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

通过该奖项，生命过程化学计划资助布朗大学的Eunsuk Kim教授阐明与NO与[Fe-S]蛋白质相互作用相关的化学模式和原理，以及由此相互作用产生的二亚硝酰铁络合物（DNIC）的后续形成和反应性。虽然NO信号传导机制在很大程度上是未知的，但已经发现铁硫蛋白是NO的主要反应靶之一，其中[Fe-S]簇被修饰并转化为DNIC。在这项研究中，将探讨以下具体问题：什么是DNIC的内在属性和反应性？DNIC的生理和/或有害作用是什么？当[Fe-S]团簇被NO降解时，桥连硫化物发生了什么变化？细胞如何科普不必要的[Fe-S]修饰NO？ 这些问题将通过采用合成化学专业知识结合一些光谱，生物化学，生物分析和机理研究来解决。一氧化氮（NO）是生物学上的一把双刃剑。 虽然NO是一种普遍存在的信号分子，但NO的失调与许多疾病有关，包括血管疾病、癌症和神经变性。拟议的研究将阐明关键细胞氧化还原组分之间的相互联系，如[Fe-S]簇，NO，O2，H2S和硫醇，这将为该领域当前的问题提供新的见解和解决方案，并可能导致生物NO信号研究的新范式。 该项目还将被纳入教育和推广活动，这将启动（一）一个专门为高中化学开发基于探究的实验室课程的计划，以及（二）在一个主要的研究会议上以学生为主导的问题解决会议，以促进学生和科学代表性不足的群体积极参与的文化。

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.