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

Brown University, Providence RI

Investigators

Abstract

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.