REACTIVE INTERMEDIATES OF ENZYMATIC REACTIONS

模型研究，在水中，以表征动力学和 平衡稳定性，以及形成和形成的机制 可能的碳负离子、碳正离子和甲基苯二酚的反应 提出了酶催化反应的中间体。(1) 已经提出，高效的酶催化作用 α-羰基化合物的去质子化部分是由于 通过质子化减少马库斯本征势垒 被酸性氨基酸结合的底物上的羰基氧。 然而，这些内在的动力学障碍的起源 人们对此知之甚少，而且有非常大的反应 在规模上的不确定性。我们建议确定 环的O-甲基化(模拟O-质子化)的影响- 取代苯乙酮类化合物的本征动力学势垒 通过羧酸根离子使这些酮去质子化。这将是 提供关于以下方面的文献建议的批判性测试 碳上质子转移的本征势垒的来源，以及 在多大程度上通过 酵素。(2)协同酸碱催化的优势 反应中产物(S)是由一个强的 氢键没有得到很好的表征。我们建议确定 强分子内氢键的形成对分子动力学的影响 环解理过渡态的稳定性 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。 结果将确定最佳酶的要求 氢键催化作用。(3)金属离子的效率 α-羰基化合物去质子化的催化作用不是 很好理解。我们建议对金属的影响进行表征 氢氧离子催化提取α-羟基苯甲酸的研究进展 简单的羧酸盐阴离子的质子，它与 金属祭品。(4)简单反应的速率定律 将对带有亲核试剂的甲基苯醌进行表征， 为了确定这些反应是否受到一般情况的影响 酸碱催化。酶促反应的研究进展 非酶模型研究的反应机理 水中的反应可能被证明是药物设计(酶)的关键 抑制物)，有助于了解代谢途径和 这对解决其他与健康有关的问题具有重要意义。

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.