Model Studies of Acetyl Coenzyme A Synthase

拟议的研究旨在解决分子和电子结构的具体问题，以及 化学反应性以获得对含镍蛋白质催化活性的基本了解 乙酰辅酶A合成酶(ACS)的合成、表征及活性研究 模型复合体。这一方法论将允许表征结构和 金属位点在分子细节水平上的功能与蛋白质结构解偶联。近期 结构生物学的结果已经确定了活性部位结构的细节，使现在成为最佳 随着目标的明确，是时候解决这个问题了。个人的反应将是系统性的 使用机械无机化学方案进行讯问，包括产品分析、动力学 测量、立体化学和自由基时钟探头研究。这个项目的长期目标是 发展一个详细的机械理解如何结构，电子和化学性质 蛋白质中的镍中心针对其预期的催化转化进行了优化。 这项拟议的研究影响了我们对基本痕迹的生物学含义的理解 镍元素，包括幽门螺杆菌的生殖力，幽门螺杆菌与消化性溃疡有关 疾病、胃癌和胃淋巴瘤以及氧化产物的致癌作用 降解DMA的物种。此外，产乙酸菌和产甲烷菌，即含有 ACS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 冒号。更广泛地说，对ACS催化的更深入的理解将促进对 氧化还原基镍毒性。

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.