Binuclear Copper-O2 Intermediates: Thermodynamic and Mechanistic Insights

双核铜-O2 中间体：热力学和机理见解

基本信息

批准号：
9154469
负责人：
T DANIEL STACK
金额：
$ 30.02万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-23 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9154469
关键词：
Aerobic Affect Affinity Alzheimer&apos s Disease Amino Acids Area Attention Attenuated Belief Benchmarking Binding Biochemistry Biological Biology Brain Catechols Cells Chemicals Complex Copper Coupled Data Dioxygen Dipeptides Electron Transport Electronics Electrons Ensure Environment Enzymes Equilibrium Geometry Goals Hemocyanin Histamine Histidine Human Hydroxylation Imidazole Investigation Isotopes Kinetics Lead Life Ligands Ligation Mediating Metabolic Metabolism Metals Methane hydroxylase Methanol Modeling Molecular Weight Mono-S Monophenol Monooxygenase Nature Oxidants Oxidation-Reduction Oxidative Stress Oxides Parkinson Disease Particulate Pathway interactions Peroxides Phenols Physiological Physiology Process Production Property Proteins Protons Reaction Reactive Oxygen Species Reducing Agents Research Resources Role Series Side Site System Temperature Thermodynamics Variant Work alkalinity base biological systems insight nervous system disorder oxidation oxidative damage phenolate self assembly small molecule

项目摘要

Project Summary: Copper enzymes that react with dioxygen are essential to our lives especially with respect to transforming 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 adventitiously bonded copper that reacts with dioxygen to form reactive dioxygen species (ROS) that lead to uncontrolled oxidative degradation of important biological molecules, ultimately leading to debilitating neurological diseases. Defining the ligation environment and the mechanism by which adventitiously bonded copper is able to create ROS is our overarching objective. 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 complexes, provide a logical starting point to define what is chemically possible or if not what is chemically probable under less-defined, mismanaged conditions. We postulate that a mechanistic understanding of dioxygen activation and oxidative reactivity will inform on how best to attenuate ROS production at mismanaged copper sites. More specifically, binuclear copper sites that activate O2 and oxidize difficult substrates will be investigated in depth. We use a synthetic approach in our research whereby structurally-related low molecular weight complexes having faithful structural relationships to biological sites are examine for their oxidative reactive at a small molecule level of detail to reveal intrinsic structural, electronic, and properties. As our work lacks the superstructure of the biological systems, we use extremely low solution temperature to perform the investigation. The operating premise is that such complexes will provide important mechanistic insights to the oxidative (Cu(I) + O2) and reductive (Cu-O2 + substrate) half- reactions of biological systems if appropriate attention is directed to creating appropriate copper ligation environments.

项目摘要：与二恶英反应的铜酶对我们的生活至关重要，尤其是在转变方面从一种形式到另一种形式的生物分子。然而，在高代谢活动（例如大脑）的地区据认为，铜资源管理不善会导致与之反应的铜二氧化物形成反应性二氧化物（ROS），导致不受控制的氧化降解生物分子，最终导致令人衰弱的神经系统疾病。定义连接环境而且，粘合铜能够创建ROS的机制是我们的总体目标。由于铜是生物学中所有氧化还原活性金属中最不稳定的，因此定义了导致这样的协调 ROS具有挑战性。铜与二氧化物在高度控制配位中的反应机制环境，例如蛋白质或小型铜复合物，提供了一个合乎逻辑的起点来定义什么是在较不明显的，不雄厚的条件下，在化学上可能或者如果不是化学上的可能性。我们假设对二氧化激活和氧化反应性的机械理解将告知如何最好在不雄厚的铜现场减弱ROS生产。更具体地说，双核铜站点激活的O2和氧化困难的底物将深入研究。我们在我们的研究结构相关的低分子量复合物具有忠实的结构关系与生物位点在小分子的细节水平上检查其氧化反应性，以揭示内在的结构，电子和特性。由于我们的工作缺乏生物系统的上层建筑，我们使用极低的溶液温度进行研究。运营的前提是这样的综合体将为氧化（Cu（i） + O2）和还原性（CU-O2 +底物）提供重要的机械见解生物系统的反应，如果关注适当的关注，则可以建立适当的铜结扎环境。