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

镍(III/II)-硫醇配合物的化学：深入了解含镍 SOD 的结构和机制

• 批准号: 1506375
• 负责人: Todd Harrop
• 金额: $ 46.52万
• 依托单位: University of Georgia Research Foundation Inc
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1506375&HistoricalAwards=false
• 关键词: Chemistry; Nickel; III; II; Thiolate

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.

有了这个奖项，化学系的生命过程化学项目正在资助托德教授。Harrop在格鲁吉亚大学研究模拟重要酶超氧化物歧化酶的模型镍-硫醇盐复合物。 含镍超氧化物歧化酶（NiSOD）是存在于需氧菌中的唯一具有氧化还原活性的镍酶，尽管在其活性位点存在ROS（活性氧物质）敏感的半胱氨酸-S-配体。该项目涉及制备和研究具有有氧功能的NiSOD含镍活性部位的合成模型。特别是，该项目将研究与镍结合的实体在决定活性部位的催化性能方面的作用。已经制定计划，为传统上在STEM学科中代表性不足的群体提供基础化学科学的实践研究机会。其中一个这样的计划，有先前的成功，是提供一个夏季研究实习和终身职业导师本科化学专业从历史上黑人学院和大学（HBCU）在东南地区。PI和他的团队还将参加格鲁吉亚大学的Young Dawgs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。这项研究的目的是制备NiSOD活性位点上发现的镍中心的合成模型络合物，并研究配位的肽-N和半胱氨酸-S配体在该酶的氧化还原机制中所起的作用。生物学中的镍-半胱氨酸位点是参与全球影响反应的中心催化剂，包括活性氧（ROS）的解毒，细胞碳的固定和替代能源供应的产生，即，析氢/耗氢。因此，镍酶及其相应的合成模型是促进具有高度经济和环境重要性的化学转化的理想系统。然而，大多数这些镍酶被发现在严格的厌氧生物。 尽管半胱氨酸-S与ROS的敏感性，这些供体原子在酶的周转期间对ROS表现出惰性。先进的合成技术将被用来构建N/S的配体框架和相应的Ni（III/II）配合物，准确地再现NiSOD活性位点。这些构建体的设计中的关键因素是轴向N-供体的掺入和微调S-配体的亲核性以促进Ni基与S基氧化还原化学的能力。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特性，并研究它们与ROS和其他活性小分子（如NO）的反应性，以揭示在这个独特的镍位点发生的氧化还原机制。