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，与其在二氧化碳(O2)和氮氧化物(NOx)的生化处理中的重要作用相关。关于铜(I)/O2的相互作用、加合物的形成、衍生结构及其相关的光谱学、O-O键断裂和底物氧化化学仍有许多问题。这些也可能与氧化应激的情况有关，例如，在阿尔茨海默氏症或普里恩病等神经疾病中。铜-NOx的研究涉及一氧化二氮还原酶的活性中心化学，以及铜离子在一氧化氮(.NO)生物化学中可能的关键作用，包括(半胱氨酸)硫醇亚硝化化学，或介导氮氧基(NO-)化学和过氧亚硝酸根氧化应激。研究方法分成几个子项目，分别针对不同的主题、问题或化学体系。这些包括：(1)基础铜/氧化学的放大：研究通过铜(I)/一氧化碳光化学触发的亚毫秒CuI/O2相互作用，以及配体对铜/氧结合和羟化的电子效应，(2)铜超氧化物的研究，(3)铜/氧介导的底物氧化的机理研究，包括探测二铜侧向过氧基与双钼氧基的相互转化，以及铜(III)2(O)2部分的质子化-还原，(4)与蛋氨酸(硫醚)型配体产生相关化学，与铜(N)-OOR物种的O-O裂解化学，(5)氨基酸修饰的铜蛋白质活性中心辅因子的模拟，它们的生物发生和化学，(6)铜离子与NO，NO-，过氧亚硝酸盐的化学及其与铜/氧衍生物种的关系，以及铜介导的牙合作用的研究，即，铜(I)+RSNO，(7)与铜氧化酶相关的三铜铜簇合物的O2化学的发展，以及(8)与亚硝酸还原酶相关的新的铜硫化物化学和N2O反应的阐述。拟议的研究有助于更广泛地了解铜的生物化学、蛋白质对O2和/或NOx的激活/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.