Thiamin is an essential component of the human diet with an RDA of 1.2 mg. It is also an important commercial chemical and it is w/idely used as a food additive and flavoring agent. Annual production, by chemical synthesis, is on the order of 3,300 tons. Thiamin-dependent enzymes play an important role in carbohydrate and branched-chain amino acid metabolism. At this time, our mechanistic understanding of this class of enzymes is sophisticated. In contrast, while thiamin was the first vitamin identified, our understanding of its biosynthesis is still incomplete because the biosynthetic pathway is complex and involves unprecedented reaction chemistry. The long-term goal of our research is the complete mechanistic understanding ofthe enzymology of thiamin biosynthesis, salvage and catabolism, in all forms of life and the elucidation of connections between thiamin metabolism and other aspects of cellular physiology. In the next grant period, we describe studies designed to elucidate the biosynthesis ofthe thiamin thiazole and pyrimidine in both bacteria and eukaryotes. These heterocycle forming reactions involve novel biological chemistry. Our strategy will involve a combination of kinetics, modified substrates, protein mutagenesis and structural studies. We will also identify the genes involved in thiamin breakdown and salvage. Bacteria, in the human digestive tract, containing these genes are likely to play an important role in controlling the human thiamin RDA. Finally, we will explore the use of 18F-thiamin as a PET imaging agent, ultimately to determine the global thiamin distrubution in healthy and diseased humans.
Thiamin (vitamin B1) is essential for all forms of life. Our studies will facilitate the commercial production of thiamin by fermentation and have potential applications in the design of new antibiotics. Understanding thiamin catabolism and salvage will enable us to evaluate the importance of these activities in the human digestive tract. 18F-thiamin has potential use, as an imaging agent, in basic human biology and in tumor rifitfictinn. . '.
|Zhang, Xuan; Eser, Bekir E; Chanani, Prem K et al. (2016) Structural Basis for Iron-Mediated Sulfur Transfer in Archael and Yeast Thiazole Synthases. Biochemistry 55:1826-38|
|Xu, Hui; Chakrabarty, Yindrila; Philmus, Benjamin et al. (2016) Identification of the First Riboflavin Catabolic Gene Cluster Isolated from Microbacterium maritypicum G10. J Biol Chem 291:23506-23515|
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|Mehta, Angad P; Abdelwahed, Sameh H; Fenwick, Michael K et al. (2015) Anaerobic 5-Hydroxybenzimidazole Formation from Aminoimidazole Ribotide: An Unanticipated Intersection of Thiamin and Vitamin Bâ‚â‚‚ Biosynthesis. J Am Chem Soc 137:10444-7|
|Mehta, Angad P; Abdelwahed, Sameh H; Mahanta, Nilkamal et al. (2015) Radical S-adenosylmethionine (SAM) enzymes in cofactor biosynthesis: a treasure trove of complex organic radical rearrangement reactions. J Biol Chem 290:3980-6|
|Fenwick, Michael K; Mehta, Angad P; Zhang, Yang et al. (2015) Non-canonical active site architecture of the radical SAM thiamin pyrimidine synthase. Nat Commun 6:6480|
|Mehta, Angad P; Abdelwahed, Sameh H; Begley, Tadhg P (2015) Molybdopterin biosynthesis-Mechanistic studies on a novel MoaA catalyzed insertion of a purine carbon into the ribose of GTP. Biochim Biophys Acta 1854:1073-7|
|Philmus, Benjamin; Decamps, Laure; Berteau, Olivier et al. (2015) Biosynthetic versatility and coordinated action of 5'-deoxyadenosyl radicals in deazaflavin biosynthesis. J Am Chem Soc 137:5406-13|
|Cooper, Lisa E; O'Leary, SeÃ¡n E; Begley, Tadhg P (2014) Biosynthesis of a thiamin antivitamin in Clostridium botulinum. Biochemistry 53:2215-7|
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