Model Studies of Acetyl Coenzyme A Synthase

描述(由申请人提供)：拟议的研究旨在解决特定的分子和电子结构以及化学反应活性问题，通过合成、表征和阐明模型络合物的反应活性，从根本上了解含镍蛋白质乙酰辅酶A合成酶(ACS)的催化活性。这种方法将允许在与蛋白质结构分离的分子细节水平上表征金属位置的结构和功能的内在属性。结构生物学的最新结果已经确定了活性部位结构的细节，使现在成为解决这个问题的最佳时机，因为目标已经明确。将使用机械无机化学的方案系统地审问个别反应，包括产品分析、动力学测量、立体化学和自由基时钟探针研究。该项目的长期目标是对蛋白质中镍中心的结构、电子和化学性质如何针对其预期的催化转化进行优化的详细机制理解。拟议的研究影响了我们对必需微量元素镍的生物学意义的理解，这些元素包括幽门螺杆菌的生殖力，它与消化性溃疡疾病、胃癌和胃淋巴瘤有关，以及通过产生降解DNA的氧化性物种而致癌。此外，产乙酸菌和产甲烷菌，即含有ACS的有机体，可能对人类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。更广泛地说，对ACS催化的深入了解将促进对基于氧化还原的镍毒性的基本理解。

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.