Copper Dioxygen Reactivity in Model Complexes

模型配合物中的铜双氧反应性

基本信息

批准号：
7591777
负责人：
T DANIEL STACK
金额：
$ 32.16万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-07-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7591777
关键词：
Alzheimer&apos s Disease Area Attention Attenuated Binding Biological Biology Brain Catechols Chemistry Classification Complex Copper Data Dementia Development Dioxygen Disease Electrodes Electronics Environment Enzymes Equilibrium Eye Galactose Oxidase Gel Goals Hydroxylation Imidazole Investigation Lead Life Ligands Ligation Literature Measurable Metabolic Metals Methods Modeling Molecular Weight Mononuclear Natural graphite Nature Neurons Oxidants Oxidation-Reduction Oxidative Stress Phenols Process Production Property Protein Fragment Proteins Reaction Reactive Oxygen Species Research Resources Silicon Dioxide Site Solutions Solvents System Temperature Testing Variant alcohol oxidase analog biological systems catalyst cold temperature density flexibility insight metalloenzyme nervous system disorder oxidation oxidative damage phenolate phenoxy radical public health relevance small molecule tool

项目摘要

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.

描述（由申请人提供）：与二恶英反应的铜酶对我们的生活至关重要，尤其是在将某些生物分子从一种形式转化为另一种形式的情况下。然而，在高代谢活动（例如大脑）的领域，铜资源管理不善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。这些疾病的标志是形成了斑块，这些斑块经常被氧化而损坏。我们要理解的是，定义结扎环境和外观粘合或故意隔离的铜物种（ROS）的机制是我们努力理解的。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的协调是具有挑战性的。在高度控制的配位环境中，铜与二氧化物反应的机制（例如蛋白质或小铜配合物中）提供了逻辑开端，以定义什么是化学上可能的，或者如果不是在不太定义的生物条件下化学上可能的东西。广泛的长期目标是如何通过了解激活机制来衰减铜部位的ROS形成，从而激活二恶英。更具体地说，将在酚酸/酚类组存在下激活O2的铜位点在深度研究，因为与AD相关的斑块中，此类位点被暗示为ROS发电机。合成模拟方法将是我们的研究工具，从结构相关的低分子量复合物将在小分子级别的细节级别进行合成和检查，以揭示与蛋白质基质的影响与固有的结构，电子和反应特性。操作前提是，这样的复合物将为氧化（CUI + O2）和还原性（CU-O2 +底物）的一半反应提供重要的机械见解，如果适当的注意力用于创建适当的铜连接环境。特别注意的是最高度氧化的铜，以及不同的电子分布如何导致不同的反应性。公共卫生相关性：与二氧化物反应的铜酶对我们的生活至关重要，尤其是将某些生物分子从一种形式转变为另一种形式的铜酶。人们认为，包括阿尔茨海默氏病在内的许多突出的神经疾病被认为是由于这些铜资源的管理不善而造成的，在氧化应激的条件下会产生，活性氧（ROS），导致神经细胞和痴呆症的不可逆转损害。我们的研究试图定义蛋白质如何持有铜，从而产生这些破坏性ROS，以期开发适当的铜结合剂，这些铜结合剂可能会减弱ROS的产生和这些衰弱的疾病的发展。