SYNTHETIC MODELING OF COPPER PROTEIN ACTIVE SITES

铜蛋白活性位点的综合建模

• 批准号: 6018887
• 负责人: WILLIAM B Tolman
• 金额: $ 20.91万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6018887
• 关键词: Raman spectrometry; active sites; chemical synthesis; copper; cytochrome oxidase; electron spin resonance spectroscopy; electron transport; enzyme model; hydrogen bond; metalloproteins; model design /development; nitric oxide; nitrous oxide; oxygen

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.

描述：拟议研究的目的是获得 基本结构，光谱和机械化学 了解生物学和 通过综合，表征和 检查模型复合物的反应性。 通过这种方法 控制中心的结构和功能的原理 生物氮循环中的酶（亚硝酸盐和一氧化物 还原酶），代谢过程中结合或减少氧气的蛋白质 过程（血红素，细胞色素氧化酶）和酶 功能化有机基材以提供重要的代谢产物 （酪氨酸酶，多巴胺β-单加氧酶，肽基甘氨酸衰变 酶，颗粒甲烷单加氧酶和半乳糖氧化酶）将 被揭示。 虽然在结构和功能上多样化。这些 生物分子遵循具有通用钥匙化学的反应路径 涉及二氧化物或氮的结合和/或激活的步骤 氧化物。小分子的消费和产生是 至关重要的是生活的运作。 特定施舍 拟议的研究是详细了解 与二氧化物相互作用的蛋白质的活性位点 氮氧化物，并揭示如何激活这些小分子 在期间，酶促过程。 尤其。一组不同的配体 尽管如此，将使用特定的N-Donor框架 构建旨在模仿关键方面的独特铜配合物 蛋白活性位点。 这些复合物将充分表征 通过结构，光谱和。在某些情况下。理论 为了对生物系统进行比较，方法。 对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。 在这些建模研究期间的重点将进行 解决以下问题（i）铜蛋白的特性 二氧化加合物和二氧化合物O-O键的途径 切割和底物被氧化。 （ii）次级的影响 铜 - 二氧和氧化氮的氢键相互作用 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桥。混合的瓦伦特。 Dicopper“ Cu-A”， 细胞色素氧化酶和一氧化二氮中存在的电子转移位点 还原酶。 （iv）结构，光谱特征和反应性 蛋白质中的铜 - 有机自由基阵列。 （v）范围和 新铜复合物没有释放的机制 可能具有药理应用的氮氧化物。最终， 合成的合成，物理化学。和我们的机械研究 建议将有助于阐明基本 基于铜蛋白结构和功能的化学原理。 还可以发现新的催化剂或试剂。