CAREER: Chemistry of Iron-Sulfur Clusters in Nitric Oxide Signaling

通过这一奖项，生命过程化学项目资助布朗大学的金恩锡教授阐明了NO与[Fe-S]蛋白质相互作用的化学模式和原理，以及这种相互作用导致的二亚硝酰铁复合体(DNIC)的形成和反应活性。尽管NO信号转导机制尚不清楚，但已发现铁硫蛋白是NO的主要反应靶点之一，其中[Fe-S]簇被修饰并转化为DNICs。在这项研究中，将探讨以下具体问题：DNIC的固有属性和反应性是什么？DNIC的生理和/或有害作用是什么？当[Fe-S]团簇被NO降解时，桥联硫化物会发生什么变化？细胞如何应对NO引起的不必要的[铁-S]修饰？这些问题将通过利用合成化学专业知识结合一些光谱、生化、生物分析和机械研究来解决。一氧化氮(NO)在生物学上是一把双刃剑。虽然NO是一种普遍存在的信号分子，但NO的错误调节与许多疾病有关，包括血管疾病、癌症和神经退行性变。这些研究将阐明细胞氧化还原关键成分如[Fe-S]簇、NO、O2、H_2S和硫醇之间的相互关系，这将为该领域当前的问题提供新的见解和解决方案，并可能为生物NO信号转导的研究带来新的范式。该项目还将被纳入教育和外联活动，这将启动(I)一项致力于为高中化学开发基于探究的实验室课程的计划和(Ii)在一次重大研究会议上由学生主导的问题解决会议，以促进学生和未被充分代表的群体积极参与科学的文化。

Through this award, the Chemistry of Life Processes Program is funding Professor Eunsuk Kim from Brown University to elucidate chemical patterns and principles related to the interaction of NO with [Fe-S] proteins, and the subsequent formation and reactivity of dinitrosyl iron complexes (DNICs)resulting from this interaction. Although NO signaling mechanisms are largely unknown, it has been found that iron-sulfur proteins are one of the main reaction targets for NO, wherein [Fe-S] clusters become modified and convert to DNICs. In this study, the following specific questions will be probed: What are the intrinsic properties and reactivity of DNICs? What are the physiological and/or deleterious roles of DNICs? What happens to the bridging sulfides when [Fe-S] clusters are degraded by NO? How do cells cope with unwanted [Fe-S] modifications by NO? These questions will be addressed by employing synthetic chemistry expertise in combination with a number of spectroscopic, biochemical, bioanalytical and mechanistic studies. Nitric oxide (NO) is a double-edged sword in biology. While NO is a ubiquitous signaling molecule, misregulation of NO is implicated in numerous conditions including vascular diseases, cancer, and neurodegeneration. The proposed studies will elucidate the interconnections among the key cellular redox components such as [Fe-S] clusters, NO, O2, H2S, and thiols, which will provide fresh insights and solutions to current questions in the field and may lead to new paradigms in the study of biological NO signaling. This project will also be integrated into educational and outreach activities, which will initiate (i) a program dedicated to develop inquiry-based laboratory curricula for high school chemistry and (ii) a student-led problem solving session at a major research conference to promote a culture of active participation from students and underrepresented groups in science.