Synthetic Modeling of Copper Protein Active Sites

铜蛋白活性位点的综合建模

基本信息

批准号：
9320793
负责人：
WILLIAM B Tolman
金额：
$ 32.98万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9320793
关键词：
Active Sites Address Anabolism Applications Grants Binding Binding Proteins Biological Biological Assay Biological Process Biology Chemicals Chemistry Complex Copper Data Decarboxylation Dioxygen Disease Doctor of Philosophy Electrons Encapsulated Enzymes Geometry Glean Goals Grant Health Histidine Homeostasis Hormones Human Hydroxylation Inorganic Chemistry Ions Iron Kinetics Knowledge Laboratories Life Ligands Metabolic Metalloproteins Metals Methane hydroxylase Mixed Function Oxygenases Modeling Molecular Molecular Weight Mono-S Nature Neurotransmitters Nitrites Nitrogen Nitrogen Oxides Nitrous Oxide Oxidants Oxidases Oxidation-Reduction Oxides Oxygen Particulate Pathway interactions Play Process Production Property Proteins Public Health Publications Reaction Reagent Research Respiration Respiratory Process Role Route Side Site Structure Structure-Activity Relationship Sulfides Sulfur Testing Work analog biological systems catalyst chemical reaction design electronic structure enzyme model enzyme structure greenhouse gases insight interest microbial nitrous oxide reductase novel oxidation peptide hormone protein function protein structure protein structure function small molecule

项目摘要

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.

铜在许多环境和生物学上重要的过程中起关键作用，尤其是当封装在广泛分布在自然界的酶内时。酶的活性位点中的铜离子执行多种重要功能，包括二氧化基因（O2）的结合和激活，以实现代谢上具有重要意义的化学反应的作用，以及在小动物呼吸器过程中，在整体氮气中，在微生物呼吸器过程中，含氮和二氮（N2O）（N2O）（N2O）的氧化化合物的减少。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，许多问题仍然没有解决。本文描述的研究通过合成建模方法解决了其中一些问题。在这种方法中，旨在复制铜酶活性位点结构和功能方面的低分子量复合物的表征，并研究了它们的反应性。目标是对与生物系统相关的几何，电子结构，粘结和反应机制进行详细的了解。最终，对合成化合物的研究表明，从结构，键合，反应性和反应途径方面，铜蛋白活性位点的可能性，从而为理解铜蛋白结构/功能关系提供了基本基础。特别是，该研究旨在详细了解与O2和N2O的结合和激活有关的重要子集的重要子集的基本化学。自最初的赠款提案（2007年7月）以来的21种出版或已提交出版的出版物以及3博士学位的进展。这些论文和无机化学“论坛”是根据当前赠款的划定的。未来的研究将解决：（1）用于建模一氧化二氮还原酶的CUZ位点，（2）单室位点的二氧化物激活，以及（3）多能位点的二氧化物激活。在AIM（1）中，将合成一个不寻常的四甲磺化簇（CUZ）的新的多型硫化物模型（CUZ），在环境重要的酶（一二氮还原酶）中，将合成，并研究其与N2O的反应性。在AIM（2）和（3）中，将准备高反应性单和多掌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结构/功能关系外，拟议的工作还旨在发展具有基本意义的新型铜化学。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rapid C-H bond activation by a monocopper(III)-hydroxide complex.

DOI：
10.1021/ja207882h
发表时间：
2011-11-09
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Donoghue, Patrick J.;Tehranchi, Jacqui;Cramer, Christopher J.;Sarangi, Ritimukta;Solomon, Edward I.;Tolman, William B.
通讯作者：
Tolman, William B.

Perturbing the Copper(III)-Hydroxide Unit through Ligand Structural Variation.