Copper Dioxygen Reactivity in Model Complexes

描述(申请人提供)：与氧气反应的铜酶对我们的生活是必不可少的，特别是在将某些生物分子从一种形式转化为另一种形式方面。然而，在大脑等代谢活动较高的地区，铜资源管理不善被认为会导致许多令人衰弱的疾病，包括阿尔茨海默氏症(AD)和帕金森氏症。这些疾病的特点是形成带有错误折叠的蛋白质片段的斑块，这些片段经常被氧化破坏。定义连接环境和意外键合或故意隔离的铜能够产生活性氧物种(ROS)的机制是我们努力了解的。由于铜是生物中所有氧化还原活性金属中最不稳定的，定义导致这种ROS的配位是具有挑战性的。铜与氧气在高度受控的配位环境(如蛋白质或小铜络合物)中的反应机理，提供了一个合理的起点，以确定在较不确定的生物条件下，什么是化学上可能的，或者如果不是，什么是化学上可能的。广泛和长期的目标是如何通过了解活化机制来减少活化氧气的铜位上ROS的形成。更具体地说，在酚酸盐/酚基团存在的情况下激活O2的铜位置将被深入调查，因为这些位置被认为是与AD相关的斑块中的ROS生成器。合成模拟方法将是我们的研究工具，通过该方法，将合成结构相关的低分子化合物，并在小分子细节水平上进行研究，以揭示不受蛋白质基质影响的内在结构、电子和反应性能。操作前提是，如果适当注意创造合适的铜连接环境，这类络合物将为生物体系的氧化(CuI+O2)和还原(CuO2+底物)半反应提供重要的机理见解。将特别关注氧化程度最高的铜(S)，以及不同的电子分布如何导致不同的反应性。与公共健康相关：与氧气反应的铜酶对我们的生活至关重要，特别是在将某些生物分子从一种形式转化为另一种形式方面。包括阿尔茨海默病在内的许多突出的神经系统疾病被认为是由于对这些铜资源管理不善造成的，在氧化应激条件下，会产生活性氧物种(ROS)，导致神经细胞不可逆转的损害和痴呆。我们的研究试图定义铜是如何被产生这些破坏性ROS的蛋白质持有的，并着眼于开发适当的铜结合剂，这些结合剂可能会减弱ROS的产生和这些衰弱疾病的进展。

DESCRIPTION (provided by applicant): Copper enzymes that react with dioxygen are essential to our lives especially with respect to transforming certain biological molecules from one form to another. Yet, in areas of high metabolic activity such as the brain, mismanagement of copper resources is thought to lead to many debilitating diseases including Alzheimer's (AD) and Parkinsons. The hallmark of these diseases is the formation of plaques with misfolded protein fragments that are often damaged by oxidization. Defining the ligation environment and the mechanism by which adventitiously bonded or purposely sequestered copper is able to create reactive dioxygen species (ROS) is what we endeavor to understand. As copper is the most labile of all redox active metals in biology, defining the coordination that leads to such ROS is challenging. Mechanisms of the reaction of copper with dioxygen in highly controlled coordination environments, such as proteins or in small copper complex, provides a logical start to define what is chemically possible or if not what is chemically probable under less-defined biological conditions. The broad and long-term objectives are how to attenuate the formation of ROS at copper sites that activate dioxygen through an understanding of the mechanism of activation. More specifically, copper sites that activate O2 in the presence of phenolates/phenols groups will be investigated at depth as such sites have been implicated as ROS generators in plaques associated with AD. The synthetic analog approach will be our investigation tool whereby structurally-related low molecular weight complexes will be synthesized and examined at a small molecule level of detail to reveal intrinsic structural, electronic, and reactivity properties uncoupled from the influences of the protein matrix. The operating premise is that such complexes will provide important mechanistic insights to the oxidative (CuI + O2 ) and reductive (Cu-O2 + substrate) half-reactions of biological systems if appropriate attention is directed to creating appropriate copper ligation environments. Particular attention will be focused on the most highly oxidized form(s) copper and how different electronic distributions lead to different reactivity. PUBLIC HEALTH RELEVANCE: Copper enzymes that react with dioxygen are essential to our lives especially with respect to transforming certain biological molecules from one form to another. A number of prominent neurological diseases including Alzheimer's disease are thought to result from a mismanagement of these copper resources and, under the conditions of oxidative stress create, reactive oxygen species (ROS) that lead to irreversible damage of nerve cells and dementia. Our research attempts to define how copper is held by proteins that create these damaging ROS with an eye toward developing appropriate copper binding agents that might attenuate ROS production and the progression of these debilitating diseases.