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).
- Tao, L., Pattenaude, S. A., Joshi, S., Begley, T. P., Rauchfuss, T. B., & Britt, R. D. (2020). Radical SAM Enzyme HydE Generates Adenosylated Fe(I) Intermediates En Route to the [FeFe]-Hydrogenase Catalytic H-Cluster.. Journal of the American Chemical Society.
- Wang, Y., & Begley, T. P. (2020). Mechanistic Studies on CysS - A Vitamin B12-Dependent Radical SAM Methyltransferase Involved in the Biosynthesis of the tert-Butyl Group of Cystobactamid.. Journal of the American Chemical Society. 142(22), 9944-9954.
- Joshi, S., Fedoseyenko, D., Mahanta, N., Ducati, R. G., Feng, M. u., Schramm, V. L., & Begley, T. P. (2019). Antibacterial Strategy against H. pylori: Inhibition of the Radical SAM Enzyme MqnE in Menaquinone Biosynthesis. ACS MEDICINAL CHEMISTRY LETTERS. 10(3), 363-366.
- Adak, S., & Begley, T. P. (2019). Hexachlorobenzene Catabolism Involves a Nucleophilic Aromatic Substitution and Flavin-N5-Oxide Formation. BIOCHEMISTRY. 58(9), 1181-1183.
- Mahanta, N., Hicks, K. A., Naseem, S., Zhang, Y., Fedoseyenko, D., Ealick, S. E., & Begley, T. P. (2019). Menaquinone Biosynthesis: Biochemical and Structural Studies of Chorismate Dehydratase.. BIOCHEMISTRY. 58(14), 1837-1840.
- Adak, S., & Begley, T. P. (2019). Flavin-N5-oxide intermediates in dibenzothiophene, uracil, and hexachlorobenzene catabolism. MACROMOLECULAR CRYSTALLOGRAPHY, PT D. Methods in Enzymology. Elsevier.
- Joshi, S., Fedoseyenko, D., Mahanta, N., & Begley, T. P. (2018). Aminofutalosine Synthase (MqnE): A New Catalytic Motif in Radical SAM Enzymology. Methods in Enzymology. (pp. 179-198).
- Wang, Y., Schnell, B., MÃ¼ller, R., & Begley, T. P. (2018). Iterative Methylations Resulting in the Biosynthesis of the t-Butyl Group Catalyzed by a B
12-Dependent Radical SAM Enzyme in Cystobactamid Biosynthesis. Methods in Enzymology. (pp. 199-216).
- Bhandari, D. M., Fedoseyenko, D., & Begley, T. P. (2018). Mechanistic Studies on the Radical SAM Enzyme Tryptophan Lyase (NosL). Methods in Enzymology. (pp. 155-178).
- Burns, K. E., & Begley, T. P. (2013). Mec+ Peptidase (Mycobacterium tuberculosis). Handbook of Proteolytic Enzymes. (pp. 1567-1570).
- Decamps, L., Benjdia, A., Berteau, O., Decamps, L., Benjdia, A., Berteau, O., ... Latour, J. (2014). One enzyme for two radical reactions: Deciphering the mechanism of a novel radical SAM enzyme critical for F-420 cofactor biosynthesis. JBIC Journal of Biological Inorganic Chemistry. 19, S308-S308.
- Abdelwahed, S. H., & Begley, T. P. (2013). Biosynthesis of dimethylbenzimidazole: Catalysis of a remarkable flavin degradation reaction. ACS Photonics. 246,
- Hanes, J. W., Burns, K. E., Hilmey, D. G., Chatterjee, A., Dorrestein, P. C., Keresztes, I., & Begley, T. P. (2008). BIOL 155-Mechanistic studies on pyridoxal phosphate synthase: The reaction pathway leading to a chromophoric intermediate. ACS Photonics. 235,
- Mueller, I. B., Eschbach, M., Begley, T. P., Walter, R. D., & Wrenger, C. (2008). Vitamin B1 synthesis and salvage in Plasmodium falciparum.. Int J Parasitol. 38, S43-S43.
- Begley, T. P. (2005). Tryptophan catabolism: Gene identification and mechanistic studies. ACS Photonics. 230, U587-U587.
- Xie, Lina (2018-12). Enzyme-Catalyzed Acylium Ion Formation and Reagents for the Detection of Thiocarboxylates Involved in the Biosynthesis of the NAD Derived Pincer Cofactor. (Doctoral Dissertation)
- Bhandari, Dhananjay (2017-12). Studies on the Flavin-mediated Cysteine Salvage Pathway, Structural Enzymology of Riboflavin Lyase and Mechanistic Investigation of the Radical S-adenosyl-L-methionine-mediated Tryptophan Lyase. (Doctoral Dissertation)
- Shome, Brateen (2017-05). Synthetic and Biochemical Exploration of the Degradation and Utilization of Thiamin Analogs and Preliminary Studies on Methanopterin methyltransferase. (Doctoral Dissertation)
- Liu, Yiquan (2015-12). Development of Chemical Strategies for Specifically Probing and Identifying Sulfur Carrier Proteins and Vitamin B6-Dependent Enzymes in Bacteria. (Doctoral Dissertation)
- Lai, Rung Yi (2015-08). The Mechanistic Investigation of the Bacterial Thiamin Thiazole Synthase and the Eukaryotic Thiamin Pyrimidine Synthase. (Doctoral Dissertation)