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，这些方面与其在分子氧（O2）和氮氧化物（NOx）的生化处理中的重要作用有关。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，仍存在许多问题。这些也可能与氧化应激的情况有关，例如，神经系统疾病如阿尔茨海默氏症或朊病毒疾病。铜氮氧化物的研究与一氧化二氮还原酶中的活性位点化学有关，并且铜离子在一氧化氮（.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，或硝酰基（NO-）化学和过氧亚硝酸盐氧化应激的介导。研究方法分为子项目，沿着沿着各种主题，问题或化学系统。这些包括：（1）基本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，包括探测双铜侧-对-过氧与双-μ-氧相互转化，和Cu（III）2（O）2部分的质子化还原，（4）与甲硫氨酸产生相关化学反应（硫醚）型配体，和与Cu（n）-OOR物质的O-O裂解化学，（5）氨基酸修饰的Cu-蛋白活性位点辅因子的建模，它们的生物起源和化学，（6）与NO，NO-，过氧亚硝酸盐，它们与Cu/O2衍生物质的关系，以及Cu介导的牙苷化的研究，即，Cu（I）+ RSNO，（7）与铜氧化酶相关的三铜Cu 3-簇络合物的O2-化学的发展，和（8）与一氧化二氮还原酶相关的新的Cu-硫化物化学和N2 O反应性的阐述。所提出的研究有助于更广泛地理解铜生物化学、蛋白质活化/还原O2和/或NOx，如应用于其他金属（即，血红素或非血红素铁）和疾病状态。潜在的应用包括酶抑制剂和相关疾病治疗策略的开发。

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.