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Work in the Frantom group is focused on the field of mechanistic enzymology. In broad terms, mechanistic enzymologists seek a chemical understanding of how enzymes are able to dramatically increase reaction rates, perform unique and stereospecific chemistry, and provide mechanisms for regulation using a limited toolbox consisting of 20 amino acids and various cofactors. In order to answer these types of questions, we utilize a wide array of genetic, biochemical, biophysical, kinetic, and spectroscopic techniques. In addition, the individual aims below provide a spectrum of projects that can be successfully completed by students and postdoctoral researchers with varying scientific backgrounds, research interests, and levels of experience. Current projects include:
1. Understanding the role of protein dynamics in allosteric regulation of enzymes. As drug design expands from active site-based therapeutics to include small molecules that will affect the dynamics of a protein to achieve either inhibition or activation, it will be critical to have a detailed understanding of the architecture of such allosteric networks. Our work focuses on the essential enzyme isopropylmalate synthase from Mycobacterium tuberculosis, which is feedback inhibited by L-leucine. Recently, we reported the mapping of several structural elements involved in the 50 Å long allosteric network activated by L-leucine binding. Currently, we are characterizing this allosteric network from a structural, functional, and evolutionary perspective utilizing EPR and UV-Vis spectroscopy, hydrogen/deuterium exchange, steady-state kinetics, and site-directed mutagenesis.
2. Determining the chemical mechanism and transition-state structures for retaining glycosyltransferase enzymes. Enzymes that catalyze the transfer of sugar molecules are involved in numerous essential biosynthetic pathways. We are interested in understanding the chemical mechanism of retaining glycosyltransferase enzymes on an atomic level and leveraging that information toward the design of tight-binding and specific inhibitors as possible therapeutics. In order to accomplish this goal, enzymatic synthesis of radiolabeled sugar nucleotides and computational modeling will be required. Using these tools, kinetic isotope effects at various positions in the substrates can be determined and used to predict the transition-state structure.
Identification of a Complete Allosteric Pathway in the Regulation of α-Isopropylmalate Synthase from Mycobacterium tuberculosis by the Feedback Inhibitor L-Leucine.” Frantom, P. A.; Zhang, H.; Emmett, M. R.; Marshall, A. G.; and Blanchard, J. S. Biochemistry 48, 7457-7464 (2009).
“Kinetic Evidence for Interdomain Communication in the Allosteric Regulation of α-Isopropylmalate Synthase from M. tuberculosis” de Carvalho, L. P.; Frantom, P. A.; Argyrou, A.; and Blanchard, J. S. Biochemistry 48, 1996-2004 (2009).
“Structural and Enzymatic Analysis of MshA from Corynebacterium glutamicum: Substrate-assisted Catalysis” Vetting, M. W.; Frantom, P. A.; Blanchard, J. S. J. Biol. Chem. 283, 15834-15844 (2008).
“Direct Spectroscopic Evidence for a High-Spin Fe(IV) Intermediate in Tyrosine Hydroxylase” Eser, B. E.; Barr, E. W.; Frantom, P. A.; Saleh, L.; Bollinger, J. M.; Krebs, C.; Fitzpatrick, P. F. J. Am. Chem. Soc. 129, 11334-11335 (2007).
“Reduction and Oxidation of the Active Site Iron in Tyrosine Hydroxylase: Kinetics and Specificity” Frantom, P. A.; Seravalli, J.; Ragsdale, S. W.; Fitzpatrick, P. F. Biochemistry 45, 2372-2379 (2006).
“Uncoupled Forms of Tyrosine Hydroxylase Unmask Kinetic Isotope Effects on Chemical Steps.” Frantom, P. A.; Fitzpatrick, P. F. J. Am. Chem. Soc. 125, 16190-16191 (2003).
“Intrinsic Deuterium Isotope Effects on Benzylic Hydroxylation by Tyrosine Hydroxylase” Frantom, P. A.; Pongdee, R.; Sulikowski, G. A.; Fitzpatrick, P. F. J. Am. Chem. Soc. 124, 4202-4203 (2002).
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