Research Initiation Award: Mechanistic Insights into RNO and XNO Product Formations: The Role of Hemoglobin and Ligand Sterics in Physiological RNO Binding and Synthesis

Lincoln University, Lincoln University

Investigators

Abstract

Non-technical Abstract: Research Initiation Awards support faculty at Historically Black Colleges and Universities in developing new research programs or enhancing existing ones. These awards aim to advance the research capabilities of faculty members, improve research and teaching at their home institutions, and engage undergraduate students in meaningful research experiences. The award to Lincoln University investigates the interactions between organic nitrosoalkanes and human hemoglobin. Nitrosoalkanes are compounds formed through the oxidation of amines or the reduction of nitro-containing compounds, and their interactions with hemoglobin can cause health issues such as methemoglobinemia and hemolytic anemia. This project enhances our understanding of these interactions and addresses a significant knowledge gap regarding the structural impacts of nitrosoalkanes binding with hemeproteins and their functions. Beyond its scientific objectives, the project provides essential research training for undergraduate students and includes outreach efforts targeting rural high school students to inspire interest in science. Together, these initiatives promise to foster the next generation of professionals and contribute to the development of a skilled scientific workforce. Technical Abstract: The project aims to elucidate the structural and functional consequences of organic nitrosoalkanes (RNOs) binding to human hemoglobin (Hb). RNOs, compounds formed through the oxidation of amines or the reduction of nitro-containing compounds, interact with Hb and can cause health issues such as methemoglobinemia and hemolytic anemia. The specific goals of this project are to: (1) employ UV-vis spectroscopy to quantify the binding rates of Hb-RNO interactions; (2) use X-ray crystallography to capture the binding modes of these interactions; and (3) delineate the conformational changes and potential structural damages resulting from this binding. Understanding these structural alterations is crucial, as they provide insight into the fundamental mechanisms by which RNOs disrupt Hb function. In parallel, the project aims to investigate the physiological synthesis of RNOs by Hb, focusing on the role of hemoglobin in activating nitric oxide (NO) for nitrosyl transfer to different nucleophiles, particularly contrasting carbon and sulfur nucleophiles. These findings have significant implications for understanding the broader roles of hemeproteins in health and disease, potentially guiding the development of protective measures against RNO-related damage. 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.