SYNTHETIC MODELING OF COPPER PROTEIN ACTIVE SITES

描述：（改编自申请人摘要）含铜蛋白质 在它们的活性位点代表了一个大的和功能上重要的类别， 在生命过程中起核心作用的金属生物分子。Electro 分子氧的转移、可逆结合和活化、有机物的氧化 分子，和氮氧化物活化是广泛应用的说明性实例。 铜蛋白进行的一系列重要反应。该功能 多样性与几何形状的高度可变性相匹配， 铜活性中心的电子结构和光谱特征。 尽管在将这些特征与功能属性联系起来方面做了大量的努力， 通过实验和理论研究， 分子水平上的结构/功能关系是不完整的， 关于铜介导过程的详细机制的问题， 生物学仍然没有答案。这些问题将在拟议的 通过合成建模方法进行研究，其中低分子量 设计用于复制金属蛋白活性位点结构的复合物， 功能的特点和他们的反应性检查。通过这个 方法，对铜位点结构的基本化学见解， 将获得作用机制。建议的具体目标 研究的目的是： 1.了解铜蛋白处理氮氧化物的机制 如亚硝酸盐和一氧化二氮还原酶，在全球 氮循环为此，合成，表征，和 将以铜-次硝酸盐络合物的反应性为目标。 2.了解结构扰动如何影响 普遍存在的铜-硫醇盐电子转移位点。特别是 微扰单核细胞1型和 双核，混合价CuA中心将被追求。 3.获得分子氧途径的基本化学信息 单核铜位点的活化，例如在 多巴胺-β-单加氧酶和肽基甘氨酸α羟基化 单加氧酶是哺乳动物激素生物合成的重要催化剂。的 新型单铜分子氧化合物合成、表征及反应活性 将被研究。 4.了解分子氧在三核铜位点的活化， 多铜氧化酶和颗粒甲烷单加氧酶， 预组装氮给体三铜（I）配合物合成及其氧反应性 配体。 5.为铜介导的辅因子生物合成提供新的机制见解， 胺氧化酶和半乳糖氧化酶，这两种酶都具有不寻常的有机 在涉及Cu的反应中后修饰的辅因子， O2 .特别地，研究了配位酚盐和/或配位酚盐的活化。 硫酚盐配体将被执行。

DESCRIPTION: (adapted from applicant's abstract) Proteins that contain copper in their active sites represent a large and functionally significant class of metallobiomolecules that play central roles in life processes. Electro transfer, reversible binding and activation of dioxygen, oxidation of organic molecules, and nitrogen oxide activation are illustrative examples of the wide range of important reactions performed by copper proteins. This functional diversity is matched by a high degree of variability in the geometric, electronic structural and spectroscopic features of the copper active sites. Despite extensive efforts to relate these features to functional attributes through experimental and theoretical studies, our understanding of structure/function relationships at the molecular level is incomplete and many questions concerning the detailed mechanisms of copper-mediated processes in biology remain unanswered. Such issues will be addressed in the proposed research through the synthetic modeling approach, wherein low molecular weight complexes designed to replicate metalloprotein active site structure and function are characterized and their reactivity examined. Through this approach, fundamental chemical insights into copper site structure and mechanisms of action will be obtained. The specific aims of the proposed research are to: 1.Understand the mechanisms of nitrogen oxide processing by copper proteins such as nitrite and nitrous oxide reductase, important players in the global nitrogen cycle. Toward this end, the synthesis , characterization, and reactivity of copper-hyponitrite complexes will be targeted. 2.Understand how structural perturbations influence the function of the ubiquitous copper-thiolate electron transfer sites. In particular, the synthesis and characterization of models of perturbed mononuclear type 1 and dinuclear, mixed-valence CuA centers will be pursued. 3.Obtain fundamental chemical information on the pathways of dioxygen activation at mononuclear copper sites such as those found in dopamine-beta-monooxygenase and peptidylglycine alpha hydroxylating monooxygenase, important catalysts in mammalian hormone biosynthesis. The synthesis, characterization , and reactivity of new monocopper-dioxygen species will be studied. 4.Understand dioxygen activation at trinuclear copper sites found in the multicopper oxidases and particulate methane monooxygenase by targeting the synthesis and O2 reactivity of tricopper(I) complexes of preorganized N-donor ligands. 5.Provide new mechanistic insights into copper-mediated cofactor biogenesis in the amine oxidases and galactose oxidase, both of which have unusual organic cofactors that are post-translationally modified in reactions involving Cu and O2 . In particular, studies of the activation of coordinated phenolate and/or thiophenolate ligands will be performed.