Ada Repair Protein: The Role of Electronic Effects on the Rate and Mechanism of Zinc Thiolate Alkylations

Although it is widely acknowledged that the Ada repair metalloprotein undergoes methylation as a way of repairing DNA, the mechanism by which this process occurs is not yet understood. Two mechanisms have been proposed that differ in whether or not the zinc-sulfur bond remains intact throughout the process of repair. Using zinc thiolate complexes synthesized to mimic the protein\u27s active site, this research focuses on the impact of electron donating and withdrawing groups on the dissociation of the zinc-sulfur bond. The electronic modifications resulted in changes in reaction rates and a plot of the observed rate constants as well as a nonlinear Hammett parameter σp. The nonlinear correlation is indicative of a change in rate determining step as the substituents change, which provides support for a dissociative mechanism where thiolate dissociation of the thiolate moiety from the zinc thiolate complex must occur prior to methylation. Furthermore, solid-state characterization and mass spectrometry provide additional evidence for a dissociative mechanism and will be discussed