Bioinorganic Copper Coordination Chemistry

描述（由申请人提供）：拟议研究的目标是进一步发展铜配位化学的基本方面，其在二氧（O2）和氮氧化物（NOx）的生化处理中的重要作用。关于铜(I)/O2的相互作用、加合物的形成、衍生结构及其相关光谱、O-O键裂解和底物氧化化学，还有许多问题有待解决。这些也可能与氧化应激的情况有关，例如，在阿尔茨海默病或朊病毒疾病等神经系统疾病中。铜- nox的研究与氧化亚氮还原酶的活性位点化学有关，以及铜离子在一氧化氮（NO）生物化学中的可能的关键作用，包括（半胱氨酸）硫醇亚硝基化化学，或硝基（NO-）化学和过氧亚硝酸盐氧化应激的调解。研究方法分解成子项目，沿着不同的主题，问题或化学系统。这些包括：(1)基础Cu/O2化学的放大；通过Cu(I)/一氧化碳光化学触发研究亚毫秒级CuI/O2相互作用，以及配体电子效应对Cu/O2结合和羟基化的影响，(2)Cu-超氧化物的研究，(3)Cu/O2介导的底物氧化的机理研究，包括探测diccopper side-on - peroxo与bismu -oxo的相互转化，以及Cu(III)2(O)2基团的质子还原，(4)与甲硫氨酸（硫醚）型配体的相关化学生成。(5)氨基酸修饰的Cu-蛋白活性位点辅助因子的建模及其生物成因和化学性质；(6)铜离子与Cu(n)-OOR的化学性质。NO, NO-，过氧亚硝酸盐，它们与Cu/O2衍生物的关系，以及Cu介导的牙基化（即Cu(I) + RSNO）的研究，(7)与铜氧化酶相关的三铜cu3簇配合物的O2化学的发展，以及(8)与氧化亚氮还原酶相关的新的Cu硫化化学和N2O反应性的阐述。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，如应用于其他金属（即血红素或非血红素铁）和疾病状态。潜在的应用包括开发酶抑制剂和相关的疾病治疗策略。

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.