Mechanism and inhibition of organic and enzymatic isomerizations

With the support of the Chemistry of Life Processes program of the Division of Chemistry, Andrew Murkin of the University at Buffalo, the State University of New York, is studying the mechanisms of isomerization in organic and enzymatic reactions. Isomerization—the conversion of one compound into another without a change in molecular formula—is critical to the synthesis of many chemicals and biomolecules. Three examples of a specific isomerization reaction will be investigated, one using organic compounds in the presence of a catalyst and the other two using enzymes from organisms that cause severe infections such as tuberculosis. Learning how these reactions proceed may lead to the development of improved catalysts and of pharmaceuticals that act by inhibiting enzymes associated with various diseases. Educational development will be provided to undergraduate and graduate students of diverse backgrounds, and local teachers will be trained to develop hands-on lessons that introduce enzymes to K–12 students. This project seeks to determine the mechanisms of Lewis acid- and enzyme-catalyzed rearrangement of alpha-ketol substrates using substituent effects and kinetic isotope effects (KIEs). The BF3-catalyzed rearrangement of dibenzylglycolaldehyde derivatives will be investigated first, and estimates the transition state structure will be established by quantum mechanical calculations that utilize the experimental results on the nature of the rate-determining step. This structure will serve as a model for comparison with the transition states of two enzyme-catalyzed reactions that also involve rearrangement of alpha-ketols. Of the two enzymes, one is expected to utilize a mechanism analogous to the Lewis acid-catalyzed reaction and should be directly comparable. Most evidence to date on the second enzyme, however, favors an alternative mechanism not possible for the first enzyme. This project therefore aims to clarify this uncertainty, the outcome of which may guide the design of inhibitors tailored to these enzymes. In the longer term, these studies have the potential to guide the development of transition state analogue inhibitors for isomerase enzymes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.