SYNTHETIC MODELING OF COPPER PROTEIN ACTIVE SITES

描述：拟议研究的目标是获得 基础结构、光谱和机械化学 对生物铜蛋白活性部位的认识 对环境的重要性通过合成、表征和 模型络合物反应性的考察。通过这种方法 控制中央银行结构和功能的原则 生物氮循环中的酶(亚硝酸盐和一氧化二氮 还原酶)，代谢过程中结合或还原氧气的蛋白质 过程(血蓝蛋白、细胞色素氧化酶)和酶 使有机底物功能化以提供重要的代谢物 (酪氨酸酶、多巴胺β-单加氧酶、氨基甘氨酸酰胺化 酶、颗粒甲烷单加氧酶和半乳糖氧化酶)将 会被揭穿。尽管在结构和功能上是多样化的。这些 生物分子遵循具有共同关键化学物质的反应路径 涉及结合和/或激活氧气或氮气的步骤 氧化物。在自然界中消耗和生成的小分子 对生命的运转至关重要。的具体施舍 建议的研究是为了详细了解 与氧气和各种蛋白质相互作用的活性部位 以及揭开这些小分子是如何被激活的 在此过程中，酶过程。尤其是。一组不同的配体 尽管如此，仍有一个特定的N捐助者框架将被使用 构建独特的铜络合物，旨在模仿 蛋白质的活性部位。这些复合体将得到充分的表征 通过结构、光谱和。在某些情况下。理论性 方法与生物系统进行比较。 这些化合物的仿生反应机理的平行研究 为了理解结构/功能，将进行复杂的操作 两性关系。在这些建模研究中，重点将放在 关于解决以下问题：(I)铜蛋白的性质- 氧加成物与氧O-O键的作用途径 解理和底物被氧化。(二)二次世界大战的影响 铜-氧-氮氧化物上的氢键相互作用 加合物结构和反应性。(三)结构/职能关系 对于不寻常的二硫代桥联。混合价。双铜合金， 细胞色素氧化酶和一氧化二氮中存在的电子转移位 还原酶。(4)结构、光谱特征和反应性 蛋白质中的铜-有机自由基阵列。和(V)范围和 某些高阶新型铜配合物释放NO的机理 可能具有药理应用的氮氧化物。最终， 综合合成的、物理化学的。以及我们的机械论研究 建议将有助于阐明基本的 构成铜蛋白质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.