Bioinorganic Copper Coordination Chemistry

生物无机铜配位化学

• 批准号: 6767526
• 负责人: KENNETH D. KARLIN
• 金额: $ 1.42万
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6767526
• 关键词: Raman spectrometry; active sites; adduct; alkylation; chemical models; chemical reaction; copper; dopamine beta monooxygenase; enzyme mechanism; enzyme substrate complex; free radical oxygen; metal complex; metalloproteins; monophenol monooxygenase; nitrogen oxides; oxidation reduction reaction; oxidoreductase; oxygen transport; phenylalanine 4 monooxygenase; photochemistry; protein structure function

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(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 Cu(I)/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 dicopper side-on peroxo vs. bis-mu-oxo interconversion, and protonation-reduction of Cu(III)2(O)2 moieties, (4) generation of relevant chemistry with methionine (thioether) type ligands, and O-O cleavage chemistry with Cu(n)-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(I) + RSNO, (7) development of O2-chemistry with tricopper Cu3-cluster complexes relevant to copper oxidases, and (8) elaboration of new Cu-sulfide chemistry and N2O reactivity relevant to nitrous oxide reductase. The proposed studies contribute to a broader understanding of copper biochemistry, to protein activation/reduction of O2 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.

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)/O2 相互作用、加合物的形成、衍生结构及其相关光谱、O-O 键断裂和底物氧化化学，仍然存在许多问题。这些也可能与氧化应激的情况有关，例如阿尔茨海默病或朊病毒病等神经系统疾病。铜-NOx 研究与一氧化二氮还原酶的活性位点化学相关，以及铜离子在一氧化氮 (.NO) 生物化学中可能发挥的关键作用，包括（半胱氨酸）硫醇亚硝基化化学或硝酰基 (NO-) 化学的介导和过氧亚硝酸盐氧化应激。研究方法分为子项目，针对不同的主题、问题或化学系统。这些包括，(1) 基本 Cu/O2 化学的放大：研究 Cu(I)/一氧化碳光化学触发的亚毫秒 CuI/O2 相互作用，以及配体电子对 Cu/O2 结合和羟基化的影响，(2) 研究Cu-超氧化物，(3) Cun/O2 介导的底物氧化的机理研究，包括探测二铜侧过氧与双-mu-氧相互转化，以及Cu(III)2(O)2 部分的质子化还原，(4) 使用甲硫氨酸（硫醚）型配体生成相关化学，以及使用 Cu(n)-OOR 物质进行 O-O 裂解化学，(5) 氨基-酸修饰的铜蛋白活性位点辅助因子，它们的生物发生和化学，(6) 阐明铜离子与 .NO、NO-、过氧亚硝酸盐的化学反应，它们与 Cu/O2 衍生物种的关系，铜介导的齿基化，即 Cu(I) + RSNO 的研究，(7) 与铜氧化酶相关的三铜 Cu3 簇复合物的 O2 化学的发展，以及 (8) 新的硫化铜化学和相关 N2O 反应性的阐述一氧化二氮还原酶。拟议的研究有助于更广泛地了解铜的生物化学、O2 和/或 NOx 的蛋白质活化/还原，以及应用于其他金属（即血红素或非血红素铁）和疾病状态。潜在的应用包括酶抑制剂的开发和相关疾病治疗策略。