Biosynthesis of Thiamin

A number of the genes involved in the biosynthesis of thiamine in E. coli (89—92), i hium meliloti (93), B. suhtilis (94), and Schi saccharomycespomhe (95,96) have been mapped, cloned, sequenced, and associated with biosynthetic functions. Thiamine biosynthesis is tightly controlled by feedback and repression mechanisms limiting overproduction (97,98). A cost-effective bioprocess for production of thiamine will require significant additional progress. 

Anaerobic pathway of vitamin Bl2 biosynthesis 98H(47)1051. Biosynthesis of thiamine 97AG(E)1032. 

Biosynthesis of Thiamine Diphosphate from Thiazole and Pyrimidine... 

Thiamine is present in cells as the free form 1, as the diphosphate 2, and as the diphosphate of the hydroxyethyl derivative 3 (Scheme 1) in variable ratio. The component heterocyclic moieties, 4-amino-5-hydroxymethyl-2-methylpyrimidine (4) and 4-methyl-5-(2-hydroxyethyl)thiazole (5) are also presented in Scheme 1, with the atom numbering. This numbering follows the rules of nomenclature of heterocyclic compounds for the ring atoms, and is arbitrary for the substituents. To avoid the use of acronyms, compound 5 is termed as the thiazole of thiamine or more simply the thiazole. This does not raise any ambiguity because unsubstituted thiazole is encountered in this chapter. Other thiazoles are named after the rules of heterocyclic nomenclature. Pyrimidine 4 is called pyramine, a well established name in the field. A detailed account of the present status of knowledge on the biosynthesis of thiamine diphosphate from its heterocyclic moieties can be found in a review by the authors.1 This report provides only the minimal information necessary for understanding the main part of this chapter (Scheme 2). 

Scheme 2.—Phosphorylations and condensation in the biosynthesis of thiamine pyrophosphate.

Lewin, L.M. Brown, G.M. The Biosynthesis of thiamine. III. Mechanism of enzymatic formation of the pyrophosphate ester of 2-methyl-4-ammo-5-hy-droxymethylpyrimidine. J. Biol. Chem., 236, 2768-2771 (1961)... 

Reddick, J.J. Kinsland, C. Nicewonger, R. Christian, T Downs, D.M. Winkler, M.E. Begley, T.P. Overexpression, purification and characterization of two pyrimidine kinases involved in the biosynthesis of thiamin 4-amino-5-hydroxymethyl-2-methylpyrimidine kinase and 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate kinase. Tetrahedron, 54, 15983-15991 (1998)... 

Thiamin. Investigation of the biosynthesis of thiamin has been difficult because only minute amounts are formed by microorganisms such as E. coli or yeast. Furthermore, significant differences in the routes of synthesis in different organisms have caused confusion.372,372a The pathways outlined in Fig. 25-21 are incomplete. 

Figure 25-21 Proposed pathways for biosynthesis of thiamin phosphate and pyridoxol phosphate.

Commercial thiamine dietary supplements are prepared by synthesis Pyrimidine + thiazole nuclei synthesized separately and then condensed also build on pyrimidine with acelaiiudiiie. Precursors in the biosynthesis of thiamine include thiazole and pyrimidine pyrophosphate, with thiamine phosphate as an intermediate. In plants, production sites arc found in grain and cereal germ. 

The persulfide intermediate 2 can also serve as a sulfur source for the biosynthesis of thiamine (6), lipoic acid (7), molybdopterin (8), and biotin (9) (Fig. 1). 

The biosynthesis of thiamine pyrophosphate (46) in microorganisms and plants is characterized by extraordinary complexity (21, 23). Animals are dependent on nutritional sources but can convert unphosphorylated thiamine (that is not an intermediate of the bacterial biosynthetic pathway) into thiamine pyrophosphate in two steps. 

Figure 4 Biosynthesis of thiamine (vitamin ). 37, aminoimidazole ribotide 38, 2-methyl-4-amino-5-hydroxymethyl-pyrimidine phosphate 39, pyridoxal 5 -phosphate 40, histidine 41, 2-methyl-4-amino-5-hydroxymethyl-pyrimidine pyrophosphate 42, 4-methyl-5-p-hydroxyethylthiazole phosphate 43,1 -deoxy-D-xylulose 5-phosphate 44, 5-ADP-D-ribulose 45, thiamine phosphate 46, thiamine pyrophosphate.

Some coenzymes serve as biosynthetic precursors that afford structural parts of other coenzymes. Thus, the benzenoid moiety of the flavocoenzyme FMN serves as a precursor for the lower ligand 26 of the central cobalt ion in vitamin B12 (20) (Fig. 3) (5). Pyridoxal and NAD are used as precursors for the biosynthesis of thiamine in yeast (Fig. 4) (23, 24). 

Chatteijee A, Jurgenson CT, Schroeder PC, Ealick SE, Begley TP. Biosynthesis of thiamin thiazole in eukaryotes conversion of NAD to an advanced intermediate. J. Am. Chem. Soc. 46. 2007 129 2914-2922. 

Figure 23.8. Biosynthesis of Thiamine. The biosynthesis of thiamine begins with the addition of sulfide to the carboxyl terminus of the protein ThiS. This protein is activated by adenylation and conjugated in a manner analogous to the first steps in the ubiquitin pathway.

Another example of the biosynthesis of a thiazole ring is in enzymatic biosynthesis of thiamin. Thiamin is a thiazole-containing vitamin whose supply in humans relies on diet. It acts as a coenzyme and plays an important role in carbohydrate and amino acid metabolism <2003NPR184>. Thiamin deficiency can be fatal. 

Deoxy-D-xylulose has been found as an intermediate in the biosynthesis of thiamine (vit. Bi) andpyridoxal (vit. Bs) [103]. It has been found also to be an alternate nonmevalonate biosynthetic precursor to terpenoid building blocks [104,105]. 

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