Mechanistic Studies of Dinuclear Metalloenzymes - A Model Approach
Abstract: With the goal to study the mechanisms of dinuclear metalloenzymes, a new line of synthetic and computational models were prepared and studied. Mixed imidazole and carboxylate multidentate complexes were synthesized to better simulate carboxylate-rich ligand environments. Of the compounds, which showed to be the most useful, were one symmetric and the other one asymmetric and in both cases they were both found to be based on a central phenoxide moiety. To study the mechanism of the dinickel enzyme urease, complexes containing two nickel ions were prepared from the two ligands. Analysis of the crystal structures of the synthesized model complexes indicated that the urea prefers the coordinatively unsaturated ion for its initial coordination. From kinetic studies comparing the complexes it became apparent that an open coordination site is important in facilitating hydrolytic catalytic activity. Computational models, based on the native crystal structure of the enzyme, were also used. The conclusions showed that the first coordination of urea most likely occurs on Ni1 trans to the carbamylated lysine ligand and that the published proposal based on the attack of the bridging hydroxy group is less likely due to the high energy barrier for the formation of the tetrahedral intermediate. When ICIMP is reacted with zinc, a tetranuclear zinc complex is formed. It can easily be dissociated to dinuclear complexes. Both the structure of the complex and the structure of the environment around the avtive site in the enzyme resemble the nickel model. The complex has also been found to be very potent as a functional model for hydrolytic enzymes. Homo- and heteronuclear iron complexes were also synthesized. As a useful precursor, a mononuclear complex could be isolated and crystallographically characterized. Based on the mononuclear system, four new heterodinuclear iron complexes were isolated.
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