Grant: Discovery Grants Program - Individual

Enzymes are proteins that accelerate (catalyze) biological reactions. My research focuses on developing a detailed understanding of how enzymes accomplish this acceleration of reactions rates. Specifically, I am developing a detailed understanding of the interactions that occur between enzymes and the substrate molecules that they act on. This knowledge is essential to understanding how enzymes work, to engineer synthetic enzyme catalysts, and to design potential inhibitors of enzymes (drugs). For this purpose, I am studying mandelate racemase. This enzyme catalyzes the interconversion of D- and L-mandelic acid and plays a role in the metabolism of some soil bacteria. The enzyme serves as a paradigm for understanding how enzymes catalyze unfavorable reactions (e.g., C-H bond cleavage). Building on previous work, I will determine how substrate binding changes the acidity of amino acid side chains that reside in the enzyme's catalytic center. I have discovered that mandelate racemase is inhibited by substrate-product analogues and I will develop this finding further by assessing whether other racemases are also inhibited by substrate-product analogues and whether this is a general strategy for the development of inhibitors of related enzymes that are targets for drug design. I am also conducting experiments to address the fundamental question of how, over the course of evolution, enzymes lower the energy barrier of a reaction to achieve catalysis. Finally, I am studying enzymes that function at extremes of temperature. These so-called extremozymes have many practical applications. The present proposal addresses fundamental issues in enzymology and evolution, and the results should provide insights into general strategies for inhibitor design which will be useful knowledge for aiding drug development.