Bioinorganic Copper Coordination Chemistry

拟议研究的目标是进一步发展铜配位的基本方面。 与其在二氧化碳(02)和氮氧化物生化过程中的重要作用有关的化学 (NOx)。许多问题仍然集中在铜(I)/O2的相互作用，加合物的形成，衍生结构 及其相关的光谱分析、O-O键断裂和底物氧化化学。这些也可能是 与氧化应激状态有关，例如，在阿尔茨海默氏症或普里恩病等神经疾病中。 铜-NOx的研究与一氧化二氮还原酶的活性中心化学有关，并且 铜离子在一氧化氮(.NO)生化中可能的关键作用，包括(半胱氨酸)硫醇亚硝化 化学，或硝基(NO-)化学和过氧亚硝酸氧化应激的中介。研究方法 根据不同的主题、问题或化学系统，分成几个子项目。这些措施包括： (1)基础铜/氧化学的放大：用CuI/C-研究亚毫秒CuI/O2相互作用 一氧化氮光化学触发和配体电子效应对铜/氧结合和羟化的影响，(2) 铜超氧化物的研究，(3)CuN/O2介导底物氧化的机理研究，包括 探讨CuN_2(O)_2的侧向过氧化氢与双-L氧基的相互转化和质子化还原 部分，(4)蛋氨酸(硫醚)型配体的相关化学生成和O-O裂解 化学与铜，-OOR物种，(5)氨基酸修饰的铜蛋白活性中心辅因子的模拟，其 生物成因和化学，(6)铜离子化学与NO、NO-、过氧亚硝酸根及其 与铜/氧衍生物种的关系及铜介导的牙合作用的研究，即Cu_+RSNO，(7) 与铜氧化酶相关的三铜铜簇合物的氧化学研究进展 阐述与一氧化二氮还原酶有关的新的铜硫化物化学和N20反应活性。这个 拟议的研究有助于更广泛地了解铜的生物化学、蛋白质的激活/还原 适用于其他金属(即，血红素或非血红素铁)和疾病状态的02和/或NOx。潜力 应用包括开发酶抑制剂和相关的疾病治疗策略。

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.