Iron-sulfur Clusters as Biological Sensors: Mechanistic Investigations by Synthetic Modeling Studies

铁硫簇作为生物传感器：通过综合建模研究进行机理研究

• 批准号: 2203879
• 负责人: Eunsuk Kim
• 金额: $ 45.02万
• 依托单位: Brown University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2203879&HistoricalAwards=false
• 关键词: Iron; sulfur; Clusters; Biological; Sensors

With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Professor Eunsuk Kim from Brown University is studying the development of synthetic modeling systems to understand how iron-sulfur (Fe-S) clusters act as sensors for environmental signals. Iron-sulfur clusters are ubiquitous cofactors present in all animal kingdoms. Organisms have evolved to exploit the inherent reactivity of Fe-S clusters with small molecules like O2 and NO to assess their environment. For example, bacteria sense environmental O2 and NO and adjust their gene expression profiles for survival using regulatory proteins that contain Fe-S clusters. The human Fe-S mitoNEET protein acts as a redox sensor and regulates mitochondrial functions, failure of which leads to metabolic and neurodegenerative diseases. The proposed study will offer molecular insights into the modification and repair of iron-sulfur clusters by small redox signaling molecules. Molecular insights gained in this project will inform research focused on the development of biomarkers for disease detection, of antimicrobial agents, and of therapeutics for metabolic diseases. Students who will implement the research will gain knowledge, expertise and skills in chemical synthesis, reactivity, structural characterization of molecules, and spectroscopy. This project is also integrated into an outreach program focused on the improvement of the educational environments of students from groups underrepresented in STEM (science, technology, engineering and mathematics) and students from public high schools. This research project seeks to understand strategies used by Fe-S regulatory proteins to battle oxidative and nitrosative stress at the molecular level. This goal is achieved by studying the geometric and electronic structure, reactivity, and bonding properties of discrete biomimetic, model Fe-S complexes. The chemical reactivity of Fe-S clusters will be studied in three different areas. Firstly, mechanistic details for the reactions of 4Fe-4S clusters with NO will be examined. These include the characterization of novel iron nitrosyl products and investigations on how reactive sulfur species are generated through the action of NO upon Fe-S clusters. Secondly, mitoNEET model clusters will be synthesized and bonding properties of the Fe-S cluster will be correlated to cluster transfer activity. Lastly, persulfide-ligated Fe-S clusters will be synthesized used to study the role of persulfides in the Fe-S repair process. Overall then, these fundamental mechanistic and spectroscopic studies have real promise to enhance understanding of Fe-S complexes in biology, in general, and their specific roles in electron transfer-initiated processes including interactions with signaling molecules such as NO and persulfides.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学学部生命过程化学（CLP）项目的支持下，布朗大学的Eunsuk Kim教授正在研究合成建模系统的开发，以了解铁硫（Fe-S）簇如何作为环境信号的传感器。铁硫团簇是所有动物王国中普遍存在的辅助因子。生物已经进化到利用Fe-S簇与O2和NO等小分子的固有反应性来评估其环境。例如，细菌感知环境中的O2和NO，并通过含有Fe-S簇的调节蛋白来调节其基因表达谱以维持生存。人类Fe-S mitoNEET蛋白作为氧化还原传感器并调节线粒体功能，线粒体功能的失败导致代谢和神经退行性疾病。提出的研究将提供小氧化还原信号分子对铁硫簇的修饰和修复的分子见解。在该项目中获得的分子见解将为疾病检测、抗菌剂和代谢性疾病治疗的生物标志物的开发提供信息。参与研究的学生将获得化学合成、反应性、分子结构表征和光谱学方面的知识、专业知识和技能。该项目还被整合到一个外展计划中，该计划的重点是改善STEM（科学、技术、工程和数学）中代表性不足的群体的学生和公立高中学生的教育环境。本研究项目旨在了解Fe-S调节蛋白在分子水平上对抗氧化和亚硝化应激的策略。这一目标是通过研究离散仿生模型Fe-S配合物的几何和电子结构、反应性和键合性质来实现的。Fe-S簇的化学反应性将在三个不同的领域进行研究。首先，研究4Fe-4S簇与NO反应的机理细节。这些包括新的铁亚硝基产物的表征，以及如何通过NO作用于Fe-S簇产生活性硫的研究。其次，合成mitoNEET模型簇，并将Fe-S簇的键合性质与簇转移活性进行关联。最后，将合成过硫化物连接的Fe-S簇，用于研究过硫化物在Fe-S修复过程中的作用。总的来说，这些基本的机制和光谱研究确实有希望增强对生物学中Fe-S复合物的理解，以及它们在电子转移启动过程中的特定作用，包括与NO和过硫化物等信号分子的相互作用。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。