Intellectual merit.

Nitric oxide (NO) is an important messenger molecule that is involved in many physiological and pathological functions.  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 dinitrosyl iron complexes (DNICs). The goal of the project was to identify the cluster degradation products derived from the [Fe-S]/NO reaction and establish their chemical reactivity so that chemical knowledge and insights can be extrapolated to currently unknown biological consequences of cluster modifications. During the funding period, the Kim laboratory established chemistry suggesting that key cellular redox components such as [Fe-S] clusters, NO, molecular oxygen (O₂), hydrogen sulfide (H₂S), and thiols are closely intertwined and controlled, thus propagating their redox signals. Major conceptual advances that had been made by the Kim group include, (i) a signaling molecule H₂S can be produced upon an action of NO on [2Fe-2S] clusters, (ii) NO damaged [2Fe-2S] clusters can be repaired by cysteine analogs, and (iii) oxidation chemistry of DNICs leads to important post-translational modifications such as cysteine oxidation and tyrosine nitration. Notable highlights include,

–the first report of chemical evidence suggesting that [Fe-S] clusters are likely to be a site for the crosstalk between two important biological signaling molecules, NO and H₂S (J. Am. Chem. Soc., 2014, 136, 11874).

–the first report of the regeneration (i.e., repair) of an [2Fe-2S] cluster, coming from a cysteine analogue mediated conversion of an iron nitrosyl species (J. Am. Chem. Soc.  2014, 136, 7229).

–the first report of chemical evidence suggesting that, via their novel reactions with O₂, cellular DNICs can be converted to Roussin’s red esters (RREs) and cause cysteine oxidation (Chem. Commun., 2013, 49, 5550).

–the first report that DNICs possess anti-inflammatory activity (Chem. Sci. 2014, 5, 2374).

The results were published in one book chapter, one review paper, and eight research articles, one of which was featured on the cover of Inorganic Chemistry.  

Broader Impacts.

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. Our results elucidating the interconnections among the key cellular redox components such as [Fe-S] clusters, NO, O₂, H₂S, and thiols provide fundamental insights and chemistry necessary for the development of new drugs that can combat against the above-mentioned diseases. The project led to a total of seven national and international collaborations, one of which was also recognized by the American Chemical Society (ACS) to win 2013 ACS-GREET (Global Research Experiences Exchanges and Training) Award. Students involved in the project were exposed to an exciting and diverse research experience in chemical synthesis, structural characterizations, spectroscopic techniques and biochemical assays.

As for broader educational efforts, the project also led to promote better educational environments for students from historically underrepresented group (HUG) and female scientists. The goal was to achieve a race and gender distribution in the STEM field that reflects the general population of the nation. Toward this goal, the PI worked on the Brown-HHMI Gateway STEM Course Initiatives in which the PI and her  team developed problem-solving teaching packets particularly tailored for students from HUG. These teaching packets have been used by a full-time lecturer who is dedicated to tutoring the targeted students. The PI also worked with Brown’s Women in Science (WiSE) to promote young female scientists to science and with Society of Sigma Xi to help students improve their science communication skills and provide opportunities for students to network and connect with scientists in related fields. The PI’s efforts were recognized by the University and she was selected for the Deans' Award for Excellence in Teaching in the Physical/Life Sciences in 2015.

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

Last Modified: 04/22/2018
Modified by: Eunsuk Kim