The research plan is to define and develop the coordination chemistry of zinc and its spectral probe metals as a basis for understanding the biochemistry of enzymes that contain zinc. The study of zinc metallobiomolecules is of vast biological and medical significance. Emphasis will be given to the preparation and study of synthetic analogs for enzymes that contain zinc- cysteine coordination centers. These enzymes include alcohol dehydrogenase, E. coli RNA polymerase, beta-lactamase II, aspartate transcarbamylase, aminoleuvulinc acid dehydratase, and metallothionein. Also, it has recently been suggested that zinc- cysteine coordination units are responsible for creating repeated structural domains which enable certain proteins to bind to nucleic acids. These nucleic acid binding proteins includes Transcription Factor IIIA which activates the transcription of the Xenopus 5 S RNA genes. Zinc-sulfur interactions are also important in drug based enzyme inhibitors. Synthetic model compounds that reproduce the (Zn(his)3) coordination of carbonic anhydrase and alkaline phosphatase (M1) will also be studied. The investigation will involve the synthesis, structural characterization and spectroscopic study of complexes of zinc(II) and its spectral probe metals, cobalt(II) and cadmium(II). The study of the synthetic analogs will be directed to answer several basic questions which are prevalent in the chemistry of zinc enzymes: (1) the identification of the set of ligands which are bound to the zinc centers; (2) the coordination number and geometry of the metal center in the resting state, the catalytically viable intermediate states and the chemically inhibited states; (3) the role of zinc-OH2 and zinc-OH coordination in the enzymatic mechanisms; (4) the coordination chemistry of probe metals which have been substituted for zinc centers. In addition, investigations of iron(III)-thiolate and metal-phenolate compounds as models for iron(III)-cysteine and metal-tyrosine coordination centers in metalloproteins will be continued. The ultimate goal of this work is the synthesis and characterization of complexes which will duplicate the structural, electronic and reactivity properties of the metal centers in enzymes that contain zinc and iron. In the efforts to achieve this goal, new, fundamental information will be discovered about the biochemistry and chemistry of these metal ions in biologically revelant coordination environments.
