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：
7166829
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 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7166829
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 Chemical Structure Chemicals Colon Communities Complex Crystallography DNA Depth Electronics Ensure Enzymes Functional disorder Gastric lymphoma Genus Cola Goals Helicobacter pylori Human Individual Inorganic Chemistry Investigation Kinetics Knowledge Laboratories Libraries Measurement Metals Methodology Modeling Molecular Molecular Weight Mononuclear Nickel Numbers 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 functional group interest novel oxidation programs research study structural biology

项目摘要

DESCRIPTION (provided by applicant): 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 DNA. 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.

描述（由申请人提供）：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，以通过合成，表征和模型复合物反应性的合成，表征和阐明。该方法将允许表征金属位点的固有特性，并在与蛋白质结构分离的细节分子水平上的结构和功能。结构生物学的最新结果已经确定了活动现场结构的细节，这使得由于目标的定义很好，现在可以解决此问题的最佳时间。使用机械无机化学方案，包括产品分析，动力学测量，立体化学和激进时钟探针研究，将系统询问个别反应。该项目的长期目标是对蛋白质中镍位点的结构，电子和化学特性如何针对其预期的催化转化进行优化。拟议的研究影响了我们对基本痕量元素镍的生物学意义的理解，这些镍包括幽门螺杆菌的活力，与幽门螺杆菌疾病，胃癌和胃淋巴瘤有关，以及通过产生去脱脂DNA的氧化物种而产生的癌变。此外，含有AC的生物体的乙酰植物和甲烷菌细菌可能对人的消化功能和功能障碍很重要，因为它们占据了大量的结肠。从更广泛的角度来看，对ACS催化的更深入了解将提高对基于氧化还原Ni毒性的基本理解。