Chemistry of Iron-sulfur clusters in redox signaling

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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.