Yong Zhang Receives $446,664 NIH R15 Grant to Study Mechanisms of Metal-Mediated Biological Functions

Yong Zhang, professor in the Department of Chemistry and Chemical Biology, recently received a grant of $446,664 from the National Institutes of Health (NIH) for his project “Molecular Mechanisms of Metal-Mediated Biological Functions for NO, O2, and HNO."

Nitric oxide (NO) has considerable biomedical significance in cardiovascular regulation, immune response, neurotransmission, and global nitrogen cycle. Oxygen (O2) is vital for many fundamental biological functions such as bioenergy, metabolism, and redox signaling. Nitroxyl (HNO) also plays a significant role in vascular relaxation, enzyme activity regulation, and neurological function regulation.

Despite progress in studying the mechanisms of these biological functions, many important questions have yet to be answered, such as what causes one electron NO coupling in heme models activated by Lewis acids, what drives the rewiring of NO/O2-sensing functions of a heme enzyme, and what causes the formation of HNO in the clinical drug hydroxyurea via heme proteins.

Zhang aims to answer these questions by building on his long-term research on biological complexes of NO, O2, and HNO with metalloproteins and models.

“Since NO, O2, and HNO participate in a broad range of physiological and pathological processes related to health and offer promising treatments for various diseases, results here will facilitate future studies of health, diseases, and therapeutic treatments involving these important biological molecules,” said Zhang.

Zhang’s first objective is to determine one electron NO coupling mechanisms via recently reported heme models activated by Lewis acids, which differ from the conventional two-electron process by bacterial nitric oxide reductases. To provide a complete understanding of the kinetic and thermodynamic factors of this new reaction, systematic computational studies will be done to reveal the full reaction pathways for the reported heme models and explore the pathways for other biologically available structural components.

Next, he will aim to determine the rewiring mechanisms of NO/O2-sensing functions of a heme enzyme. How enzymes differentiate between two important redox reagents NO and O2 despite their similarity in shape, size, and charge remain unknown, however, Zhang’s experimental collaborator has recently reversed an NO sensing heme protein to be O2 sensing via multiple mutations. Zhang will attempt to reveal specific contributions of each mutation and their combinations on geometric and electronic properties and protein environment effects. The identified correlations of structural and electronic features with sensitivity functions will help rational design to rewire redox sensing functions in future biomedical research.

Zhang’s third objective – determining HNO formation mechanisms of a clinical drug hydroxyurea via heme proteins – may be achieved by calculating the complete reaction pathways using active site models with varying size of nearby residues and full proteins, to reveal basic mechanisms and roles of active site residues and protein environments for their differential reactivities.

The reactions have been experimentally studied using different heme proteins with different reactivities. However, HNO formation mechanistic details and the origin for such reactivity differences are yet to be elucidated.

"This project will provide numerous novel results of critical structures and functional mechanisms for NO reduction via nitric oxide reductase models, rewiring NO/O2 sensing to adjust signal transduction, and HNO formation from a clinic drug hydroxyurea catalyzed by metalloproteins,” Zhang said.