Cofactor-Dependent Amine Oxidations

描述(申请人提供)：含铜的胺氧化酶 (CAO)由所有生物体内普遍存在的一类酶组成。在……里面 植物和哺乳动物的CAO在生物胺的代谢中起着重要作用 参与生长、细胞分裂、分化和应激反应，如 以及异物胺的代谢，在某些情况下具有细胞毒性 后果。所有CAO都使用翻译后派生的苯二酮辅因子 从活性部位的酪氨酸残基来介导转氨酶的转化 伯胺转化为醛，不同于 依赖黄素的胺氧化酶和那些代谢胺的血红素酶。 在过去的赠款期间使用辅因模型的研究启发了 新型酶激活抑制机制的发现，以及这些 研究，以及其他传统灭活策略的发展， 已经产生了非常有希望的抑制选择性程度。重要 此外，还揭示了苯二酚辅因子生物发生的本质。在……里面 在下一个赠款期间，对选择性的更多关注应提供 对单个CAO具有选择性的候选抑制剂，特别是 可溶性和组织结合型血浆单胺和二胺氧化酶 氨基脲敏感的胺氧化酶和赖氨酸氧化酶。这些酶是 从新兴的角度看缓蚀剂开发的重要目标 认识它们在肝纤维化中的重要生理作用 糖尿病和糖尿病晚期并发症中的关节炎和动脉粥样硬化 心血管疾病，以及脂肪组织生理学。高度恶性的案例 选择性酶失活将受到光谱和蛋白质的影响 消化/质谱学研究以揭示其结构性质 选择性。计划继续进行模型研究，以澄清机械方面的问题 辅因子操作(托喹酮或赖氨酸酪氨酸喹酮)对 设计额外的选择性灭活剂，以及辅因子生物生成 目前仍不清楚。

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.