The Begley Group is interested in the mechanistic chemistry and enzymology of complex organic transformations, particularly those found on the vitamin biosynthetic pathways. We are currently working on the biosynthesis of thiamin, molybdopterin, pyridoxal phosphate and menaquinone. Our research involves a combination of molecular biology, protein biochemistry, organic synthesis and structural studies and provides a strong training for students interested in understanding the organic chemistry of living systems and in pursuing careers in biotechnology, drug design or academia.
Thiamin pyrophosphate plays a key role in the stabilization of the acyl carbanion synthon in carbohydrate and amino acid metabolism. The biosyntheses of the thiamin pyrimidine and thiazole are complex and are different from any of the characterized chemical or biochemical routes to these heterocycles. We are particularly interested in cellular physiology and the mechanistic enzymology of thiamin biosynthesis. As an example of one of the complex transformations on this pathway, the figure below shows the structure of the pyrimidine synthase catalyzing the complex rearrangement of aminoimidazole ribotide (left) to the thiamin pyrimidine (right).
Textbook: The Organic Chemistry of Biological Pathways by John McMurry and Tadhg Begley.
Chatterjee, A.; Li, Y.; Zhang, Y.; Grove, Tyler L.; Lee, M.; Krebs, C.; Booker, S.J.; Begley, T. P.; Ealick, S.E. Reconstitution of ThiC in thiamine pyrimidine biosynthesis expands the radical SAM superfamily. Nature Chemical Biology 2008, 4(12), 758-765.
Hanes, J. W.; Keresztes, I.; Begley, T. P. 13C NMR snapshots of the complex reaction coordinate of pyridoxal phosphate synthase. Nature Chemical Biology 2008, 4(7), 425-430.
Begley, T. P.; Chatterjee, A.; Hanes, J.W.; Hazra, Amrita; Ealick, S.E. Cofactor biosynthesis - still yielding fascinating new biological chemistry. Current Opinion in Chemical Biology 2008, 12(2), 118-125.
Hanes, J.W.; Keresztes, I.; Begley, T.P. Trapping of a chromophoric intermediate in the Pdx1-catalyzed biosynthesis of pyridoxal 5'-phosphate. Angewandte Chemie, International Edition 2008, 47(11), 2102-2105.
Jenkins, A.H.; Schyns, G.; Potot, S.; Sun, G.; Begley, T.P. A new thiamin salvage pathway. >em>Nature Chemical Biology 2007, 3(8), 492-497.
Hanes, J.W.; Ealick, S.E.; Begley, T.P. Thiamin Phosphate Synthase: The Rate of Pyrimidine Carbocation Formation. Journal of the American Chemical Society 2007, 129(16), 4860-4861.