Chemistry of Iron-sulfur clusters in redox signaling

氧化还原信号传导中铁硫簇的化学

• 批准号: 1807845
• 负责人: Eunsuk Kim
• 金额: $ 42万
• 依托单位: Brown University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1807845&HistoricalAwards=false
• 关键词: Chemistry; Iron; sulfur; clusters; redox

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.

有了这个奖项，化学部的生命过程化学项目资助布朗大学的Eunsuk Kim博士阐明氧化还原信号中铁硫（Fe-S）簇的化学。Fe-S簇和细胞信号在人体中有许多用途，因此，了解这些化合物对于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，例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，有时还会导致癌症等疾病。 细胞依靠氧化还原信号分子来激活抗氧化剂，以抵消氧化剂。 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蛋白来适应它们的基因表达谱，使人类不会生病。人类还使用Fe-S蛋白来感知铁的可用性，并保持细胞中铁离子的恒定水平，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，可调节细胞对能量的使用。Kim教授的研究基于化学实验室中Fe-S簇的合成，以了解簇如何在整个身体中传递信息。她实验室的学生在化学合成，结构测定，光谱技术和生物化学测定方面有着令人兴奋和多样化的研究经验。他们在实验室获得的知识和技能为他们的生产STEM职业做好准备。金博士和她的学生还参加了一个外展计划，为那些在STEM职业中背景不足的学生以及女性科学家创造更好的教育环境。Fe-S蛋白质调节活性的共同主题似乎是Fe-S簇对特定的氧化剂，如分子氧，活性氧和一氧化氮做出反应。这些调节蛋白通常含有相同的[2Fe-2S]或[4Fe-4S]单元，但对不同的信号作出反应;这一事实表明，自然界利用Fe-S簇的化学多功能性来实现不同的目标。Kim博士通过合成建模方法研究了Fe-S簇的不同反应性的化学基础，其中在她的实验室中制备的Fe-S簇与离散小分子的反应允许明确识别反应产物。 这些研究揭示了Fe-S团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团簇与一氧化氮（NO）的反应模式，从而描述环境如何导致不同的反应产物。 他们还寻求了解[2 Fe-2S]和[4 Fe-4S]簇在辅因子生物合成和细菌氧感测中的相互转化，并合成最近发现的[2 Fe-2S] mitoNEET蛋白中金属簇的模型复合物。 通过研究这些模型复合物的反应，他们增加了对mitoNEET在不同pH和氧化还原条件下能量代谢活性的理解。该奖项反映了NSF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。

项目成果

Controlled Protonation of [2Fe–2S] Leading to MitoNEET Analogues and Concurrent Cluster Modification

[2Fe-2S] 的受控质子化导致 MitoNEET 类似物和并发簇修饰

• DOI: 10.1021/acs.inorgchem.1c02622
• 发表时间: 2021
• 期刊: Inorganic Chemistry
• 影响因子: 4.6
• 作者: Oakley, Kady;Sterling, Kevin;Shearer, Jason;Kim, Eunsuk
• 通讯作者: Kim, Eunsuk

Dioxygen reactivity of a biomimetic [4Fe-4S] compound exhibits [4Fe-4S] to [2Fe-2S] cluster conversion

仿生 [4Fe-4S] 化合物的分子氧反应性表现出 [4Fe-4S] 到 [2Fe-2S] 簇的转化

• DOI: 10.1016/j.jinorgbio.2022.111714
• 发表时间: 2022
• 期刊: Journal of Inorganic Biochemistry
• 影响因子: 3.9
• 作者: Oakley, Kady M.;Lehane, Ryan L.;Zhao, Ziyi;Kim, Eunsuk
• 通讯作者: Kim, Eunsuk

Generation of H 2 S from Thiol-Dependent NO Reactivity of Model [4Fe-4S] Cluster and Roussin’s Black Anion

从 [4Fe-4S] 模型簇和 Roussin 黑阴离子的硫醇依赖性 NO 反应性生成 H 2 S

• DOI: 10.1021/acs.inorgchem.1c01328
• 发表时间: 2021
• 期刊: Inorganic Chemistry
• 影响因子: 4.6
• 作者: Oakley, Kady M.;Zhao, Ziyi;Lehane, Ryan L.;Ma, Ji;Kim, Eunsuk
• 通讯作者: Kim, Eunsuk