Synthetic Modeling of Copper Protein Active Sites

铜在许多环境和生物重要过程中起着关键作用，特别是当被封装在自然界广泛分布的酶中时。在酶的活性位点中的铜离子执行各种重要功能，包括结合和活化双氧（O2）以实现代谢上重要的化学反应，以及在全球氮循环中重要的微生物呼吸过程期间还原氧化的含氮化合物如亚硝酸盐和一氧化二氮（N2 O）。尽管进行了广泛的研究，但关于这些过程的详细分子水平途径的许多问题仍然没有答案。本文所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，低分子量的配合物，旨在复制铜酶活性位点的结构和功能方面的特点，并研究其反应性。目标是发展对与生物系统相关的几何结构，电子结构，键合和反应机制的详细理解。最终，合成化合物的研究显示了铜蛋白活性位点在结构、键合、反应性和反应途径方面的可能性，从而为理解铜蛋白结构/功能关系提供了基础。特别是，这项研究的目的是提供详细的了解基本化学的功能的一个重要子集的含铜酶参与O2和N2 O的结合和激活。自最初的赠款提案（2007年7月）以来的进展记录在21篇出版物中，这些出版物已经出现或已提交出版，以及3个博士学位。论文和无机化学“论坛”共同编辑下的标题目前的赠款。今后的研究将涉及：（1）用于模拟一氧化二氮还原酶的Cuz位点的铜-硫化学，（2）在单铜位点的分子氧活化，和（3）在多铜位点的分子氧活化。在目标（1）中，我们将合成一种新的多铜硫化物模型化合物，并研究其与N_2O的反应性。在目标（2）和（3）中，将制备高反应性单铜和多铜氧化物质的合成类似物，以评估它们在结合和活化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，拟议的工作旨在开发具有根本意义的新型铜化学。

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.