Alkylation of Zinc Thiolate Proteins: Reactions with Model Compounds




Smith, Jennifer Nicole

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Many metalloproteins are known to tetra hedrally coordinate a zinc atom into their folded conformation. The zinc is ligated to nitrogen, sulfur, and/or oxygen donor atoms, which come from amino acid residues, such as histidine, cysteine, tyrosine, aspartic acid, and glutamic acid. The operative roles of the proteins are classified as either for structural support, or for enzymatic activity. The reactive proteins can utilize the same tetrahedral coordination to the same donor atoms as the nonenzymatic proteins. To date, it is unclear how nature is controlling the reactivity of zinc thiolate proteins. Learning how to control the reactivity of zinc-thiolate bonds can have major implications in the development of new pharmaceuticals, in addition to fundamental protein chemistry. The research presented here involves the synthesis and characterization of small molecule chemical models, which mimic the active sites of zinc-thiolate proteins. The zinc complexes studied are of the general type, LZn-SR, where L represents a tripodal heteroscorpionate ligand, and SR represents a thiophenol. 'H NMR kinetic studies were performed to determine the influence of the ligand donor atoms and of the hydrogen bonding interactions during the alkylation of a variety of model compounds. The reactions were run in chloroform, acetonitrile, and methanol with either of two methylating agents, methyl iodide or trimethyloxonium tetrafluoroborate. The comparison of rate constants firstly shows that hydrogen bonding to the sulfur donor decreases the rate of alkylation, and secondly that the strength of the hydrogen bond only mildly influences the rate. In addition to controlling zinc thiolate reactivity, it is shown that hydrogen bonding also generates exquisite specificity when multiple thiolate targets are present. Finally, the data also support the proposal that a zinc-bound thiolate is the actual nucleophile in the alkylation mechanism.



proteins, alkylation, zinc proteins


Smith, J. N. (2003). Alkylation of zinc thiolate proteins: Reactions with model compounds (Unpublished thesis). Southwest Texas State University, San Marcos, Texas.


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