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Current Activities

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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).

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Selected Publications

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BOOK: The Organic Chemistry of Biological Pathways by John McMurry and Tadhg Begley.

BOOK: Encyclopedia of Chemical Biology, Volumes 1-4, (2009), Edited by Tadhg P. Begley

BOOK: Cofactor Chemistry, Volume 7 of Comprehensive Natural Products Chemistry, 2010. Edited by Tadhg P. Begley

Mehta, A. P.; Hanes, J. W.; Abdelwahed, S. H.; Hilmey, D. G.; Hanzelmann, P.; Begley, T. P.: Catalysis of a New Ribose Carbon-Insertion Reaction by the Molybdenum Cofactor Biosynthetic Enzyme MoaA. Biochemistry 2013, 52, 1134-1136

Mehta, A. P.; Abdelwahed, S. H.; Begley, T. P.: Molybdopterin Biosynthesis: Trapping an Unusual Purine Ribose Adduct in the MoaA-Catalyzed Reaction. Journal of the American Chemical Society 2013, 135, 10883-10885

Cooper, L. E.; Fedoseyenko, D.; Abdelwahed, S. H.; Kim, S.-H.; Dairi, T.; Begley, T. P.: In Vitro Reconstitution of the Radical S-Adenosylmethionine Enzyme MqnC Involved in the Biosynthesis of Futalosine-Derived Menaquinone. Biochemistry 2013, 52, 4592-4594

Philmus, B.; Abdelwahed, S.; Williams, H. J.; Fenwick, M. K.; Ealick, S. E.; Begley, T. P.: Identification of the Product of Toxoflavin Lyase: Degradation via a Baeyer-Villiger Oxidation. Journal of the American Chemical Society 2012, 134, 5326-5330

Lai, R.-Y.; Huang, S.; Fenwick, M. K.; Hazra, A.; Zhang, Y.; Rajashankar, K.; Philmus, B.; Kinsland, C.; Sanders, J. M.; Ealick, S. E.; Begley, T. P.: Thiamin pyrimidine biosynthesis in Candida albicans: A remarkable reaction between histidine and pyridoxal phosphate. Journal of the American Chemical Society 2012, 134, 9157-9159

Huang, S.; Mahanta, N.; Begley, T. P.; Ealick, S. E.: Pseudouridine Monophosphate Glycosidase: A New Glycosidase Mechanism. Biochemistry 2012, 51, 9245-9255

Decamps, L.; Philmus, B.; Benjdia, A.; White, R.; Begley, T. P.; Berteau, O.: Biosynthesis of F0, Precursor of the F420 Cofactor, Requires a Unique Two Radical-SAM Domain Enzyme and Tyrosine as Substrate. Journal of the American Chemical Society 2012, 134, 18173-18176

Hazra, A. B.; Han, Y.; Chatterjee, A.; Zhang, Y.; Lai, R.-Y.; Ealick, S. E.; Begley, T. P.: A missing enzyme in thiamin thiazole biosynthesis: Identification of TenI as a thiazole tautomerase. Journal of the American Chemical Society 2011, 133, 9311-9319

Hanes, J. W.; Chatterjee, D.; Soriano, E. V.; Ealick, S. E.; Begley, T. P.: Construction of a thiamin sensor from the periplasmic thiamin binding protein. Chemical Communications (Cambridge, United Kingdom) 2011, 47, 2273-2275

Chatterjee, A.; Abeydeera, N. D.; Bale, S.; Pai, P.-J.; Dorrestein, P. C.; Russell, D. H.; Ealick, S. E.; Begley, T. P.: Saccharomyces cerevisiae THI4p is a suicide thiamine thiazole synthase. Nature (London, United Kingdom) 2011, 478, 542-546

Mukherjee, T.; Zhang, Y.; Abdelwahed, S.; Ealick, S. E.; Begley, T. P.: Catalysis of a Flavoenzyme-Mediated Amide Hydrolysis. Journal of the American Chemical Society 2010, 132, 5550-5551

Krishnamoorthy, K.; Begley, T. P.: Reagent for the Detection of Protein Thiocarboxylates in the Bacterial Proteome: Lissamine Rhodamine B Sulfonyl Azide. Journal of the American Chemical Society 2010, 132, 11608-11612

Chatterjee, A.; Hazra, A. B.; Abdelwahed, S.; Hilmey, D. G.; Begley, T. P.: A "Radical Dance" in Thiamin Biosynthesis: mechanistic Analysis of the Bacterial

Hydroxymethylpyrimidine Phosphate Synthase. Angewandte Chemie, International Edition 2010, 49, 8653-8656