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The research in this laboratory focuses on the catalytic mechanisms of enzymes from a kinetic, chemical and structural perspective. Currently, the laboratory is focusing on two enzymes both of which have medical relevance. One enzyme is acetyl CoA carboxylase, which catalyzes the committed and regulated step in fatty acid synthesis in all animals, plants and bacteria. This enzyme is a target for antibiotics and anti-obesity agents. Acetyl CoA carboxylase is a multifunctional biotin-dependent enzyme and consists of three components: (1) biotin carboxylase, (2) biotin carboxyl carrier protein, which contains the biotin cofactor and (3) carboxyltransferase. The other enzyme under investigation is GDP-mannose 4,6 dehydratase, which catalyzes the first committed step in the biosynthesis of fucose. This enzyme is a target for anti-inflammatory drugs and anti-metastatic agents. To study the catalytic mechanism of these enzymes we use a variety of mechanistic techniques including steady-state and rapid reaction kinetics, inhibitor design, isotope effects and site-directed mutagenesis. Structural analyses are carried out by x-ray crystallography.
Molecular Dynamics Simulations of Biotin Carboxylase. Nilsson Lill, S.O., Gao, J. and Waldrop, G.L. (2008). J. Phys. Chem. B, In press.
DNA Inhibits Catalysis by the Carboxyltransferase Subunit of Acetyl-CoA Carboxylase: Implications for Active Site Communication. Benson, B. K., Meades, G., Jr., Grove, A., Waldrop, G.L. (2008). Protein Sci. 17, 34-42.
Modeling and Numerical Simulation of Biotin Carboxylase Kinetics: Implications for Half-Sites Reactivity. de Queiroz, M.S. and Waldrop, G.L. (2007). J. Theor. Biol. 246, 167-175.
A High Throughput Screening Assay for the Carboxyltransferase Subunit of Acetyl-CoA Carboxylase. Santoro, N., Brtva, T., Vander Roest, S., Siegel, K. and Waldrop,G.L. (2006). Analytical Biochem. 354, 70-77.
The Structure of the Carboxyltransferase Component of Acetyl-CoA Carboxylase Reveals a Zinc-binding Motif Unique to the Bacterial Enzyme. Bilder, P., Lightle, S., Bainbridge, G., Jeffrey Ohren, Barry Finzel, Fang Sun, Susan Holley, Loola Al-Kassim, Cindy Spessard, Michael Melnick, Marcia Newcomer and Waldrop,G.L. (2006).
Biochemistry 279, 15772-15778.
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