Synthetic Modeling of Copper Protein Active Sites

铜在许多重要的环境和生物过程中发挥着关键作用，特别是当铜被包裹在自然界中广泛分布的酶中时。酶活性部位的铜离子具有多种重要功能，包括结合和激活氧气(O2)以实现代谢上重要的化学反应，以及在微生物呼吸过程中还原氧化性含氮化合物，如亚硝酸盐和一氧化二氮(N2O)，这些过程在全球氮循环中至关重要。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然没有得到回答。这里描述的研究通过综合建模方法解决了这些问题中的一些。在这种方法中，设计的复制铜酶活性中心结构和功能的低分子量络合物被表征，并研究它们的反应性。目标是详细了解与生物系统相关的几何结构、电子结构、成键和反应机制。最终，对合成化合物的研究揭示了铜蛋白活性中心在结构、成键、反应活性和反应途径等方面的可能性，从而为理解铜蛋白结构/功能关系提供了基础。特别是，这项研究的目的是详细了解参与O2和N2O结合和激活的一组重要的含铜酶的功能的基本化学基础。自最初的赠款提案(2007年7月)以来的进展被记录在21份已出版或已提交出版的出版物中，以及3篇博士论文和一份在当前赠款范围内共同编辑的无机化学“论坛”。未来的研究将涉及：(1)用于模拟一氧化二氮还原酶CUZ位置的铜硫化学，(2)单铜位置的氧活化，以及(3)多铜位置的氧活化。在目标(1)中，将合成一个新的多铜(L)-硫化物模型，该模型是在一种环境重要的酶-一氧化二氮还原酶中发现的罕见的四铜-硫化物簇合物(CuZ)，并将研究它们与N2O的反应活性。在AIMS(2)和(3)中，将制备高活性的单铜和多铜氧化物种的合成类似物，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，拟议的工作还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.