SYNTHETIC MODELING OF COPPER PROTEIN ACTIVE SITES

描述：(摘自申请者的摘要)含铜的蛋白质 在它们的活跃站点中代表了一大类具有重要功能的 在生命过程中发挥核心作用的矿物生物分子。电学 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都是广泛的 铜蛋白执行的一系列重要反应。此功能 与多样性相匹配的是几何上的高度可变性， 铜活性中心的电子结构和光谱特征。 尽管做出了大量努力将这些特征与功能属性相关联 通过实验和理论研究，我们对 分子水平上的结构/功能关系是不完整的 关于铜介导的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 旨在复制金属蛋白活性中心结构的复合体 对功能进行了表征，并检测了它们的反应性。通过这件事 方法，对铜位结构的基本化学见解和 将获得行动机制。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 铜-次亚硝酸盐络合物的反应性将成为目标。 2.了解结构扰动如何影响 无处不在的铜-硫代电子转移中心。尤其是， 扰动单核1型和单核型模型的合成与表征 将追求双核、混合价态的CUA中心。 3.获取有关氧气途径的基本化学信息 单核铜位的活化，如在 多巴胺-β-单加氧酶与甘氨酸肽α羟化 单加氧酶，哺乳动物激素生物合成的重要催化剂。这个 新的单铜氧物种的合成、表征及反应活性 将会被研究。 4.了解在三核铜位上发现的氧气活化 多铜氧化酶和颗粒甲烷单加氧酶通过靶向 预组织N-供体三铜(I)配合物的合成及其氧反应活性 配基。 5.对铜介导的辅因子生物生成提供了新的机制见解 胺氧化酶和半乳糖氧化酶，两者都有不同寻常的有机 在涉及铜和铜的反应中被翻译后修饰的辅因子 氧气。特别是，配位酚类和/或配位酚类化合物的活化研究 将进行硫代苯酚配体的合成。

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.