Synthesis and characterization of structural and functional divalent metal complexes of a flexible heptadentate binucleating ligand as phosphohydrolase mimics




Joy, Rebecca A.

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This research presents the synthesis and characterization of structural and functional model complexes of phosphohydrolases. Hydrolase enzymes play a significant role in the proper processing of nucleic acids; an essential function to sustain life. Phosphohydrolase enzymes are a special type of hydrolase involved in the hydrolytic cleavage of highly stable phosphate esters. Despite efforts to understand this extremely important process through the study of various synthetic model systems, very little is known about the mechanism of action. This project focuses on new mono- and polynuclear metal complexes utilizing a highly versatile heptadentate ligand that mimic the structure and function of phosphohydrolases. The hydrolytic activity of each complex was monitored and analyzed by means of spectrophotometric measurements in aqueous solutions under different reaction conditions. The ability of these complexes as nucleophilic agents in hydrolytic processes was tested using bis(4-nitrophenyl) phosphate, BNPP, as a DNA model substrate. The kinetic rates (under optimal conditions) of hydrolysis for each metal's (Zn 2+, Cu2+, Ni2+) mono-, di-, and/or polynuclear metal complex were determined and compared to determine whether hydrogen bonding, in the case of the mononuclear analogues, or the presence of a second metal ion plays a more significant role in the hydrolysis of phosphate esters. Additionally, the metal ions incorporated within each complex are compared in terms of efficiency towards activating hydrolysis. A proposed mechanism of action has been formulated using the kinetic data, with the assistance of X-ray crystallographic and mass spectrometry information. The data indicates that the second metal ion is more important in the hydrolysis of phosphodiesters than the presence of a hydrogen bonding network, and that the metal ions ranked in order of decreasing efficiency towards activating hydrolytic cleavage is Ni > Cu > Zn.


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BNPP hydrolysis, Catalysis, model complexes, Multiple metal significance, Phosphodiester cleavage, Phosphohydrolase mimics