Analogues of Zinc Enzymes with Sulfur-Rich Active Sites

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DESCRIPTION (provided by applicant): Zinc is widely recognized as an element that is essential to all forms of life, and especially that of humans. Thus, zinc plays important functions in numerous biological processes (e.g. carbohydrate, lipid, protein and nucleic acid synthesis, regulation and degradation; gene transcription; viral and immune phenomena) and is an indispensable element for effective growth and development, with deficiency resulting in organ malformations. The public health implications of zinc have, therefore, recently been strongly emphasized, thereby making the bioinorganic chemistry of zinc an essential and critical area of investigation. The principal aims of the proposed research are concerned with an effort to elucidate the biological chemistry of zinc that is performed by more than 300 enzymes, with representatives for each of the fundamental enzyme classes (oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases). Paramount to understanding the many roles of zinc in biological systems is a determination of how the chemistry of zinc is modulated by its coordination environment. A specific objective of the research proposed is to provide an understanding of the chemistry of zinc in a sulfur rich environment which is of relevance to enzymes such as liver alcohol dehydrogenase, the Ada DNA repair protein, and 5-aminolevulinate dehydratase. For example, the zinc enzyme 5-aminolevulinate dehydratase is necessary for the early steps of heme formation, and its inactivation by lead is one of the principal reasons why lead is poisonous to humans. The objectives of this proposal will be achieved by investigating synthetic analogues (i.e. small molecules that mimic both the structures and functions of the active sites of zinc enzymes) that are constructed using sulfur donor tripodal ligands to emulate the protein residues that coordinate to zinc in the enzymes. Elucidation of the roles that zinc plays in biological systems will provide the information that is necessary to allow for the possibility of rational therapeutic intervention.