Crystallographic Studies On Enzymes Involved In Vitamin B1 Biosynthesis And The Degradation Of Vitamin B6

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Macromolecular crystallography allows for the structures of biologically interesting molecules to be determined to atomic resolutions. The enzymes involved in metabolic pathways often catalyze interesting and novel chemical reactions, and understanding the structure of these enzymes can offer insight into the function and mechanism of the enzyme. In the thiamin biosynthetic pathway, the two moieties of thiamin are biosynthesized separately and then stitched together by thiamin phosphate synthase. Recent work has shown that one of the heterocyclic moieties is carboxylated; the crystal structure and kinetic characterization of Bacillus subtilis thiamin phosphate synthase with carboxylated thiazole phosphate and the pyrimidine moiety demonstrate the activity of this enzyme with this substrate. Additionally, thiamin phosphate synthase is an ideal drug target in some pathogens as thiamin is an essential cofactor and humans do not have this enzyme. The crystal structure of thiamin phosphate synthase from Mycobacterium tuberculosis was determined and used for identifying potential drug compounds. The final step in thiamin biosynthesis is the phosphorylation of thiamin phosphate to produce the biologically active thiamin pyrophosphate and the crystal structure of Aquifex aeolicus thiamin monophosphate kinase has shown that this reaction proceeds via an in-line phosphate transfer. While much work has been devoted to the study of the biosynthesis of cofactors, the degradation pathways can also contain interesting chemistry. The degradation of PLP occurs over seven steps in Mesorhizobium loti MAFF303099 and the final three steps have been structurally characterized. 2-Methryl-3hydroxypyridine-4,5-dicarboxylate decarboxylase shows significant similarity to class II aldolases and uses a retro-Aldol type reaction to catalyze its decarboxylation reaction. The following enzyme, 2-methyl-3-hydroxypyridine-5-carboxylic acid oxygenase, catalyzes an oxidative ring opening and incorporates two atoms of oxygen to produce E-2-(acetamidomethylene)succinate. The structure of this enzyme demonstrates its similarity to flavin monooxygenases and offers clues to catalytically important residues. The final enzyme, E-2-(acetamidomethylene)succinate hydrolase, is an alpha/beta hydrolase and catalyzes the production of succinic semialdehyde, ammonia, acetate, and carbon dioxide using a modified catalytic triad consisting of a serine, histidine, and aspartic acid.

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