COFACTOR DEPENDENT AMINE OXIDATIONS

描述：阐明生物氧化的机制， 胺的各种胺氧化酶将提供有关活性的信息 网站结构和许可证的合理设计高效和选择性 具有治疗潜力的机制（自杀）抑制剂。 的 目前赠款期的主要重点将是黄素依赖型 线粒体单胺氧化酶（MAO）（项目I）和醌- 含有胺氧化酶（项目II），其中一个家族含有 铜和另一个家庭似乎不含铜 （称为氨基脲敏感胺氧化酶）。 醌- 含有酶似乎利用转氨作用机制， 伯胺的脱氨基，而电子转移，氢原子， 转移、转移-转移和添加-消除机制， 继续为毛泽东争光。 该补助金的目的之一是解决 机械问题，通过模型研究的进行，并 设计和评估新的探针， 机制等 模拟感兴趣的酶化学的模型可以 然后用于（i）“筛选”抑制剂设计的新想法，以及（ii） 为理解光谱特征提供参考导数 由酶显示。 设计抑制剂的初步筛选 将在PI的实验室中进行，而纯 酶制剂将与教授合作进行 Greenaway（克拉克大学），Kagan（波士顿大学），Dooley（蒙大拿州 州立大学）、帕尔契奇（阿尔伯塔大学）和埃德蒙森（埃默里 大学）。 铜胺氧化酶的相关研究 是三羟基苯丙氨酸醌的生物合成机制 辅因子从活性位点酪氨酸残基。 铜的机制- 介导的苯酚氧化和可能的铜催化 随后的氧化/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.