Bioinorganic Copper Coordination Chemistry

生物无机铜配位化学

• 批准号: 7364906
• 负责人: KENNETH D. KARLIN
• 金额: $ 11.11万
• 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 2007-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364906
• 关键词: Active Sites; Alzheimer' s Disease; Amino Acids; Binding; Binding Sites; Biochemical Process; Biochemistry; Biogenesis; Biological; Carbon Monoxide; Chemicals; Chemistry; Complex; Copper; Coupling; Cysteine; Depth; Development; Dioxygen; Disease; Disulfides; Electronics; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Equilibrium; Exhibits; Generations; Goals; Heme; Heme Iron; Hydroxylation; Imidazole; Investigation; Ions; Isotopes; Kinetics; Ligands; Light; Mediating; Mediation; Metalloproteins; Metals; Methionine; Modeling; Monophenol Monooxygenase; Nature; Nitric Oxide; Nitrogen Oxides; Nitrous Oxide; Object Attachment; Oxidative Stress; Oxidoreductase; Peroxonitrite; Phenols; Photochemistry; Positioning Attribute; Prion Diseases; Process; Proteins; Protons; Reaction; Research; Research Methodology; Research Personnel; Role; Side; Site; Solutions; Solvents; Spectrum Analysis; Structure; Sulfhydryl Compounds; Sulfides; Sulfur; Superoxides; System; Therapeutic; Time; Variant; Work; adduct; base; cofactor; cold temperature; copper oxidase; cysteinyltyrosine; design; desire; electron donor; insight; interest; millisecond; nervous system disorder; nitrous oxide reductase; nitroxyl; oxidation; protein activation; protonation; thioether; tyrosyl-lysine; tyrosyltyrosine

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 (02) and nitrogen oxides (NOx). Many questions remain conceming copper(I)/O2 interactions, formation of adducts, derived structures and their associated spectrocopy, O-O bond cleavage, and substrate oxidation chemistries. These may also be relevant to situations of oxidative stress, e.g., in neurological disorders such as Alzheimer's or prion diseases. Copper-NOx investigations are relevant to the active site chemistry in nitrous oxide reductase, and the possibly crucial role of copper ion in nitric oxide (.NO) biochemistry, including (cysteine) thiol nitrosylation chemistry, or mediation of nitroxyl (NO-) chemistry and peroxynitrite oxidative stress. The research methods break down into sub-projects, directed along various themes, questions or chemical systems. These include, (1) amplification of basic Cu/O2 chemistry: study sub-millisecond CuI/O2 interactions by CuI/carbon - monoxide photochemical triggering, and ligand electronic effects on Cu/O2 binding and hydroxylation, (2) study of Cu-superoxides, (3) mechanistic investigation of Cun/O2 mediated substrate oxidations, including probing dieopper side-on peroxo vs. bis-l_-oxo interconversion, and protonation-reduction of culn2(o)2 moieties, (4) generation of relevant chemistry with methionine (thioether) type ligands, and O-O cleavage chemistry with Cu,-OOR species, (5) modeling of amino-acid modified Cu-protein active-site cofactors, their biogenesis and chemistry, (6) elucidation of copper ion chemistry with .NO, NO-, peroxynitrite, their relationship to Cu/O2 derived species, and study of Cu mediated dentirosylation, i.e., Cu _ + RSNO, (7) development of O2-chemistry with tricopper Cu3-cluster complexes relevant to copper oxidases, and (8) elaboration of new Cu-sulfide chemistry and N20 reactivity relevant to nitrous oxide reduetase. The proposed studies contribute to a broader understanding of copper biochemistry, to protein activation/reduction of 02 and/or NOx, as applied to other metals (i.e., heme or non-heme iron) and disease states. Potential applications include development of enzyme inhibitors and relevant disease therapeutic strategies.

这项研究的目标是进一步发展铜协调的基本方面 与其在分子氧（O2）和氮氧化物的生物化学处理中的基本作用有关的化学 （NOx）。许多问题仍然涉及铜（I）/O2相互作用，加合物的形成，衍生结构 及其相关的光谱学、O-O键断裂和底物氧化化学。这些也可以 与氧化应激的情况相关，例如，神经系统疾病如阿尔茨海默氏症或朊病毒疾病。 铜-NOx研究与一氧化二氮还原酶中的活性位点化学有关， 铜离子在一氧化氮（.NO）生物化学中可能起关键作用，包括（半胱氨酸）巯基亚硝基化 化学，或调解硝酰基（NO-）化学和过氧亚硝酸盐氧化应激。研究方法 分解为分项目，按照沿着不同的主题、问题或化学系统。这些措施包括， (1)放大基本的Cu/O2化学：研究亚毫秒CuI/O2相互作用的CuI/碳- 一氧化物光化学触发和配体电子效应对Cu/O2结合和羟基化的影响，（2） Cu-超氧化物的研究，（3）Cun/O2介导的底物氧化的机理研究，包括 探索CuIn 2（O）2的过氧化与双-L-氧代互变以及质子化还原 部分，（4）与甲硫氨酸（硫醚）型配体产生相关化学反应，以及O-O裂解 （5）氨基酸修饰的Cu-蛋白活性位点辅因子的建模，其 （6）阐明了铜离子与NO、NO-、过氧亚硝酸根的化学关系， 与Cu/O2衍生物质的关系，以及Cu介导的牙苷化的研究，即，Cu _ + RSNO，（7） 开发与铜氧化酶相关的三铜Cu 3-簇合物的O2化学，以及（8） 阐述了与一氧化二氮还原酶相关的新的硫化铜化学和N2 O反应性。的 拟议的研究有助于更广泛地了解铜的生物化学，蛋白质活化/还原 O2和/或NOx，如应用于其它金属（即，血红素或非血红素铁）和疾病状态。潜在 应用包括酶抑制剂和相关疾病治疗策略的开发。