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.

Public Health Relevance

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. . '.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37DK044083-23
Application #
8610374
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sechi, Salvatore
Project Start
1991-09-15
Project End
2018-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
23
Fiscal Year
2013
Total Cost
$389,706
Indirect Cost
$116,483
Name
Texas A&M University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
020271826
City
College Station
State
TX
Country
United States
Zip Code
77845
Mehta, Angad P; Abdelwahed, Sameh H; Xu, Hui et al. (2014) Molybdopterin biosynthesis: trapping of intermediates for the MoaA-catalyzed reaction using 2'-deoxyGTP and 2'-chloroGTP as substrate analogues. J Am Chem Soc 136:10609-14
Cooper, Lisa E; O'Leary, Seán E; Begley, Tadhg P (2014) Biosynthesis of a thiamin antivitamin in Clostridium botulinum. Biochemistry 53:2215-7
Sikowitz, Megan D; Shome, Brateen; Zhang, Yang et al. (2013) Structure of a Clostridium botulinum C143S thiaminase I/thiamin complex reveals active site architecture . Biochemistry 52:7830-9
Mehta, Angad P; Hanes, Jeremiah W; Abdelwahed, Sameh H et al. (2013) Catalysis of a new ribose carbon-insertion reaction by the molybdenum cofactor biosynthetic enzyme MoaA. Biochemistry 52:1134-6
Mahanta, Nilkamal; Fedoseyenko, Dmytro; Dairi, Tohru et al. (2013) Menaquinone biosynthesis: formation of aminofutalosine requires a unique radical SAM enzyme. J Am Chem Soc 135:15318-21
Mehta, Angad P; Abdelwahed, Sameh H; Begley, Tadhg P (2013) Molybdopterin biosynthesis: trapping an unusual purine ribose adduct in the MoaA-catalyzed reaction. J Am Chem Soc 135:10883-5
Chatterjee, Abhishek; Abeydeera, N Dinuka; Bale, Shridhar et al. (2011) Saccharomyces cerevisiae THI4p is a suicide thiamine thiazole synthase. Nature 478:542-6
French, Jarrod B; Begley, Tadhg P; Ealick, Steven E (2011) Structure of trifunctional THI20 from yeast. Acta Crystallogr D Biol Crystallogr 67:784-91
Hanes, Jeremiah W; Chatterjee, Debashree; Soriano, Erika V et al. (2011) Construction of a thiamin sensor from the periplasmic thiamin binding protein. Chem Commun (Camb) 47:2273-5
Mukherjee, Tathagata; Hanes, Jeremiah; Tews, Ivo et al. (2011) Pyridoxal phosphate: biosynthesis and catabolism. Biochim Biophys Acta 1814:1585-96

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