Chemistry of Iron-sulfur clusters in redox signaling

凭借这一奖项，化学学部的生命过程化学项目资助了布朗大学的Eunsuk Kim博士，以阐明氧化还原信号中铁硫（Fe-S）簇的化学作用。Fe-S簇和细胞信号在人体中有许多用途，因此，了解这些化合物对保护和改善人类健康至关重要。例如，生物体存在于充满氧化剂的环境中，如大气中的氧气和来自太阳的紫外线。这些氧化剂会导致细胞老化，有时还会引发癌症等疾病。细胞依靠氧化还原信号分子来激活抗氧化剂来平衡氧化剂。氧化还原信号分子还可以激活免疫系统，控制细菌和病毒。为了应对环境条件，细菌，包括人类病原体，使用Fe-S蛋白来调整其基因表达谱，从而使人类不会生病。人类也使用铁- s蛋白来感知铁的可用性，并在细胞中维持恒定的铁离子水平，从而预防贫血并帮助大脑活动。目前使用的II型糖尿病药物靶点之一mitoNEET是一种Fe-S蛋白，它调节细胞对能量的利用。金教授的研究是以在化学实验室合成Fe-S簇为基础的，目的是了解这些簇如何在全身传递信息。她实验室的学生在化学合成、结构测定、光谱技术和生化分析方面有着令人兴奋和多样化的研究经验。他们在实验室中获得的知识和技能为他们从事富有成效的STEM职业做好了准备。金博士和她的学生们还参加了一个外展项目，该项目旨在为那些背景在STEM职业中代表性不足的学生以及女科学家创造更好的教育环境。铁- s蛋白调控活性的共同主题似乎是铁- s簇响应特定的氧化剂，如分子氧、活性氧和一氧化氮。这些调节蛋白通常含有相同的[2Fe-2S]或[4Fe-4S]单元，但响应不同的信号；这一事实表明，大自然利用Fe-S簇的化学多样性来实现一系列不同的目标。Kim博士通过一种合成建模方法研究了Fe-S簇不同反应活性的化学基础，其中在她的实验室中用离散小分子制备的Fe-S簇的反应允许对反应产物进行明确的鉴定。这些研究揭示了Fe-S簇在不同反应条件下的反应模式。该研究的具体目标是建立Fe-S簇与一氧化氮（NO）的反应模式，从而描绘环境如何导致不同的反应产物。他们还试图了解[2Fe-2S]和[4Fe-4S]簇在辅助因子生物合成和细菌对氧的感知中的相互转化，并合成最近发现的[2Fe-2S] mitoNEET蛋白中金属簇的模型配合物。通过对这些模型配合物反应的研究，增加了对mitoNEET在不同pH和氧化还原条件下能量代谢活性的认识。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。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Eunsuk Kim from Brown University to elucidate the chemistry of iron-sulfur (Fe-S) clusters in redox signaling. There are many uses for Fe-S clusters and cell signaling in the human body and thus, understanding these compounds is critical to protecting and improving human health. For example, living organisms exist in an environment filled with oxidants such as the oxygen in the atmosphere and the ultraviolet light from the Sun. These oxidants cause cell aging and sometimes diseases such as cancer. Cells rely on redox signaling molecules to activate the antioxidants that counterbalance the oxidants. The redox signaling molecules can also activate the immune system that keeps bacteria and viruses in check. In response to environmental conditions, bacteria, including human pathogens, use Fe-S proteins to adapt their gene expression profiles, so that humans do not get sick. Humans also use Fe-S proteins to sense iron availability and maintain a constant level of iron ions in the cells, thus preventing anemia and helping brain activity. One of the currently used type II diabetes drugs targets, mitoNEET, is an Fe-S protein that regulates the use of energy by cells. The research of Professor Kim is based on the synthesis of Fe-S clusters in the chemistry laboratory to understand how the clusters can transmit messages throughout the body. Students in her lab have an exciting and diverse research experience in chemical synthesis, structural determinations, spectroscopic techniques and biochemical assays. The knowledge and skills they acquire in the lab prepare them for productive STEM careers. Dr. Kim and her students also participate in an outreach program that creates better educational environments for students whose backgrounds are underrepresented in STEM careers as well as for women scientists.The common theme in the regulatory activity of Fe-S proteins appears to be that the Fe-S clusters respond to specific oxidants such as molecular oxygen, reactive oxygen species, and nitric oxide. These regulatory proteins often contain the same [2Fe-2S] or [4Fe-4S] units but respond to different signals; this fact suggests that nature exploits the chemical versatility of Fe-S clusters to achieve a diverse set of goals. Dr. Kim investigates the chemistry that underlies the diverse reactivity of Fe-S clusters though a synthetic modeling approach, wherein the reactions of Fe-S clusters prepared in her lab with discrete small molecules allow unambiguous identification of the reaction products. These studies reveal the reactivity patterns of Fe-S clusters under various reaction conditions. The specific goals of the research are to establish the reactivity pattern of Fe-S clusters with nitric oxide (NO) and, consequently, to delineate how the environment leads to different reaction products. They also seek to understand the interconversion of [2Fe-2S] and [4Fe-4S] clusters in cofactor biosynthesis and in the sensing of oxygen by bacteria, and to synthesize model complexes for the metal cluster in a recently discovered [2Fe-2S] mitoNEET protein. Through the study of the reactions of these model complexes, they increase understanding of the activity of mitoNEET in energy metabolism under different pH and redox conditions.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.