest that an unanticipated level of intermediate stabilization occurs via an electrophilic interaction through the pi-molecular orbital as opposed to traditional lone pair directed coordination. We do not postulate that hydrogen bonding to pi-systems is intrinsically stronger than to lone pairs, but rather that there is a greater change in bond strength during deprotonation when the hydrogen bonds are oriented at the pi-system. Through these studies, we conclude that many enzymes preferentially activate their carbon acid substrates through an electrophilic coordination directed towards the pi-bond of the carbonyl rather than the conventional lone pair directed model.
最常见但却最未被充分理解的酶促转化反应之一，是从诸如羰基等活化碳酸中夺取质子。理解这些质子夺取反应的机制是深入了解酶功能的基础。对于特定酶促进这些去质子化反应的方式，已经出现了重大争议。创建酶的小分子模拟物以及对酶进行建模的物理有机研究，是探究酶机制学的良好方法。本综述详细介绍了一些分子识别和物理有机研究，包括我们实验室和其他实验室的研究，旨在阐明这一难题。我们的分析始于对几种酶催化碳酸去质子化反应的活性位点和提出的机制的研究。这一分析突出了在酶活性位点发现的氢键的几何结构。我们发现证据支持π取向的氢键，而非孤对电子取向的氢键。我们的观察结果促使我们研究激活羰基α - 碳进行去质子化的氢键的立体化学。本文回顾了我们自己的热力学、动力学和计算研究结果，这些结果表明，与传统的孤对电子定向配位相反，通过π分子轨道的亲电相互作用会发生意想不到程度的中间体稳定化。我们并非假定与π体系形成的氢键本质上比与孤对电子形成的氢键更强，而是认为当氢键取向于π体系时，去质子化过程中键强度的变化更大。通过这些研究，我们得出结论，许多酶优先通过朝向羰基π键的亲电配位而非传统的孤对电子定向模型来激活其碳酸底物。
