CAREER: Understanding the Role of Nickel-Sulfur Complexes in Catalytic ROS Detoxification: Insight From Ni-SOD Synthetic Analogues

化学催化计划支持佐治亚大学的托德·C·哈罗普教授的一个研究项目，该项目将促进我们对生物相关的金属-硫配位单元作为金属酶中活性氧物种(ROS)清除剂的催化作用的化学理解。目前在这一领域的知识规定，这种配位单元应该倾向于基于配体的氧化，而不是主要以金属为中心的氧化还原。因此，为了了解这些体系的基本化学性质，哈罗普教授将启动一种合成生物无机模拟方法，研究最新和最不寻常的超氧化物歧化酶，即镍超氧化物歧化酶(Ni-SOD)。为了解决生物配位的作用，PI将合成和表征一系列镍-N/S络合物，这些络合物是镍-超氧化物歧化酶的直接电子和结构模拟。Ni与ROS的基本反应化学，特别是Ni-S和Ni(III)络合物，目前还没有明确的定义，也相对没有被探索。因此，这些络合物将与超氧化物、H_2O_2和NO等ROS反应。这些反应性研究将通过各种光谱和计算方法进行监测，这些方法将首次谨慎地定义这些生物上重要的相互作用。总而言之，这些研究的贡献将使人们能够理解Ni-SOD独特的配位和反应化学中的新概念，并导致具有SOD活性的分子的智能设计，用于催化和制药，从而为大量研究做出贡献。在国家科学基金会化学部化学催化计划的支持下，Harrop博士将为生物化学家和理论家提供潜在物种的光谱、结构和活性基准，这些基准对于理解Ni-SOD催化途径非常重要。这项工作还将通过各种协同活动对科学教育产生更广泛的影响。这些综合教育活动的主要目标是提高对STEM学科中代表性不足的少数群体，特别是化学领域的非裔美国人的认识、参与和留住他们。这些努力涉及一项新的研究伙伴关系倡议，该倡议将与乔治亚州的公立HBCU-堡谷州立大学(FVSU)建立。在整个授权期内，FVSU化学专业的一名本科生将每年获得暑期研究实习机会，在PI的实验室进行镍-SOD类似物的研究。该奖项将与该州的HBCU建立新的联系，并将导致FVSU学生攻读化学高级学位的强大和持续的渠道，希望在UGA。这项奖励将支持本科生夏季研究人员的工资和他们参加会议的旅费，为这些年轻科学家在化学研究领域的职业生涯做好更好的准备。

The Chemical Catalysis Program supports Professor Todd C. Harrop at the University of Georgia for a research project that will advance our understanding of the chemistry of biologically relevant metal-sulfur coordination units in their catalytic role as scavengers of reactive oxygen species (ROS) in metalloenzymes. Current knowledge in this area stipulates that such coordination units should be prone to ligand-based oxidation instead of primarily metal-centered redox. Thus, to understand the fundamental chemical properties of these systems, Professor Harrop will initiate a synthetic bioinorganic-modeling approach towards the newest and most unusual superoxide-detoxifying enzyme namely, nickel superoxide dismutase (Ni-SOD). To address the role of biological coordination, the PI will synthesize and characterize a range of Ni-N/S complexes that are direct electronic and structural mimics of Ni-SOD. The fundamental reaction chemistry of Ni with ROS, in particular Ni-S and Ni(III) complexes, is poorly defined and relatively unexplored. Thus, the reactions of these complexes with ROS like superoxide, H2O2, and NO will be performed. These reactivity studies will be monitored by a variety of spectroscopic and computational methods that will define discreetly for the first time these biologically important interactions. Collectively, the contribution of these studies will allow the understanding of new concepts in the unique coordination and reaction chemistry of Ni-SOD and result in the intelligent design of molecules with SOD activity for use in catalysis and pharmaceuticals, thus contributing to a significant stream of research.With the support of the Chemical Catalysis Program in the Chemistry Division at the National Science Foundation, Dr. Harrop will provide biochemists and theoreticians with spectroscopic, structural, and reactive benchmarks of potential species that are important to understanding the Ni-SOD catalytic pathway. This work will also have a broader impact on science education through a variety of synergistic activities. The principal goal of these integrated educational activities is to increase awareness, participation, and retention of underrepresented minority groups in the STEM disciplines, specifically African-Americans in chemistry. These efforts involve a new research-partnership initiative that the PI will establish with Fort Valley State University (FVSU), a public HBCU in the state of Georgia. A summer research internship will be awarded annually throughout the grant period to an undergraduate chemistry major from FVSU to be conducted in the PI's lab on Ni-SOD analogues. The award will establish a new link with an HBCU in the state and will lead to a strong and continual pipeline of FVSU students pursuing advance degrees in chemistry and hopefully at UGA. This award will support salary for the undergraduate summer researcher and for their travel to conferences, better preparing these young scientists for careers in chemical research.