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MetaCyc Pathway: superpathway of thiamine diphosphate biosynthesis III (eukaryotes)
Inferred from experiment

Enzyme View:

Pathway diagram: superpathway of thiamine diphosphate biosynthesis III (eukaryotes)

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.

Synonyms: vitamin B1 biosynthesis IV (eukaryotes), thiamine diphosphate biosynthesis (plants)

Superclasses: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisVitamins BiosynthesisThiamine Biosynthesis

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Plasmodium falciparum, Saccharomyces cerevisiae

Expected Taxonomic Range: Alveolata, Fungi, Viridiplantae

General Background

Thiamine 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 thiamine-containing husk [Begley96]. Thiamine is synthesized de novo by microorganisms, plants and some lower eukaryotes (e.g. Plasmodium ), but not by higher eukaryotes, which must obtain it through their diet.

About This Pathway

The thiamine biosynthesis pathway illustrated here has been most extensively studied in the yeast Saccharomyces cerevisiae and the plant Arabidopsis thaliana col.

Thiamine 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. In eukaryotes thiamine phosphate is first dephosphorylated into thiamine, which is diphosphorylated to thiamine diphosphate, the activive form of thiamine.

The occurrence of thiamine triphosphate in plants has also been demonstrated; however the physiological function of that compound remains to be shown [Makarchikov03].

While many of the enzymes involved in eukaryotic thiamine biosynthesis have been identified, most of the enzymes have not been extensively characterized at a biochemical level. Moreover, several steps in the pathway require further clarification. For example, the source of the sulfur in thiazole has not been identified, and the gene encoding the putative TMP phosphatase has not been discovered.

The subcellular compartmentalization of thiamine biosynthesis is also a subject of on-going investigation. The Arabidopsis proteins TH1, ThiC, and TH1 all localize to the chloroplasts [Raschke07, Kong08, Ajjawi07, Chabregas01], but THI1 can also localize to the mitochondria [Chabregas01]. 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 thiamine diphosphate synthesis to be completed. In addition, because TPP is used as a cofactor for enzymes present in different organelles, TPP transporters likely exist as well [Ajjawi07a].

Citations: [Vander93, Machado97, Zurlinden94, Julliard91 , Estevez00, Belanger95, JacobWilk97 , Kim98, Machado96, Ribeiro96, Ribeiro05, Godoi06]

Subpathways: 4-amino-2-methyl-5-diphosphomethylpyrimidine biosynthesis, thiamine diphosphate biosynthesis IV (eukaryotes), thiazole biosynthesis III (eukaryotes)

Unification Links: AraCyc:THISYNARA-PWY, PlantCyc:THISYNARA-PWY

Reviewed 26-Jul-2007 by Foerster H, TAIR
Revised 18-Dec-2008 by Dreher KA, TAIR
Revised 23-Sep-2011 by Caspi R, SRI International


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

Begley96: Begley, T.P. (1996). "The biosynthesis and degradation of thiamin (vitamin B1)." Natural products report.

Belanger95: Belanger FC, Leustek T, Chu B, Kriz AL (1995). "Evidence for the thiamine biosynthetic pathway in higher-plant plastids and its developmental regulation." Plant Mol Biol 29(4);809-21. PMID: 8541506

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

Estevez00: Estevez JM, Cantero A, Romero C, Kawaide H, Jimenez LF, Kuzuyama T, Seto H, Kamiya Y, Leon P (2000). "Analysis of the expression of CLA1, a gene that encodes the 1-deoxyxylulose 5-phosphate synthase of the 2-C-methyl-D-erythritol-4-phosphate pathway in Arabidopsis." Plant Physiol 124(1);95-104. PMID: 10982425

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

JacobWilk97: Jacob-Wilk D, Goldschmidt EE, Riov J, Sadka A, Holland D (1997). "Induction of a Citrus gene highly homologous to plant and yeast thi genes involved in thiamine biosynthesis during natural and ethylene-induced fruit maturation." Plant Mol Biol 35(5);661-6. PMID: 9349287

Julliard91: Julliard JH, Douce R (1991). "Biosynthesis of the thiazole moiety of thiamin (vitamin B1) in higher plant chloroplasts." Proc Natl Acad Sci U S A 88(6);2042-5. PMID: 11607160

Kim98: Kim YS, Nosaka K, Downs DM, Kwak JM, Park D, Chung IK, Nam HG (1998). "A Brassica cDNA clone encoding a bifunctional hydroxymethylpyrimidine kinase/thiamin-phosphate pyrophosphorylase involved in thiamin biosynthesis." Plant Mol Biol 37(6);955-66. PMID: 9700068

Kong08: Kong D, Zhu Y, Wu H, Cheng X, Liang H, Ling HQ (2008). "AtTHIC, a gene involved in thiamine biosynthesis in Arabidopsis thaliana." Cell Res 18(5);566-76. PMID: 18332905

Lawhorn04: Lawhorn BG, Mehl RA, Begley TP (2004). "Biosynthesis of the thiamin pyrimidine: the reconstitution of a remarkable rearrangement reaction." Org Biomol Chem 2(17);2538-46. PMID: 15326535

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

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

Makarchikov03: Makarchikov AF, Lakaye B, Gulyai IE, Czerniecki J, Coumans B, Wins P, Grisar T, Bettendorff L (2003). "Thiamine triphosphate and thiamine triphosphatase activities: from bacteria to mammals." Cell Mol Life Sci 60(7);1477-88. PMID: 12943234

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

Ribeiro05: Ribeiro DT, Farias LP, de Almeida JD, Kashiwabara PM, Ribeiro AF, Silva-Filho MC, Menck CF, Van Sluys MA (2005). "Functional characterization of the thi1 promoter region from Arabidopsis thaliana." J Exp Bot 56(417);1797-804. PMID: 15897230

Ribeiro96: Ribeiro A, Praekelt U, Akkermans AD, Meacock PA, van Kammen A, Bisseling T, Pawlowski K (1996). "Identification of agthi1, whose product is involved in biosynthesis of the thiamine precursor thiazole, in actinorhizal nodules of Alnus glutinosa." Plant J 10(2);361-8. PMID: 8771789

Vander93: Vander Horn PB, Backstrom AD, Stewart V, Begley TP (1993). "Structural genes for thiamine biosynthetic enzymes (thiCEFGH) in Escherichia coli K-12." J Bacteriol 1993;175(4);982-92. PMID: 8432721

Zurlinden94: Zurlinden A, Schweingruber ME (1994). "Cloning, nucleotide sequence, and regulation of Schizosaccharomyces pombe thi4, a thiamine biosynthetic gene." J Bacteriol 176(21);6631-5. PMID: 7961415

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Backstrom95: Backstrom AD, McMordie RAS, Begley TP (1995). "Biosynthesis of Thiamin I: The Function of the thiE Gene Product." J Am Chem Soc 117: 2351-2352.

Baker01: Baker LJ, Dorocke JA, Harris RA, Timm DE (2001). "The crystal structure of yeast thiamin pyrophosphokinase." Structure 9(6);539-46. PMID: 11435118

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

Chatterjee08: Chatterjee A, Li Y, Zhang Y, Grove TL, Lee M, Krebs C, Booker SJ, Begley TP, Ealick SE (2008). "Reconstitution of ThiC in thiamine pyrimidine biosynthesis expands the radical SAM superfamily." Nat Chem Biol 4(12);758-65. PMID: 18953358

Chatterjee08a: 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

Chatterjee10: Chatterjee A, Hazra AB, Abdelwahed S, Hilmey DG, Begley TP (2010). "A "Radical Dance" in Thiamin Biosynthesis: Mechanistic Analysis of the Bacterial Hydroxymethylpyrimidine Phosphate Synthase." Angew Chem Int Ed Engl 49(46);8653-6. PMID: 20886485

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

Chiu99: Chiu HJ, Reddick JJ, Begley TP, Ealick SE (1999). "Crystal structure of thiamin phosphate synthase from Bacillus subtilis at 1.25 A resolution." Biochemistry 38(20);6460-70. PMID: 10350464

Eckmann91: Eckmann C, Huneke B, Schlotfeldt TC, Carstensen MH, Reinhold S (1991). "[Prenatal diagnosis of malignant intracranial teratoma in the fetus]." Geburtshilfe Frauenheilkd 51(10);859-60. PMID: 1761179

French11: French JB, Begley TP, Ealick SE (2011). "Structure of trifunctional THI20 from yeast." Acta Crystallogr D Biol Crystallogr 67(Pt 9);784-91. PMID: 21904031

Frey01: Frey PA (2001). "Radical mechanisms of enzymatic catalysis." Annu Rev Biochem 70;121-48. PMID: 11395404

Haas05: Haas AL, Laun NP, Begley TP (2005). "Thi20, a remarkable enzyme from Saccharomyces cerevisiae with dual thiamin biosynthetic and degradation activities." Bioorg Chem 33(4);338-44. PMID: 15967475

Jansen26: Jansen, B.C.T., Donath, W.F. (1926). "On the isolation of the anti-beriberi vitamin." Proc K Acad Wet Amsterdam 29: 1390.

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

Jurgenson09: Jurgenson CT, Begley TP, Ealick SE (2009). "The structural and biochemical foundations of thiamin biosynthesis." Annu Rev Biochem 78;569-603. PMID: 19348578

Kawasaki05: Kawasaki Y, Onozuka M, Mizote T, Nosaka K (2005). "Biosynthesis of hydroxymethylpyrimidine pyrophosphate in Saccharomyces cerevisiae." Curr Genet 47(3);156-62. PMID: 15614489

Kawasaki79: Kawasaki T (1979). "Thiamine phosphate pyrophosphorylase." Methods Enzymol 1979;62;69-73. PMID: 374983

Kawasaki93: Kawasaki Y (1993). "Copurification of hydroxyethylthiazole kinase and thiamine-phosphate pyrophosphorylase of Saccharomyces cerevisiae: characterization of hydroxyethylthiazole kinase as a bifunctional enzyme in the thiamine biosynthetic pathway." J Bacteriol 175(16);5153-8. PMID: 8394314

Kayama73: Kayama Y, Kawasaki T (1973). "Purification and properties of thiaminephosphate pyrophosphorylase of Escherichia coli." Arch Biochem Biophys 1973;158(1);242-8. PMID: 4580841

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by Pathway Tools version 19.5 (software by SRI International) on Fri Apr 29, 2016, biocyc14.