COFACTOR DEPENDENT AMINE OXIDATIONS

描述：阐明生物氧化的机理 由各种胺氧化酶提供的胺类物质将提供有关活性的信息 合理的站点结构和许可设计的高效和选择性 具有治疗潜力的基于机制的(自杀)抑制剂。这个 目前赠款期间的主要重点将是依赖黄素的 线粒体单胺氧化酶(MAO)(项目I)和对苯二酚- 含有胺氧化酶(项目II)，其中一个家族含有 铜和另一类似乎不含铜的化合物 (称为氨基脲敏感的胺氧化酶)。对苯二酚- 含有酶似乎利用转氨酶机制 伯胺的脱胺作用，而电子转移，氢原子- 转移、氢化物转移和加成消除机制 继续为毛而战。这笔赠款的一个目的是解决 通过进行模型研究提出机械性问题，并 设计和评估可能区分候选对象的新探针 机械装置。模拟感兴趣的酶化学的模型可以 然后被用来(I)筛选缓蚀剂设计的新想法，以及(Ii) 为理解光谱特征提供参考导数 通过酶表现出来。设计缓蚀剂的初步筛选 将在PI的实验室进行，而PIRE的定向研究 将与教授合作进行酶制剂 Greenaway(克拉克大学)、Kagan(波士顿大学)、Dooley(蒙大拿州 州立大学)、帕尔西奇(艾伯塔大学)和埃德蒙森(埃默里大学) 大学)。关于铜胺氧化酶的一个相关兴趣 是三羟基苯丙氨酸醌的生物发生机制 活性部位酪氨酸残基的辅因子。铜的机理- 介导性苯酚氧化和可能的铜催化 后续的氧化/水合步骤将在模型研究中进行评估。

DESCRIPTION: Elucidation of the mechanisms of biological oxidation of amines by the various amine oxidases will provide information on active site structure and permit the rational design of efficient and selective mechanism-based (suicide) inhibitors with therapeutic potential. The major focus of the current grant period will be on the flavin-dependent mitochondrial monoamine oxidases (MAO) (Project I) and on the quinone- containing amine oxidases (Project II), one family of which contains copper and the another family of which appears not to contain copper (known as semicarbazide-sensitive amine oxidases). The quinone- containing enzymes appear to utilize a transamination mechanism for deamination of primary amines, whereas electron-transfer, hydrogen-atom- transfer, hydride-transfer, and addition-elimination mechanisms all remain in contention for MAO. One aim of this grant is to address mechanistic questions through the conduct of model studies, and to design and evaluate new probes which might distinguish among candidate mechanisms. Models which mimic the enzyme chemistry of interest can then be used (i) to "screen" novel ideas for inhibitor design, and (ii) to provide reference derivatives for understanding spectral features displayed by the enzymes. Preliminary screening of designed inhibitors will be carried out in the PI's lab, whereas directed studies with pure enzyme preparations will be carried out in collaboration with Professors Greenaway (Clark University), Kagan (Boston University), Dooley (Montana State University), Palcic (University of Alberta), and Edmondson (Emory University). A related interest in regard to the copper amine oxidases is the mechanism of biogenesis of the trihydroxyphenylalanine quinone cofactor from the active-site tyrosine residue. Mechanisms for copper- mediated phenol oxygenation and possibly copper catalysis of the subsequent oxidation/hydration steps will be assessed in model studies.