MECHANISTIC STUDIES OF XANTHINE OXIDASE

钼黄素酶的综合作用机理研究 黄嘌呤氧化物酶被建议集中在两个中心方面 这种重要的酶的催化行为，它催化 嘌呤分解代谢的最后两步。在第一个方面， 建议的工作，催化循环的还原半反应 将进行全面研究，目的是建立 黄嘌呤转化为黄嘌呤过程中的详细化学过程 尿酸。结果将根据具体情况进行解释 提出了还原半反应的化学机理。 四氢黄嘌呤与黄嘌呤氧化酶络合物的结构 将在拟议工作的这一方面进行具体审查。 这种复合体被认为是一种特别稳定的模拟 特异性催化中间体，也具有临床意义 因为它极大的稳定性是卓越临床表现的基础 别嘌醇的疗效。这种耐受性良好的药物用于 治疗与高尿酸血症相关的这种多样性 痛风和痛风性关节炎，以及 次黄嘌呤-鸟嘌呤磷酸核糖转移酶(Lesch-Nyhan) 和葡萄糖-6-磷酸酶(von Gierke病)。在 拟议工作的第二个方面，四个方面的互动 黄嘌呤氧化酶中的氧化还原中心将是 进行了定量检查，以努力确定 哪些还原当量在酶中平衡，以及 还原当量的平衡程度 影响催化剂的周转率。黄嘌呤氧化物酶的存在 多个站点能够可逆地接受减少 等价物提供了审查转让的机会 电子从一个生物中心转移到另一个生物中心 以固定的距离和方向在或多或少僵硬的 多肽基质。这已经成为人们非常感兴趣的一个领域 生物物理学，以及对细菌特性的仔细研究 黄嘌呤氧化物酶有望产生重要信息 关于生物中电子转移的原理 系统。中国各中心之间的互动模式 黄嘌呤氧化酶也可能与黄嘌呤的产生有关 黄嘌呤氧化物酶生成的超氧化物。这也是临床上的问题 意义重大，因为酶产生的超氧化物已经被 被认为在与缺血相关的组织中发挥重要作用 损害(动脉粥样硬化和心脏病发作)。

A comprehensive mechanistic study of the molybdoflavoenzyme xanthine oxidase is proposed focusing on two central aspects of the catalytic behavior of this important enzyme, which catalyzes the final two steps in purine catabolism. In the first aspect of the proposed work, the reductive half-reaction of the catalytic cycle will be comprehensively examined with the aim of establishing the detailed chemistry that occurs in the conversion of xanthine to uric acid. The results will be interpreted in terms of a specific chemical mechanisms proposed for the reductive half-reaction. The structure of the complex of alloxanthine with xanthine oxidase will specifically be examined in this aspect of the proposed work. This complex is thought to be a particularly stable analog to a specific catalytic intermediate, and is also of clinical significance in that its great stability is the basis for the remarkable clinical efficacy of allopurinol. This well-tolerated drug is used in the treatment of hyperuricemia associated with such diverse conditions as gout and gouty arthritis, and enzyme deficiencies in hypoxanthine-guanine phosphoribosyltransferase (Lesch-Nyhan syndrome) and glucose-6-phosphatase (von Gierke's disease). In the second aspect of the proposed work, the interaction of the four oxidation-reduction centers in xanthine oxidase will be quantitatively examined in an effort to determine the rates at which reducing equivalents equilibrate in the enzyme, and the extent to which the equilibration of reducing equivalents influences catalytic turnover. The presence in xanthine oxidase of multiple sites capable of reversibly accepting reducing equivalents offers the opportunity to examine the transfer of electrons from one biological center to another while being held at a fixed distance and orientation within a more or less rigid polypeptide matrix. This has become an area of great interest in biophysics, and the careful examination of the properties of xanthine oxidase is expectd to yield significant information regarding the principles governing electron transfer in biological systems. The mode of interaction of the various centers in xanthine oxidase may also be relevant in the production of superoxide by xanthine oxidase. This too is of clinical significance given that enzyme-generated superoxide has been proposed to play a significant role in ischemia-related tissue damage (in atherosclerosis and heart attack).