Cofactor-Dependent Amine Oxidations

说明（由申请人提供）：含铜胺氧化酶 （CAO）包括在所有活生物体中普遍存在的一类酶。在 在植物和哺乳动物中，CAO在生物胺代谢中起重要作用 参与生长、细胞分裂、分化和应激反应， 以及异生物胺的代谢，在某些情况下， 后果所有CAO都利用翻译后衍生的醌辅因子 从活性位点酪氨酸残基来介导 伯胺转化为醛，不同于 黄素依赖性胺氧化酶和那些代谢胺的血红素酶。 在过去的资助期间，使用辅因子模型的研究启发了 发现新型酶激活抑制机制，这些 研究，沿着其他传统灭活策略的发展， 已经导致了非常有希望的抑制选择性程度。重要 还揭示了醌辅因子生物合成的性质。在 在下一个赠款期，更加注重选择性， 对个体CAO具有选择性的候选抑制剂，特别是 血浆单胺和二胺氧化酶，可溶性和组织结合 氨基脲敏感性胺氧化酶和赖氨酰氧化酶。这些酶 抑制剂开发的重要目标， 认识到它们在纤维化方面的关键生理作用， 关节炎和动脉粥样硬化，糖尿病晚期并发症， 心血管疾病和脂肪组织生理学。高度案例 选择性酶失活将受到光谱和蛋白质 消化/质谱研究，以揭示 选择性。计划继续进行模型研究，以澄清机理方面 辅因子操作（托蒽醌或赖氨酸酪氨酸醌）对 设计额外的选择性灭活剂，和辅因子生物合成， 还不清楚

DESCRIPTION (provided by applicant): The copper-containing amine oxidases (CAOs) comprise a ubiquitous class of enzymes in all living organisms. In plants and mammals, CAOs play important roles in metabolizing biogenic amines involved in growth, cell division, differentiation, and the stress response, as well as in metabolism of xenobiotic amines, in some cases with cytotoxic consequences. All CAOs utilize a quinone cofactor derived postranslationally from an active site tyrosine residue to mediate a transaminative conversion of primary amines to aldehydes, distinct from the mechanism utilized by the flavin- dependent amine oxidases and those heme enzymes that metabolize amines. Studies using cofactor models in the past grant periods have inspired the discovery of new types of enzyme activated mechanisms of inhibition, and these studies, along with development of other traditional inactivation strategies, have resulted in highly promising degrees of inhibition selectivity. Important information on the nature of quinone cofactor biogenesis was also revealed. In the next grant period, an increased focus on selectivity should provide candidate inhibitors that are selective for individual CAOs, particularly the plasma monoamine and diamine oxidases, the soluble and tissue-bound semicarbazide-sensitive amine oxidases, and lysyl oxidase. These enzymes are important targets for inhibitor development on account of the emerging recognition of their key physiological roles in aspects of fibrosis in arthritis and atherosclerosis, in late-stage complications of diabetes and cardiovascular disease, and in adipose tissue physiology. Cases of highly selective enzyme inactivation will be subjected to spectroscopic and protein digestion/mass spectroscopic studies to reveal the structural nature of selectivity. Continued model studies are planned to clarify mechanistic aspects of cofactor operation (topaquinone or lysine tyrosyiquinone) important to the design of additional selective inactivators, and of cofactor biogenesis that are still unclear.