MECHANISTIC STUDY OF RADICALS IN BIOLOGY CATALYSIS

生命，最复杂和最迷人的现象，在 MAN，可以用简单的功能集成来定义 结构本身不具备 生命系统。我相信对生命过程的详细理解 包括明确功能是如何从结构中产生的。我的决定是 成为一名院士，致力于生物有机的研究 化学反映了这种担忧，因为它将使我能够探索 生物大分子的结构和相互作用，在这样做的时候， 为进一步研究它们作为离散变量的功能提供了基础 单位和作为更复杂系统的成员。本提案中概述的内容包括 旨在研究几种重要酶的实验，这些酶的机制可能 涉及形成一种自由基中间体。第一个系统是 研究了3，6-二脱氧己糖的生物合成。我们的重点将是 应致力于C-3脱氧机制的研究 形成子囊糖，这是一种重要的免疫显性糖。这个 第二个要检查的系统是普通的酰辅酶A脱氢酶，它 催化脂肪酸β-氧化的第一步。我们最初的 将致力于研究这种酶的失活 (亚甲基环丙基)乙酰辅酶A是牙买加人的病原体 呕吐症。这些研究的长期目标是建立一个 完全了解这些酶过程的功能作为一个 合理设计控制和模拟它们的方法的先决条件 生理角色。然而，对酶机制的研究代表了 只是我研究兴趣的一部分。其他一些领域，特别是 半合成酶的设计、衰老的分子基础和 免疫反应的化学机制，引起了我的注意和 都是我将来想要调查的研究问题。它是 我希望我的研究选择的领域和结果是从 它将促进化学知识的发展，并在以下领域有应用 医药和/或农业。因为我的研究进展到攻击更多 根本和困难的问题，这需要我在这方面做很多事情 关注和自我教育，颁发研究职业发展奖 在这个时候会来到一个紧要关头。它将让我充分地 专注于自己在替补席上的工作，并监督 我的同事，还可以自由地花时间在其他实验室 学习不同的技术和视角，可以带回 开拓新的调查领域。经主席同意，我将任教 每年一个季度。这次教学活动会让我有足够的时间 参与该部的人员流动，并将帮助维持形象 对于正在寻找研究顾问的研究生来说，这是必要的。 因此，研究职业发展奖将对 让我最大限度地专注于研究，这在 才能成长为一名富有成效的老牌调查员。

Life, the most complex and fascinating phenomenon within the purview of man, may be defined in terms of the functional integration of simple structures that are themselves devoid of all of the characteristics of living systems. I believe that understanding the life process in detail involves pinpointing how function arises from structure. My decision to become an academician and to devote myself to the study of bioorganic chemistry reflects this concern in that it will allow me to probe the structures and interactions of biological macro-molecules, and in so doing, provide the basis for further study of their functions both as discrete units and as members of more complex systems. Outlined in this proposal are experiments designed to study a few important enzymes whose mechanism may involve the formation of a radical intermediate. The first system to be investigated is the biosynthesis of 3,6-dideoxyhexoses. Our emphasis will be placed on the mechanistic studies of C-3 deoxygenation leading to the formation of ascarylose which is an important immuno-dominant sugar. The second system to be examined is general acyl-CoA dehydrogenase which catalyzes the first step of beta-oxidation of fatty acids. Our initial effort will be directed toward studying the inactivation of this enzyme by (methylenecyclopropyl)acetyl-CoA which is the causative agent of Jamaican vomiting sickness. The longterm goal of these studies is to establish a complete understanding of the functions of these enzymatic processes as a prerequisite to the rational design of methods to control and mimic their physiological roles. However, studies of enzymatic mechanisms represent only part of my research interests. A number of other areas, especially the design of semi-synthetic enzymes, the molecular basis of aging and the chemical mechanisms of the immune response, have attracted my attention and are research problems that I would like to investigate in the future. It is my hope that the areas chosen for my research and the results yielded from it will advance chemical knowledge, and have applications in the fields of medicine and/or agriculture. Since my research is moving on to attack more fundamental and difficult problems that will require much of me in the way of attention and self-education, a Research Career Development Award given at this time would come at a critical juncture. It will allow me to fully concentrate on working at the bench myself and supervising the efforts of my coworkers, and also give the freedom to spend time in other laboratories to learn different techniques and perspectives which can be brought back to bear on new areas of inquiry. By agreement with the Chairman, I wig teach for one quarter each year. This teaching activity will keep me sufficiently involved in the flow of the Department, and will help maintain the profile necessary to interest graduate students who are seeking a research advisor. Thus, a Research Career Development Award would make a real difference for me by allowing maximum concentration on research, which is necessary in order to mature into a productive and established investigator.