STRUCTURE/FUNCTION OF RESPIRATORY HEMOPROTEINS

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The long-term objective of this project is to understand the structure-function relationship in oxygen-linked respiratory hemoproteins such as myoglobin and hemoglobin by means of chemical modifications of specific molecular moieties of hemoproteins and characterization of physical properties and biochemical and physiological functions of such modified hemoproteins. Metal-substituted myoglobins and hemoglobins, particularly cobalt-porphyrin-substituted myoglobins and hemoglobins will be prepared and the mode of their interactions which diatomic ligands such as oxygen, carbon monoxide, and mitric oxide will be elucidated by thermodynamic and kinetic measurements and spectroscopic methods, especially EPR, NMR, resonance Raman, and Moessbauer spectroscopic techniques. Such investigations will allow us to identify stereochemical and electronic factors which affect kinetic and thermodynamic properties of ligand interaction, associated changes in the coordination of the prosthetic groups and the tertiary and quaternary structures of the molecules, to understand the molecular mechanism of reversible ligand binding, ligand activation, and ligand- and effector-linked subunit cooperativity and allostery in these respiratory hemoproteins, and eventually to design artificial hemoproteins which may be used as effective substitutes for natural hemoproteins of biomedical importance. Therefore, the proposed project sharply focuses on the physiological and biomedical vital aspects of oxygen delivery and utilization in tissues. Since the molecular mechanism of hemoglobin cooperativity and allostery will undoubtedly provide a useful clue to understand the vital regulatory role of allosteric enzymes in metabolism and since hemoprotein-nitric oxide complexes are frequently observed as intermediates/byproducts in metabolism of nitrogenous carcinogens, the proposed project will have wide-ranged biomedical implications.