This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis → Thiamin Biosynthesis|
Thiamin diphosphate, also known as vitamin B1, is known to play a fundamental role in energy metabolism. It is an essential cofactor for a variety of enzymes such as transketolase, pyruvate dehydrogenase, pyruvate decarboxylase, and α-ketoglutarate dehydrogenase [Lawhorn04]. Its discovery followed from the original early research on the anti-beriberi factor found in rice bran. Beriberi, a neurological disease, was particularly prevalent in Asia, where the refining of rice resulted in the removal of the thiamin-containing husk [Begley96]. Thiamin is synthesized de novo by microorganisms, plants and some lower eukaryotes (e.g. Plasmodium
About This Pathway
Thiamin phosphate is formed by the coupling of two moieties, the pyrimidine 4-amino-2-methyl-5-diphosphomethylpyrimidine and the thiazole 4-methyl-5-(2-phosphonooxyethyl)thiazole, which are produced by two different pathways. This pathway describes the formation of the thiazole moiety in eukaryotes.
Genetic studies in Saccharomyces cerevisiae have demonstrated that THI4 is the only gene required for thiamin thiazole formation [Praekelt94]. The donor of the sulphur incorporated in adenylated thiazole was elusive for a long time. It has been shown that THI4 promotes a very unusual chemical reaction in which it acts as a co-substrate and supplies the sulphur through an iron-dependent transfer from an internal cysteine amino acid residue (Cys-205) to the reaction product. The reaction converts Cys-205 to 2-aminoprop-2-enoate and renders THI4 inactive. Hence, THI4 represents a single-turnover (suicide) enzyme [Chatterjee11]. Insofar THI4 resembles another single-turnover enzyme, i.e. 4-amino-2-methyl-5-phosphomethylpyrimidine synthase (THI5) which is involved in the pyrimidine moiety formation in Saccharomyces cerevisiae (see 4-amino-2-methyl-5-phosphomethylpyrimidine biosynthesis (yeast)).
The protein, overexpressed in Escherichia coli, copurified with its product (adenylated thiazole) and two additional adenylated intermediates that shed light on its complex mechanism [Chatterjee08]. Similarly, in the plant Arabidopsis thaliana the multifunctional protein THI1 is sufficient for thiazole production. While it has been shown that NAD and glycine are substrates for the enzyme, the exact source of sulfur is still not known.
The THI1 protein localizes to the chloroplasts, suggesting that this part of the pathway occurs in this organelle [Raschke07, Kong08, Ajjawi07, Chabregas01]. However, THI1 can also localize to the mitochondria [Chabregas01], and the downstream TPK1 and TPK2 enzymes are both cytosolic in Arabidopsis [Ajjawi07a], suggesting that intermediates in the vitamin B1 biosynthesis pathway may need to be transported out of organelles for thiamin diphosphate synthesis to be completed.
Variants: 4-amino-2-methyl-5-diphosphomethylpyrimidine biosynthesis , 4-amino-2-methyl-5-phosphomethylpyrimidine biosynthesis (yeast) , superpathway of thiamin diphosphate biosynthesis I , superpathway of thiamin diphosphate biosynthesis II , thiamin diphosphate biosynthesis I (E. coli) , thiamin diphosphate biosynthesis II (Bacillus) , thiamin diphosphate biosynthesis III (Staphylococcus) , thiamin diphosphate biosynthesis IV (eukaryotes) , thiamin formation from pyrithiamine and oxythiamine (yeast) , thiamin triphosphate metabolism , thiazole biosynthesis I (E. coli) , thiazole biosynthesis II (Bacillus)
Ajjawi07: Ajjawi I, Tsegaye Y, Shintani D (2007). "Determination of the genetic, molecular, and biochemical basis of the Arabidopsis thaliana thiamin auxotroph th1." Arch Biochem Biophys 459(1);107-14. PMID: 17174261
Ajjawi07a: Ajjawi I, Rodriguez Milla MA, Cushman J, Shintani DK (2007). "Thiamin pyrophosphokinase is required for thiamin cofactor activation in Arabidopsis." Plant Mol Biol 65(1-2);151-62. PMID: 17611796
Chabregas01: Chabregas SM, Luche DD, Farias LP, Ribeiro AF, van Sluys MA, Menck CF, Silva-Filho MC (2001). "Dual targeting properties of the N-terminal signal sequence of Arabidopsis thaliana THI1 protein to mitochondria and chloroplasts." Plant Mol Biol 46(6);639-50. PMID: 11575719
Chatterjee08: Chatterjee A, Schroeder FC, Jurgenson CT, Ealick SE, Begley TP (2008). "Biosynthesis of the thiamin-thiazole in eukaryotes: identification of a thiazole tautomer intermediate." J Am Chem Soc 130(34);11394-8. PMID: 18652458
Chatterjee11: Chatterjee A, Abeydeera ND, Bale S, Pai PJ, Dorrestein PC, Russell DH, Ealick SE, Begley TP (2011). "Saccharomyces cerevisiae THI4p is a suicide thiamine thiazole synthase." Nature 478(7370);542-6. PMID: 22031445
Machado96: Machado CR, de Oliveira RL, Boiteux S, Praekelt UM, Meacock PA, Menck CF (1996). "Thi1, a thiamine biosynthetic gene in Arabidopsis thaliana, complements bacterial defects in DNA repair." Plant Mol Biol 31(3);585-93. PMID: 8790291
Raschke07: Raschke M, Burkle L, Muller N, Nunes-Nesi A, Fernie AR, Arigoni D, Amrhein N, Fitzpatrick TB (2007). "Vitamin B1 biosynthesis in plants requires the essential iron sulfur cluster protein, THIC." Proc Natl Acad Sci U S A 104(49);19637-42. PMID: 18048325
Chatterjee06: Chatterjee A, Jurgenson CT, Schroeder FC, Ealick SE, Begley TP (2006). "Thiamin biosynthesis in eukaryotes: characterization of the enzyme-bound product of thiazole synthase from Saccharomyces cerevisiae and its implications in thiazole biosynthesis." J Am Chem Soc 128(22);7158-9. PMID: 16734458
Chatterjee07: Chatterjee A, Jurgenson CT, Schroeder FC, Ealick SE, Begley TP (2007). "Biosynthesis of thiamin thiazole in eukaryotes: conversion of NAD to an advanced intermediate." J Am Chem Soc 129(10);2914-22. PMID: 17309261
Godoi06: Godoi PH, Galhardo RS, Luche DD, Van Sluys MA, Menck CF, Oliva G (2006). "Structure of the thiazole biosynthetic enzyme THI1 from Arabidopsis thaliana." J Biol Chem 281(41);30957-66. PMID: 16912043
Jurgenson06: Jurgenson CT, Chatterjee A, Begley TP, Ealick SE (2006). "Structural insights into the function of the thiamin biosynthetic enzyme Thi4 from Saccharomyces cerevisiae." Biochemistry 45(37);11061-70. PMID: 16964967
Machado97: Machado CR, Praekelt UM, de Oliveira RC, Barbosa AC, Byrne KL, Meacock PA, Menck CF (1997). "Dual role for the yeast THI4 gene in thiamine biosynthesis and DNA damage tolerance." J Mol Biol 273(1);114-21. PMID: 9367751
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