REACTIVE INTERMEDIATES OF ENZYMATIC REACTIONS

模型研究，在水中，以表征动力学和 平衡稳定性，以及形成和 假定碳负离子、碳正离子和醌甲基化物的反应 提出了酶催化反应的中间体。(1)它 已经表明，有效的酶催化， α-羰基化合物的去质子化部分来自于 减少马库斯固有的障碍质子化的 结合底物的羰基氧被酸性氨基酸取代。 然而，这些内在动力学障碍的起源 反应是知之甚少，有非常大的 不确定性在他们的大小。我们建议确定 环的O-甲基化（模拟O-质子化）的影响- 取代的苯乙酮的内在动力学障碍， 这些酮被羧酸根离子去质子化。这将 提供了一个关键的测试文献的建议， 质子在碳上转移的固有势垒的起源，以及 在多大程度上它可以降低的相互作用与一个 酵素(2)本文介绍了有机酸作为酸碱协同催化剂的优点， 反应，其中产物通过强的 氢键没有很好地表征。我们建议确定 分子内强氢键的形成对 开环过渡态的稳定性 取代的1-芳基乙基水杨基醚， 改变衬底结构的过渡态稳定化。 结果将确定最佳酶促反应的要求。 通过氢键的催化作用。(3)金属离子效率 催化α-羰基化合物的去质子化不是 很好理解。我们建议描述金属的影响 关于氢氧化物离子催化的α- 简单羧酸根阴离子的质子，与 金属二价阳离子。(4)本文给出了一个简单的反应的速率定律， 将表征醌甲基化物与亲核试剂， 为了确定这些反应是否受到一般的 酸碱催化酶促反应的研究进展 非酶模型研究的反应机理 水中的反应可能对药物设计至关重要（酶 抑制剂），了解代谢途径， 疾病，以及解决其他与健康有关的问题。

Model studies, in water, to characterize the kinetic and equilibrium stability, and mechanisms for the formation and reaction of putative carbanion, carbocation and quinone methide intermediates of enzyme-catalyzed reactions are proposed. (1) It has been suggested that the efficient enzymatic catalysis of deprotonation of alpha-carbonyl compounds results in part from a reduction in the Marcus intrinsic barrier by protonation of the carbonyl oxygen of the bound substrate by an acidic amino acid. However, the origin of the intrinsic kinetic barriers to these reactions is poorly understood, and there are very large uncertalnties in their magnitude. We propose to determine the effect of O-methylation (which models O-protonation) of ring- substituted acetophenones on the intrinsic kinetic barrier to deprotonation of these ketones by carboxylate ions. This will provide a critical test of literature proposals concerning the origin of the intrinsic barrier to proton transfer at carbon, and of the extent to which it can be lowered by interactions with an enzyme. (2) The advantage to concerted acid/base catalysis of reactions in which the product(s) are stabilized by a strong hydrogen bond is not well characterized. We propose to determine the effect of formation of a strong intramolecular hydrogen bond on the stability of the transition state for cleavage of ring- substituted 1-arylethyl salicyl ethers, and the changes in transition-state stabilization with changing substrate structure. The results will define the requirements for optimal enzymatic catalysis by hydrogen bonding. (3) The efficiency of metal ion catalysis of the deprotonation of alpha-carbonyl compounds is not well understood. We propose to characterize the effect of metal dications on the hydroxide-ion-catalyzed abstraction of the alpha- protons of simple carboxylate anions that form strong chelates with the metal dication. (4) The rate laws for the reactions of a simple quinone methide with nucleophilic reagents will be characterized, in order to determine if these reactions are subject to general acid-base catalysis. The advances in the understanding of enzymatic reaction mechanism that result from model studies of nonenzymatic reactions in water may prove critical to drug design (enzyme inhibitors), to the understanding of metabolic pathways and diseases, and to the resolution of other health-related problems.