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）：拟议研究的目标是进一步开发铜配位化学的基本方面，与其在双氧（O2）和氮氧化物（NOx）的生化过程中的重要作用相关。关于铜(I)/O 2 相互作用、O 2 加合物形成的动力学和能量学，以及关于结构、相关光谱、O-O键断裂（即O 2 -活化）和底物氧化化学的问题，仍然存在许多问题。这些也可能与氧化应激的情况有关，例如阿尔茨海默病等神经系统疾病。铜-NOx 研究与亚硝酸盐和一氧化二氮 (N2O) 还原酶的活性位点化学以及铜离子在一氧化氮 ("NO) 生物化学中的可能作用相关，包括 O2 与 -NO 过氧亚硝酸盐 (O=NOO) 的介导~) 化学和氧化（和/或硝化）应激研究方法分为多个子项目，针对不同的主题或化学系统，其中包括 (1) 对 O2 和一氧化碳的研究。 （CO，作为 O2-替代物）与四齿配体 Cu(l)-螯合物结合的动力学和热力学，(2) 关键配体-Cu2+(O2-)（超氧化物）溶剂氢键和光化学的研究，(3) 主要研究努力揭示配体-Cu2+(O2-)底物反应性涉及氢原子转移化学的机制细节，(4)研究新型四齿配体-Cu配合物，包括与硫醚的配合物供体，与某些铜单加氧酶相关，强调 O2 和 CO 结合动力学-热力学以及与其他系统的结构光谱比较，(5) 瞬态吸收光谱检测先前未观察到的初级 Cu/O2 =1:1 加合物并阐明其动力学-热力学和光谱学，采用高反应性三齿配体铜络合物系统，(6) 研究铜离子络合、结构、结合和化学反应性组氨酸-组氨酸肽部分（铜生物化学中的新颖结合基序），强调先前未研究的 HisHis 的铜（l）配位化学以及阿尔茨海默病相关淀粉样蛋白肽的已知金属结合部分（残基 6-14），（ 7) 硫化铜化学的阐述，包括与一氧化二氮还原酶活性位点相关的新簇化合物的生成和表征，特别强调配合物还原激活 N2O 的能力，以及 (8) 研究配体 Cu+ 与 NO 和 O2 的反应，从而产生过氧亚硝酸盐衍生的化学反应。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 的活化/还原。这项基础研究的潜在长期应用包括酶抑制剂和相关疾病治疗策略的开发。