MECHANISTIC STUDIES OF XANTHINE OXIDASE

黄酮酶作用机理的综合研究 黄嘌呤氧化酶被提出集中在两个中心方面， 这种重要的酶的催化行为，催化 最后两个步骤是嘌呤催化剂。 的第一方面中 建议的工作，还原半反应的催化循环 将全面审查，目的是建立 详细的化学反应发生在黄嘌呤转化为 尿酸。 结果将被解释为一个特定的 提出了还原半反应的化学机理。 别黄嘌呤与黄嘌呤氧化酶复合物的结构 将在拟议工作的这一方面具体加以审查。 这种复合物被认为是一种特别稳定的类似物， 特异性催化中间体，也具有临床意义 因为其更高稳定性是显著临床应用的基础 别嘌呤醇的功效。 这种耐受性良好的药物用于 高尿酸血症的治疗 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 综合征）和葡萄糖-6-磷酸酶（von Gierke病）。 在 建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 定量研究，以确定 还原当量在酶中平衡， 还原当量平衡的程度 影响催化周转。 黄嘌呤氧化酶的存在 多个位点能够可逆地接受还原 等同物提供了审查 电子从一个生物中心到另一个生物中心 以固定的距离和方向在或多或少刚性的 多肽基质 这已经成为一个非常感兴趣的领域， 生物物理学，以及仔细检查的性质， 黄嘌呤氧化酶有望产生重要的信息 关于生物学中电子转移的原理 系统. 各中心之间的相互作用模式 黄嘌呤氧化酶也可能与 通过黄嘌呤氧化酶产生超氧化物。 这也是临床的 考虑到酶产生超氧化物已经被 提出在缺血相关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).