Copper Dioxygen Reactivity in Model Complexes

描述（由申请人提供）：与分子氧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。然而，在高代谢活动的区域，如大脑，铜资源的管理不善被认为会导致许多衰弱性疾病，包括阿尔茨海默氏症（AD）和帕金森氏症。这些疾病的标志是形成带有错误折叠的蛋白质片段的斑块，这些蛋白质片段通常因氧化而受损。定义连接的环境和机制，其中偶然键合或故意螯合铜能够创造活性分子氧（ROS）是我们奋进了解。由于铜是生物学中所有氧化还原活性金属中最不稳定的，因此定义导致这种ROS的配位是具有挑战性的。在高度受控的配位环境中，如蛋白质或小铜络合物中，铜与分子氧的反应机制提供了一个逻辑起点，以定义在不太确定的生物条件下，什么是化学可能的，或者什么是化学可能的。广泛和长期的目标是如何通过对激活机制的理解来减弱在激活分子氧的铜位点处ROS的形成。更具体地说，铜的网站，激活O2在酚盐/酚类基团的存在下，将深入研究，因为这些网站已牵连作为活性氧发生器与AD相关的斑块。合成类似物的方法将是我们的调查工具，从而结构相关的低分子量复合物将被合成和检查在小分子水平的细节，揭示内在的结构，电子和反应性的影响，从蛋白质基质解耦的属性。操作的前提是，这样的配合物将提供重要的机械见解的氧化（CuI + O2）和还原（Cu-O2 +底物）半反应的生物系统，如果适当的注意力是针对创建适当的铜连接环境。特别注意将集中在最高度氧化的形式（S）铜和不同的电子分布如何导致不同的反应性。公共卫生相关性：与分子氧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这些铜资源的管理不善，并且在氧化应激的条件下产生活性氧（ROS），导致神经细胞的不可逆损伤和痴呆。我们的研究试图确定铜是如何被蛋白质保持的，这些蛋白质产生这些破坏性的ROS，着眼于开发适当的铜结合剂，可能会减弱ROS的产生和这些使人衰弱的疾病的进展。

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.