SYNTHETIC MODELING OF COPPER PROTEIN ACTIVE SITES

描述：拟议研究的目的是获得 基础结构、光谱和化学机理 了解铜蛋白的生物活性位点， 环境的重要性，通过合成，表征， 检查模型复合物的反应性。 通过这种方法 控制中央机构结构和职能的原则 生物氮循环中的酶（亚硝酸盐和一氧化二氮 还原酶），在代谢过程中结合或还原氧的蛋白质 过程（血蓝蛋白，细胞色素氧化酶），和酶， 使有机底物官能化以提供重要的代谢物 （酪氨酸酶、多巴胺β-单加氧酶、肽酰甘氨酸酰胺化 酶、颗粒甲烷单加氧酶和半乳糖氧化酶）将 被揭露。 虽然结构和功能不同。这些 生物分子遵循的反应路径， 涉及分子氧或氮的结合和/或活化的步骤 氧化物小分子，它们在自然界中的消耗和产生 对生命的运作至关重要。 的具体施舍 建议的研究是详细了解结构的 蛋白质的活性位点与分子氧和各种 氮氧化物，并解开这些小分子是如何被激活的， 在酶促过程中。 尤其是。一组不同的配体 尽管如此，将使用具有共同的特定N供体框架的 构建独特的铜络合物， 蛋白质的活性位点。 这些复合物将被充分表征 通过结构，光谱，和。在某些情况下。理论 方法，以便与生物系统进行比较。 这些仿生反应机制的平行研究 将执行复合物，以了解结构/功能 关系。 这些建模研究的重点将放在 关于解决以下问题（一）铜蛋白质的性质- 双氧加合物和双氧O-O键的途径 裂解并氧化底物。(ii)二次影响 铜-氧-氮氧化物的氢键作用 加合物结构和反应性。(iii)结构/功能关系 对于不寻常的二硫代硫酸盐桥连。混合价二铜“Cu-a”， 存在于细胞色素氧化酶和一氧化二氮中的电子转移位点 还原酶。(iv)结构、光谱特征和反应性 铜-有机自由基阵列在蛋白质中。及（v）范围及 新型高阶铜配合物释放NO的机理 可能具有药理学应用的氮氧化物。最终， 综合合成，物理化学。和机械研究， 建议将有助于阐明的基本 铜蛋白结构和功能的化学原理。 具有发现新催化剂或试剂的额外潜力。

DESCRIPTION: The objective of the proposed research is to gain a fundamental structural, spectroscopic, and mechanistic chemical understanding of copper protein active sites of biological and environmental importance through the synthesis, characterization, and examination of the reactivity of model complexes. Through this approach the principles that control the structures and functions of central enzymes in the biological nitrogen cycle (nitrite and nitrous oxide reductase), proteins that bind or reduce oxygen during metabolic processes (hemocyanin, cytochrome oxidase), and enzymes that functionalize organic substrates to provide important metabolites (tyrosinase, dopamine beta-monooxygenase, peptidyl glycine amidating enzyme, particulate methane monooxygenase, and galactose oxidase) will be revealed. Although structurally and functionally diverse. these biomolecules follow reaction paths that have in common key chemical steps involving the binding and/or activation of dioxygen or nitrogen oxides. small molecules whose consumption and generation in nature is critically important for the functioning of life. The specific alms of the proposed research are to understand in detail the structures of the active sites of the proteins that interact with dioxygen and various nitrogen oxides and to unravel how these small molecules are activated during, enzymatic processes. In particular. a divergent set of ligands that nonetheless have in common a specific N-donor framework will be used to construct unique copper complexes designed to mimic key aspects of the protein active sites. These complexes will be fully characterized by structural, spectroscopic, and. in some instances. theoretical methods in order to draw comparisons to the biological systems. Parallel studies of the mechanisms of biomimetic reactions of these complexes will be performed in order to understand structure/function relationships. Emphasis during these modeling studies will be placed on addressing the following issues (i) the properties of copper protein- dioxygen adducts and the pathways by which the dioxygen O-O bond is cleaved and substrates are oxidized. (ii) the influence of secondary hydrogen-bonding interactions on copper-dioxygen and -nitrogen oxide adduct structure and reactivity. (iii) structure/function relationships for the unusual dithiolate-bridged. mixed valent. dicopper "Cu-a," electron transfer site present in cytochrome oxidase and nitrous oxide reductase. (iv) the structural, spectroscopic features, and reactivity of copper-organic radical arrays in proteins. and (v) the scope and mechanism of NO release by new copper complexes of some higher-order nitrogen oxides that may have pharmacological applications. ultimately, the combined synthetic, physicochemical. and mechanistic studies that we propose will contribute toward the elucidation of the fundamental chemical principles that underlie copper protein structure and function. with additional potential for discovery of new catalysts or reagents.