This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Vitamin B1, the active form of which is thiamin pyrophosphate, is an essential vitamin in the human diet, although most bacteria and plants can synthesize this cofactor. Within the cell, thiamin acts as a cofactor to stabilize intermediates during decarboxylation reactions. Bacteria have developed one pathway (with some variation) for its biosynthesis, while the biosynthesis in fungi and plants follows a different pathway. Additionally, cells have developed means to salvage thiamin and the degraded moieties of thiamin. In yeast, THI4 biosynthesizes the precursor to thiazole, adenosine diphospho-5-(?-ethyl)-4-methylthiazole-2-carboxylic acid. THI6 is responsible for both phosphorylating the thiazole moiety and coupling it to the pyrimidine moiety. To salvage thiamin, yeast utilizes the bifunctional THI20 to both hydrolyze thiamin (or degraded thiamin) and to phosphorylate the pyrimidine moiety. In bacteria, TbpA, a thiamin binding protein found in the periplasm, is part of an ABC transporter to channel the various forms of thiamin into the cell. The structure of TbpA was determined to 2.25 ? and published in Biochemistry in 2008 (E. Soriano). Additionally, the Y112F mutant of the salvage thiaminase II (TenA) has been characterized with a substrate analogue bound to analyze the mechanism of this enzyme. This work was published in Bioorganic Chemistry in 2008 (A. Jenkins). The final step in vitamin B1 biosynthesis is the phosphorylation of thiamin monophosphate by ThiL to form the active thiamin pyrophosphate. The structure of Aquifex aeolicus ThiL was determined with substrate analogues and products bound and showed that the phosphate transfer catalyzed by this enzyme is done via an in-line transfer mechanism. This work was published in 2008 in Biochemistry (K. McCulloch).

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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