Bioinorganic Copper Coordination Chemistry

生物无机铜配位化学

• 批准号: 7259962
• 负责人: KENNETH D. KARLIN
• 金额: $ 24.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7259962
• 关键词: Active Sites; Alzheimer' s Disease; Amyloid; Basic Science; Binding; Biochemical Process; Biochemistry; Biochemistry, Other; Biology; Carbon Monoxide; Catechols; Chemicals; Chemistry; Classification; Complex; Copper; Detection; Development; Dioxygen; Dipeptides; Disease; Electronics; Electrons; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Generations; Goals; Heme; Heme Iron; Histidine; Hydrogen; Hydrogen Bonding; Hydrogen Peroxide; Imidazole; Investigation; Ions; Isotopes; Kinetics; Lead; Ligands; Ligation; Mediation; Metalloproteins; Metals; Mixed Function Oxygenases; Modeling; Nitrates; Nitric Oxide; Nitrites; Nitrogen Oxides; Nitrous Oxide; Object Attachment; Oxidants; Oxidative Stress; Oxidoreductase; Peptides; Peroxides; Peroxonitrite; Phenols; Photochemistry; Physiologic pulse; Play; Property; Proteins; Pulse taking; Reaction; Reactive Oxygen Species; Reducing Agents; Research; Research Methodology; Research Personnel; Research Proposals; Role; Side; Site; Solvents; Source; Spectrum Analysis; Stress; Structure; Sulfides; Sulfur; Superoxides; System; Testing; Therapeutic; Thermodynamics; absorption; adduct; chemical binding; cold temperature; design; electron density; nervous system disorder; nitrate; nitrous oxide reductase; novel; oxidation; photolysis; preference; programs; thioether

DESCRIPTION (provided by applicant): The goal of the proposed research is to further develop fundamental aspects of copper coordination chemistry relevant to its essential role in the biochemical processing of dioxygen (O2) and nitrogen oxides (NOx). Many questions remain concerning copper(l)/O2 interactions, dynamics & energetics of O2-adduct formation, as well as questions concerning structure, associated spectroscopy, O-O bond cleavage (i.e., O2- activation) and substrate oxidation chemistries. These may also be relevant to situations of oxidative stress, e.g., in neurological disorders such as Alzheimer's disease. Copper-NOx investigations are relevant to the active site chemistry in nitrite and nitrous oxide (N2O) reductases, and to the possible role of copper ion in nitrogen monoxide ("NO) biochemistry, including mediation of O2 with -NO peroxynitrite (O=NOO~) chemistry and oxidative (and/or nitrative) stress. The research methods divide into sub-projects, directed along various themes or chemical systems. These include (1) study of O2 and carbon monoxide (CO, as O2-surrogate) kinetics and thermodynamics of binding to tetradentate ligand Cu(l)-chelates, (2) study of key ligand- Cu2+(O2-) (superoxide) solvent hydrogen bonding and photochemistry, (3) a major effort to unravel mechanistic details of ligand-Cu2+(O2-) substrate reactivity involving hydrogen-atom transfer chemistry, (4) study of new tetradentate ligand-Cu complexes including with thioether donors, of relevance to certain Cu- monooxygenases, emphasizing O2 & CO binding kinetics-thermodynamics and structural-spectroscopic comparisons to other systems, (5) transient absorption spectroscopic detection of previously unobserved primary Cu/O2 =1:1 adducts and elucidation of their kinetics-thermodynamics and spectroscopy, employing highly reactive tridentate ligand Cu complex systems, (6) investigation of copper ion complexation, structure, binding and chemical reactivity with histidine-histidine peptide moieties (novel binding motifs in copper biochemistry), emphasizing previously un-researched copper(l) coordination chemistry of HisHis and the known metal binding portion (residues 6-14) of the Alzheimer's disease associated amyloid ??peptide, (7) elaboration of Cu-sulfide chemistry, including generation and characterization of new cluster compounds relevant to the active site of nitrous oxide reductase, with additional emphasis placed on the complexes' ability to reductively activate N2O, and (8) investigation of ligand Cu+ reactions with NO and O2, leading to peroxynitrite-derived chemistry. The proposed studies contribute to a broader understanding of copper biochemistry, other metalloprotein (e.g., heme or non-heme iron) activation/reduction of O2 and NOx in biology and associated disease states. Potential long-term applications of this basic research include development of enzyme inhibitors and relevant disease therapeutic strategies.

描述（由申请人提供）：拟议研究的目的是进一步发展与其在二氧化物（O2）和氮氧化物（NOX）生化过程中的重要作用相关的铜配位化学的基本方面。关于铜（L）/O2相互作用，O2-ADDUCT形成的动力学和能量学以及有关结构，相关光谱，O-O键裂解（即O2-激活）和底物氧化化学的问题。这些也可能与氧化应激的情况有关，例如在阿尔茨海默氏病等神经系统疾病中。 Copper-NOx investigations are relevant to the active site chemistry in nitrite and nitrous oxide (N2O) reductases, and to the possible role of copper ion in nitrogen monoxide ("NO) biochemistry, including mediation of O2 with -NO peroxynitrite (O=NOO~) chemistry and oxidative (and/or nitrative) stress. The research methods divide into sub-projects,沿着各种主题或化学系统的指向。配体-CU2+（O2-）底物反应性涉及氢 - 原子转移化学，（4）研究新的四齿配体-CU复合物，包括与硫醚供体，与某些Cu-单糖酶相关，强调O2和共同结合动力学和结构范围的Systroume-SonspertRospopicip sopportiant（其他）概念，并强调其他系统，并具有其他系统。检测先前未观察到的原发性Cu/O2 = 1：1加合物及其动力学 - 心理动力学和配乐的检测，采用高反应性三齿配体Cu复合体系统，（6）研究铜离子络合，结构，结构，结构，结构，结合性和化学反应性，以前与小型氨基氨基氨基氨基化剂的结合（与小组氨酸粘液蛋白的结合）（中） hishis的未研究的铜（L）配位化学和已知的金属结合部分（残基6-14）相关的相关的淀粉样蛋白肽，（7）CU-硫化物化学的精确阐述，包括与新硝基氧化物'相关的新硝化量相关的新氮化物相关的生成和表征，包括与氧化物的活跃部位相关的表征， N2O和（8）对NO和O2的配体Cu+反应的研究，导致过氧亚硝酸盐衍生的化学。拟议的研究有助于更广泛地了解铜生物化学，其他金属蛋白（例如血红素或非血红素铁）在生物学和相关疾病状态中O2和NOX的激活/减少。这项基础研究的潜在长期应用包括开发酶抑制剂和相关的疾病治疗策略。