Synthetic Modeling of Copper Protein Active Sites

铜在许多重要的环境和生物过程中起着关键作用，特别是当被包裹在自然界中广泛分布的酶中时。酶活性位点上的铜离子具有多种重要功能，包括结合和激活双氧（O2）以影响代谢重要的化学反应，以及在全球氮循环中重要的微生物呼吸过程中氧化含氮化合物（如亚硝酸盐和氧化亚氮（N2O））的还原。尽管进行了广泛的研究，但有关这些过程的详细分子水平途径的许多问题仍未得到解答。本文描述的研究通过综合建模方法解决了其中的一些问题。在这种方法中，设计了低分子量复合物来复制铜酶活性位点的结构和功能，并对其反应性进行了研究。目标是发展对与生物系统相关的几何、电子结构、键合和反应机制的详细理解。最终，对合成化合物的研究显示了铜蛋白活性位点在结构、键合、反应活性和反应途径方面的可能性，从而为理解铜蛋白的结构/功能关系提供了基础基础。特别是，该研究的目的是提供详细的基本化学基础的理解的一个重要的含铜酶亚群的功能参与结合和活化O2和N2O。自最初的资助提案（2007年7月）以来的进展记录在21篇已经出现或已经提交出版的出版物中，以及3篇博士论文和在当前资助的标题下共同编辑的无机化学“论坛”。未来的研究将集中在：(1)铜硫化学用于模拟氧化亚氮还原酶的Cuz位点，(2)单铜位点的双氧活化，(3)多铜位点的双氧活化。在目的(1)中，将合成在一种重要的环境酶——氧化亚氮还原酶中发现的罕见的四铜硫簇（Cuz）的新的多铜硫模型，并研究它们与N2O的反应性。在目的(2)和(3)中，将制备高活性的单铜和多铜氧化物质的合成类似物，以评估它们在结合和激活O2的酶中的可能作用。除了渴望深入了解铜酶的结构/功能关系外，提出的工作旨在开发具有基础意义的新型铜化学。

Copper plays a key role in numerous environmentally and biologically important processes, particularly when encapsulated within enzymes that are widely distributed in Nature. The copper ions in the active sites of enzymes perform a variety of significant functions, including the binding and activation of dioxygen (O2) for effecting metabolically significant chemical reactions and the reduction of oxidized nitrogen-containing compounds like nitrite and nitrous oxide (N2O) during microbial respiratory processes important within the global nitrogen cycle. Despite extensive research, many questions remain unanswered concerning the detailed molecular level pathways of these processes. The research described herein addresses some of these questions through the synthetic modeling approach. In this approach, low molecular weight complexes designed to replicate aspects of copper enzyme active site structure and function are characterized and their reactivity studied. The goals are to develop detailed understanding of geometries, electronic structures, bonding, and reaction mechanisms relevant to the biological systems. Ultimately, the studies of synthetic compounds show what is possible for copper protein active sites in terms of structures, bonding, reactivity, and reaction pathways, thus providing a fundamental basis for understanding copper protein structure/function relationships. In particular, the research aims to provide detailed understanding of the fundamental chemistry underlying the function of an important subset of copper-containing enzymes involved In the binding and activation of O2 and N2O. Progress since the original grant proposal (July 2007) Is documented in 21 publications that have appeared or have been submitted for publication, as well as 3 Ph.D. theses and an Inorganic Chemistry "Forum" co-edited under the rubric of the current grant. Future research will address: (1) Copper-Sulfur Chemistry for Modeling the Cuz Site of Nitrous Oxide Reductase, (2) Dioxygen Activation at Monocopper Sites, and (3) Dioxygen Activation at Multicopper Sites. In aim (1), new multicopper(l)-sulfide models of the unusual tetracopper-sulflde cluster (Cuz) found in an environmentally Important enzyme, nitrous oxide reductase, will be synthesized and their reactivity with N2O will be studied. In aims (2) and (3), synthetic analogs of highly reactive mono- and multicopper oxidizing species will be prepared in order to evaluate their possible role In enzymes that bind and activate O2. In addition to aspiring to a deep understanding of copper enzyme structure/function relationships, the proposed work is aimed at developing novel copper chemistry of fundamental significance.