Model Studies of Acetyl Coenzyme A Synthase

乙酰辅酶A合酶的模型研究

基本信息

批准号：
7544968
负责人：
CHARLES G. RIORDAN
金额：
$ 21.55万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7544968
关键词：
Acetates Acetyl Coenzyme A Active Sites Address Anabolism Architecture Area Bacteria Binding Binding Sites Biochemical Reaction Biological Biological Models Catalysis Catalytic Domain Chemicals Colon Communities Complex Crystallography Electronics Ensure Enzymes Functional disorder Gastric lymphoma Goals Helicobacter pylori Human Individual Inorganic Chemistry Investigation Kinetics Knowledge Laboratories Libraries Measurement Metals Methodology Modeling Molecular Molecular Weight Mononuclear Nickel Organism Oxidation-Reduction Peptic Ulcer Peptides Preparation Production Property Proteins Protocols documentation Reaction Research Research Personnel Scheme Site Stomach Carcinoma Structure Structure-Activity Relationship Study models System Testing Time Toxic effect Trace Elements analog base carcinogenesis chemical property design electronic structure functional group interest novel oxidation programs research study structural biology

项目摘要

The proposed research is designed to address specific questions of molecular and electronic structure, and chemical reactivity to gain a fundamental understanding of the catalytic activity of the Ni-containing protein acetyl coenzyme A synthase (ACS) through the synthesis, characterization and elucidation of reactivity of model complexes. This methodology will permit characterization of the intrinsic properties of structure and function of the metal sites at the molecular level of detail decoupled from the protein architecture. Recent results from structural biology have established details of the active site structure making now the optimum time to address this problem as the targets are well defined. Individual reactions will be systematically interrogated using the protocols of mechanistic inorganic chemistry including product analyses, kinetic measurements, stereochemical and radical clock probe investigations. The long-term goal of this project is to develop a detailed mechanistic understanding of how the structural, electronic and chemical properties of nickel sites in proteins are optimized for their intended catalytic transformations. The proposed research impacts our understanding of the biological implications of the essential trace element nickel that include the virility of Helicobacter pylori which has been associated with peptic ulcer disease, gastric carcinoma, and gastric lymphoma, and carcinogenesis through production of oxidizing species that degrade DMA. Additionally, acetogenic and methanogenic bacteria, organisms that contain ACS, may be important to human digestive function and dysfunction as they occupy a large volume of the colon. More broadly, a deeper understanding of ACS catalysis will advance fundamental understanding of redox-based Ni toxicity.

拟议的研究旨在解决分子和电子结构的特定问题，以及化学反应性以获得对含Ni蛋白的催化活性的基本理解通过合成，表征和阐明反应性的乙酰辅酶A合酶（ACS）模型复合体。该方法将允许表征结构的内在特性和蛋白质结构与细节分子水平的金属位点的功能。最近的结构生物学的结果已经确定了活动现场结构的详细信息，使现在成为最佳是时候解决这个问题了，因为目标的定义很好。个人反应将是系统的使用机械无机化学方案进行询问，包括产品分析，动力学测量，立体化学和激进时钟探测。这个项目的长期目标是为了对结构，电子和化学特性的结构，电子和化学特性有详细的理解蛋白质中的镍位点针对其预期的催化转化进行了优化。拟议的研究影响了我们对基本痕迹生物学含义的理解元素镍包括与消化性溃疡有关的幽门螺杆菌的活力疾病，胃癌和胃淋巴瘤以及通过氧化而产生的致癌作用降解DMA的物种。此外，乙酸和甲烷菌细菌，含有的生物 ACS，对于人类的消化功能和功能障碍可能很重要，因为它们占据了大量冒号。更广泛地，对ACS催化的更深入的理解将提高对基于氧化还原的Ni毒性。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthetic chemistry and chemical precedents for understanding the structure and function of acetyl coenzyme A synthase.

了解乙酰辅酶 A 合酶结构和功能的合成化学和化学先例。

DOI：
10.1007/s00775-004-0567-7
发表时间：
2004
期刊：
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry
影响因子：
0
作者：
Riordan,CharlesG
通讯作者：
Riordan,CharlesG

Coordination chemistry of poly(thioether)borate ligands.

DOI：
10.1016/j.ccr.2010.01.007
发表时间：
2010-08-01
期刊：
Coordination chemistry reviews
影响因子：
20.6
作者：
Riordan CG
通讯作者：
Riordan CG

Thiolate-bridged nickel-copper complexes: A binuclear model for the catalytic site of acetyl coenzyme A synthase?

DOI：
10.1021/ja0346577
发表时间：
2003-04-16
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Krishnan, R;Voo, JK;Rheingold, AL
通讯作者：
Rheingold, AL

Spectroscopic and computational studies on [Ni(tmc)CH3]OTf: implications for Ni-methyl bonding in the A cluster of acetyl-CoA synthase.

[Ni(tmc)CH3]OTf 的光谱和计算研究：对乙酰辅酶 A 合酶 A 簇中 Ni-甲基键合的影响。

DOI：
10.1021/ic0483996
发表时间：
2005
期刊：
Inorganic chemistry
影响因子：
4.6
作者：
Schenker,Ralph;Mock,MichaelT;Kieber-Emmons,MatthewT;Riordan,CharlesG;Brunold,ThomasC
通讯作者：
Brunold,ThomasC

Binuclear complexes containing a methylnickel moiety: relevance to organonickel intermediates in acetyl coenzyme A synthase catalysis.

DOI：
10.1021/ja803795k
发表时间：
2008-10-15
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Dougherty, William G.;Rangan, Krishnan;O'Hagan, Molly J.;Yap, Glenn P. A.;Riordan, Charles G.
通讯作者：
Riordan, Charles G.