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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：
10217146
负责人：
WILLIAM B Tolman
金额：
$ 35.08万
依托单位：
WASHINGTON UNIVERSITY
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217146
关键词：
Active Sites Amides Amines Binding Biological Biomimetics Biotechnology Catalysis Chemicals Chemistry Collaborations Complex Copper Data Development Dioxygen Electron Transport Enzymes Evaluation Food Geometry Glean Health Histidine Hormones Human Hydrogen Bonding Investigation Ions Kinetics Knowledge Laboratories Life Ligands Lytic Metabolism Metalloproteins Methane Methane hydroxylase Methods Mixed Function Oxygenases Modeling Molecular Molecular Weight Nature Nitrogen Nitrogen Oxides Oxidases Oxygen Oxygenases Particulate Pathway interactions Peroxides Play Polysaccharides Preparation Process Property Proteins Reaction Research Role Route Site Spectrum Analysis Structure Structure-Activity Relationship Sulfides System Testing Time Work catalyst chemical reaction climate impact deprotonation design electronic structure insight interest irradiation nitrous oxide reductase novel oxidation protein structure function theories

项目摘要

Project Summary/Abstract The proposed work will provide detailed understanding of geometries, electronic structures, bonding, and chemical reaction mechanisms for copper complexes relevant to key postulated intermediates in copper enzymes. In specific aim 1, the properties and bio-relevant reactivity of [CuO]+ and [CuOOR]2+ complexes will be characrterized in order to evaluate their feasibility as intermediates in oxidation catalysis by monocopper sites in enzymes. Specific emphasis will be placed on evaluating mechanistic hypotheses put forth for lytic polysaccharide monooxygenase (LPMO), which is of particular interest due to its use in biotechnology applications and the very strong (>95 kcal/mol) C-H bond of its substrate that is attacked. In specific aim 2, a novel synthetic route will be used to access the first examples of complexes with the [CuIIOCuIII]3+ core, which has been postulated on the basis of theory to be particularly reactive and thus an attractive structural candidate for the key intermediate in particulate methane monooxygenase. This route will involve O-O bond cleavage of [CuII(µ- OOR)CuIII]3+ complexes using continuous irradiation or time-resolved transient spectroscopy methods in a collaborative effort, and will provide experimental evidence pertinent to the potential involvement of such species in pMMO and other catalytic systems that attack recalcitrant C-H bonds. In specific aim 3, the preparation and exploration of the properties and reactivity of novel tricopper-peroxo [Cu3(O22-)]n+ (n = 2-4) and sulfide-containing [Cu3(µ-S)]n+ (n = 1-4) clusters supported by new multinucleating ligands are proposed. The studies of the former will test specific structural proposals for a key intermediate (“PI”) in O2 reduction to H2O by the tricopper active site in the multicopper oxidases (MCO's). The studies of the latter will aim to evaluate mechanistic hypotheses for the sulfide-bridged tetracopper CuZ site in the key global nitrogen cycle enzyme nitrous oxide reductase (N2OR), for which the targeted tricopper clusters will serve as a subunit model. Through these exploratory synthetic studies, thorough examinations of molecular properties, and detailed kinetic and mechanistic evaluation of biomimetic reactions, new insights into the fundamental chemistry of reactive species relevant to putative active site intermediates will be obtained. Ultimately, these synthetic studies will 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. Such knowledge is critically important in view of the broad importance of copper-promoted biological reactions and, ultimately, will enable strategies for manipulation of enzyme function and development of new catalysts.

项目总结/摘要拟议的工作将提供详细的了解几何形状，电子结构，键合，和化学反应机制的铜配合物有关的关键假定中间体，铜酶在具体目标1中，研究了[CuO]+和[CuOOR]2+的性质和生物相关反应性，配合物将进行表征，以评估其作为氧化中间体的可行性酶中单铜位点的催化作用。具体重点将放在评估提出了溶解性多糖单加氧酶（LPMO）的机制假说，由于其在生物技术应用中的用途和非常强（>95 kcal/mol）的C-H 被攻击的基材的结合。在具体目标2中，将使用新的合成路线来获得具有[CuIIOCuIII]3+核心的络合物的第一个实例，其已经基于以下假设：理论是特别反应性的，因此是关键中间体的有吸引力的结构候选者，微粒甲烷单加氧酶。这条路线将涉及[CuII（µ- OOR）CuIII]3+配合物的连续辐射或时间分辨瞬态光谱法在合作的努力，并将提供实验证据有关的潜在参与这些物种在pMMO和其他催化体系中攻击不稳定的C-H键。在特定目的3、新型三铜过氧化合物的制备及性质和反应活性的研究 [Cu 3（O22-）]n+（n = 2-4）和含硫化物的[Cu 3（µ-S）]n+（n = 1-4）簇合物提出了多核配体。对前者的研究将测试具体的结构建议对于通过多铜中的三铜活性位点将O2还原成H2O的关键中间体（“PI”），氧化酶（MCO）。对后者的研究旨在评估关键的全球氮循环酶一氧化二氮还原酶中的硫桥四铜CuZ位点（N2 OR），其中靶向的三铜簇将用作亚基模型。通过这些探索性的合成研究，分子性质的彻底检查，以及详细的动力学和仿生反应的机理评估，对基础化学的新见解，将获得与推定的活性位点中间体相关的活性物质。最终，这些合成研究将显示铜蛋白活性位点在结构方面的可能性，键合、反应性和反应途径，从而为理解铜蛋白结构/功能关系。这种知识是至关重要的，广泛的重要性，铜促进生物反应，并最终将使战略，操纵酶的功能和开发新的催化剂。

项目成果

期刊论文数量（68）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Using synthetic chemistry to understand copper protein active sites: a personal perspective.

使用合成化学了解铜蛋白活性位点：个人观点。

DOI：
10.1007/s00775-006-0078-9
发表时间：
2006
期刊：
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry
影响因子：
0
作者：
Tolman,WilliamB
通讯作者：
Tolman,WilliamB

X-ray absorption spectroscopic and theoretical studies on (L)2[Cu2(S2)n]2+ complexes: disulfide versus disulfide(*1-) bonding.

(L)2[Cu2(S2)n]2 配合物的 X 射线吸收光谱和理论研究：二硫键与二硫键 (*1-) 键合。

DOI：
10.1021/ja0762745
发表时间：
2008
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Sarangi,Ritimukta;York,JohnT;Helton,MatthewE;Fujisawa,Kiyoshi;Karlin,KennethD;Tolman,WilliamB;Hodgson,KeithO;Hedman,Britt;Solomon,EdwardI
通讯作者：
Solomon,EdwardI

New advances in ligand design for synthetic modeling of metalloprotein active sites.

金属蛋白活性位点合成建模的配体设计新进展。