Chemistry of Nickel(III/II)-Thiolate Complexes: Insight into the Structure and Mechanism of Ni-Containing SOD

该奖项将资助佐治亚大学的托德·C·哈罗普教授研究模仿重要酶超氧化物歧化酶的镍硫酸盐复合体模型。含镍超氧化物歧化酶是好氧菌中唯一存在的氧化还原活性镍酶，尽管其活性部位存在ROS敏感的半胱氨酸-S配体。该项目涉及具有有氧功能的镍超氧化物歧化酶活性中心的合成模型的制备和研究。特别是，该项目将审查与镍结合的实体在决定活性中心的催化性能方面的作用。已经制定了计划，向在STEM学科中传统上代表性较低的群体提供基础化学科学方面的实践研究机会。其中一个此前取得成功的计划是为东南部地区历史悠久的黑人学院和大学(HBCU)的化学专业本科生提供暑期研究实习和终身职业指导。Pi和他的团队还将参加乔治亚大学Young Dawgs大学的项目，该项目为克拉克县公立学校系统的高中生提供STEM研究实习机会。本研究的目的是制备镍中心的合成模型络合物，并研究配位的多肽-N和半胱氨酸-S配体在该酶的氧化还原机制中所起的机制作用。生物中的镍-半胱氨酸是参与全球影响的反应的中心催化剂，包括活性氧物种(ROS)的解毒、细胞碳的固定和替代能源供应的产生，即氢气的释放/消耗。因此，镍酶及其相应的合成模型是促进化学转化的理想体系，具有很高的经济和环境重要性。然而，这些镍酶中的大多数都是在严格的厌氧生物中发现的。尽管半胱氨酸-S对ROS很敏感，但在酶的周转过程中，这些供体原子对ROS似乎是惰性的。先进的合成技术将被用来构建含N/S的配体框架及其相应的Ni(III/II)配合物，以准确地再现NiSODO的活性中心。这些结构设计中的关键因素是轴向N-给体的结合以及微调S配体的亲核性以促进镍基与S基的氧化还原化学。将利用光谱、结构和计算技术。该项目旨在确定这些Ni(III/II)-N/S络合物的几何和电子结构性质，并研究它们与ROS和其他活性小分子(如NO)的反应活性，以揭示发生在这个独特的镍位置的氧化还原机制。

With this award, the Chemistry of Life Processes Program in the Division of Chemistry is funding Professor Todd C. Harrop at the University of Georgia to study model nickel-thiolate complexes that mimic the imporant enzyme superoxide dismutase. Nickel-containing superoxide dismutase (NiSOD) is the only redox-active nickel-enzyme that is present in aerobes despite the presence of ROS (reactive oxygen species)-sensitive cysteine-S-ligands at its active site. This project involves the preparation and investigation of synthetic models of the nickel-containing active site of NiSOD that are capable of aerobic function. In particular, the project will examine the role of the entities that are bound to nickel, in dictating the catalytic properties of the active site. Plans are in place to provide hands-on research opportunities in the fundamental chemical sciences to groups traditionally underrepresented in the STEM disciplines. One such plan, with which there was prior success, is to provide a summer research internship and lifelong career mentorship to undergraduate chemistry majors from Historically Black Colleges and Universities (HBCUs) in the southeast region. The PI and his group will also participate in the University of Georgia Young Dawgs program where high school students from the Clarke County public school system are provided STEM research internships.The objective of this research is to prepare synthetic model complexes of the nickel center found at the active site of NiSOD, and to investigate the mechanistic role that the coordinated peptide-N and cysteinate-S ligands play in the redox mechanism of this enzyme. Nickel-cysteine sites in biology are central catalysts that participate in reactions of global impact including the detoxification of reactive oxygen species (ROS), fixation of cellular carbon, and the generation of alternative energy supplies, i.e., hydrogen evolution/consumption. Nickel enzymes and their corresponding synthetic models are thus ideal systems to promote chemical transformations of high economic and environmental importance. However, the majority of these nickel-enzymes are found in strict anaerobic organisms. Despite the sensitive nature of cysteine-S with ROS, these donor atoms appear inert to ROS during turnover in the enzyme. Advanced synthetic techniques will be employed to construct N/S-containing ligand frames and their corresponding Ni(III/II) complexes that accurately reproduce the NiSOD active site. Key factors in the design of these constructs are the incorporation of an axial N-donor and the ability to fine-tune the nucleophilicity of the S-ligands in order to promote Ni-based versus S-based redox chemistry. Spectroscopic, structural and computational techniques will be utilized. The project aims to determine the geometric and electronic structural properties of these Ni(III/II)-N/S complexes and investigate their reactivity with ROS and other reactive small molecules, such as NO, to shed light on the redox mechanism taking place at this unique nickel site.