HNO plays significant roles in many biological processes, such as vascular relaxation, enzyme activity regulation, and neurological function regulation. It also offers a promising new treatment for diseases such as heart failure and stroke. Many HNO biological effects occur with metalloproteins. However, the atomic level structural and functional information are largely unknown. Our long-term goal is to determine how HNO binds with its biological targets and how such binding leads to protein functional responses.
Aim 1 is to determine the atomic level HNO binding modes in myoglobin (Mb). Heme proteins are frequently involved in HNO binding. But there are no X-ray structures of any HNO protein complexes. The first stable HNO complex is with Mb, enabling numerous spectroscopic characterizations, which were used by us recently with computational work to propose two novel active site models. These models exhibit unique novel features, which need to be validated with protein level investigations. Our preliminary protein level studies has shown support of our active site results, but also offered more details of effects on nearby groups. We will perform protein level investigations of various binding modes and compare with more experimental results not investigated before, to provide the first rigorous atomic level HNO binding picture with Mb. Results will facilitate investigations of HNO binding with other heme proteins.
Aim 2 is to determine HNO/NO conversion mechanism via Cu,Zn-SOD and a Cu complex with imaging function. Reaction of HNO with Cu,Zn-SOD was suggested to be important for in vivo formation of NO. A copper complex was recently reported to have similar reaction and allow selective detection and imaging for HNO. Our preliminary studies found interesting reaction pathways for them. We will study reactions using different scales of active site models and protein environment to help understand their effects on mechanisms. Additional mechanistic investigations of the Cu complex with modified ligands will be done to provide design guidelines for HNO imaging agents.
Aim 3 is to determine HNO/NO conversion mechanisms via Mb. Our preliminary studies showed some interesting reaction mechanisms to support experimental results. We will perform a series of computational investigations including protein level calculations to validate the mechanisms. As heme models were recently used to trap HNO, we will also systematically evaluate effects of metal centers and heme ligands to help future design of HNO scavengers. Results will provide useful structural and mechanistic results of HNO interactions with metalloproteins and models to facilitate studies of health, diseases, and therapeutic treatments involving HNO.
This project will provide useful novel results of structures and functional mechanisms of HNO interactions with metal centers in proteins and useful guidelines to design HNO detection and imaging agents. Since HNO participates in a broad range of physiological processes related to health and offers a promising new treatment for diseases such as heart failure and stroke, results here will assist future studies of health, diseases, and therapeutic treatments involving HNO.
|Wang, Bing; Shi, Yelu; Tejero, Jesús et al. (2018) Nitrosyl Myoglobins and Their Nitrite Precursors: Crystal Structural and Quantum Mechanics and Molecular Mechanics Theoretical Investigations of Preferred Fe -NO Ligand Orientations in Myoglobin Distal Pockets. Biochemistry 57:4788-4802|
|Malwal, Satish R; O'Dowd, Bing; Feng, Xinxin et al. (2018) Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways. J Am Chem Soc 140:7568-7578|
|Malwal, Satish R; Gao, Jian; Hu, Xiangying et al. (2018) Catalytic Role of Conserved Asparagine, Glutamine, Serine, and Tyrosine Residues in Isoprenoid Biosynthesis Enzymes. ACS Catal 8:4299-4312|
|Abucayon, Erwin G; Khade, Rahul L; Powell, Douglas R et al. (2018) Lewis Acid Activation of the Ferrous Heme-NO Fragment toward the N-N Coupling Reaction with NO To Generate N2O. J Am Chem Soc 140:4204-4207|
|Abucayon, E G; Khade, R L; Powell, D R et al. (2016) Over or under: hydride attack at the metal versus the coordinated nitrosyl ligand in ferric nitrosyl porphyrins. Dalton Trans 45:18259-18266|
|Khade, Rahul L; Yang, Yuwei; Shi, Yelu et al. (2016) HNO-Binding in Heme Proteins: Effects of Iron Oxidation State, Axial Ligand, and Protein Environment. Angew Chem Int Ed Engl 55:15058-15061|
|Abucayon, Erwin G; Khade, Rahul L; Powell, Douglas R et al. (2016) Hydride Attack on a Coordinated Ferric Nitrosyl: Experimental and DFT Evidence for the Formation of a Heme Model-HNO Derivative. J Am Chem Soc 138:104-7|
|Kong, Xianqi; Terskikh, Victor V; Khade, Rahul L et al. (2015) Solid-state ¹?O NMR spectroscopy of paramagnetic coordination compounds. Angew Chem Int Ed Engl 54:4753-7|
|Struppe, Jochem; Zhang, Yong; Rozovsky, Sharon (2015) (77)Se chemical shift tensor of L-selenocystine: experimental NMR measurements and quantum chemical investigations of structural effects. J Phys Chem B 119:3643-50|
|Khade, Rahul L; Zhang, Yong (2015) Catalytic and Biocatalytic Iron Porphyrin Carbene Formation: Effects of Binding Mode, Carbene Substituent, Porphyrin Substituent, and Protein Axial Ligand. J Am Chem Soc 137:7560-3|
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