MetaCyc Pathway: 4-amino-2-methyl-5-diphosphomethylpyrimidine biosynthesis
Inferred from experiment

Enzyme View:

Pathway diagram: 4-amino-2-methyl-5-diphosphomethylpyrimidine biosynthesis

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: HMP-PP biosynthesis

Superclasses: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisVitamins BiosynthesisThiamine Biosynthesis4-amino-2-methyl-5-diphosphomethylpyrimidine biosynthesis

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Bacillus subtilis subtilis 168, Escherichia coli K-12 substr. MG1655, Salmonella enterica enterica serovar Typhimurium

Expected Taxonomic Range: Alveolata, Archaea, Bacteria , Fungi, Viridiplantae

General Background

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 ), but not by higher eukaryotes, which must obtain it through their diet.

Thiamin biosynthesis is composed of the separate formation of the pyrimidine and thiazole moieties, which are subsequently coupled to form thiamine phosphate (see for example thiamine diphosphate biosynthesis II (Bacillus)).

About This Pathway

This pathway describes the synthesis of the pyrimidine moiety of thiamin. Starting with 5-amino-1-(5-phospho-β-D-ribosyl)imidazole, an intermdiate in purine biosynthesis, two enzymatic steps, catalyzed by ThiC and ThiD, produce 4-amino-2-methyl-5-(diphosphomethyl)pyrimidine. The first reaction is one of the most complicated rearrangement reactions known. The ThiC enzyme belongs to the radical SAM family, all members of which utilize S-adenosyl-L-methionine (SAM) to generate an 5'-deoxyadenosyl radical that in turn serves as an oxidant for a wide variety of enzymatic reactions [Chatterjee08]. The first stage of catalysis is the reduction of SAM to produce L-methionine and a 5-deoxyadenosyl radical, which is generated at the active site. The radical reacts directly with the substrate to catalyze a complex rearrangement reaction that includes two iterative hydrogen atom abstractions (which necessitates the regeneration of the radical following the first abstraction). C1' and C3' of the substrate, which are not inorporated into the product, are converted to formate and carbon monoxide, respectively [Chatterjee10].

The second enzyme, ThiD, is a simple kinase. It is a bifunctional enzyme, and can also phosphorylate 4-amino-2-methyl-5-pyrimidinemethanol, as a part of a thiamin salvage pathway (see thiamine salvage II) [Park04].

Superpathways: superpathway of thiamine diphosphate biosynthesis I, superpathway of thiamine diphosphate biosynthesis III (eukaryotes), superpathway of thiamine diphosphate biosynthesis II

Variants: 4-amino-2-methyl-5-diphosphomethylpyrimidine biosynthesis (yeast)

Unification Links: EcoCyc:PWY-6890

Created 14-Sep-2011 by Caspi R, SRI International


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

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

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

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

Park04: Park JH, Burns K, Kinsland C, Begley TP (2004). "Characterization of two kinases involved in thiamine pyrophosphate and pyridoxal phosphate biosynthesis in Bacillus subtilis: 4-amino-5-hydroxymethyl-2methylpyrimidine kinase and pyridoxal kinase." J Bacteriol 186(5);1571-3. PMID: 14973012

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

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

DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114

Dougherty06: Dougherty MJ, Downs DM (2006). "A connection between iron-sulfur cluster metabolism and the biosynthesis of 4-amino-5-hydroxymethyl-2-methylpyrimidine pyrophosphate in Salmonella enterica." Microbiology 152(Pt 8);2345-53. PMID: 16849799

Dowling12: Dowling DP, Vey JL, Croft AK, Drennan CL (2012). "Structural diversity in the AdoMet radical enzyme superfamily." Biochim Biophys Acta 1824(11);1178-95. PMID: 22579873

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

GOA00: GOA (2000). "Gene Ontology annotation based on Swiss-Prot keyword mapping."

GOA01: GOA, MGI (2001). "Gene Ontology annotation based on Enzyme Commission mapping." Genomics 74;121-128.

GOA01a: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

GOA06: GOA, SIB (2006). "Electronic Gene Ontology annotations created by transferring manual GO annotations between orthologous microbial proteins."

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

Ishihama08: Ishihama Y, Schmidt T, Rappsilber J, Mann M, Hartl FU, Kerner MJ, Frishman D (2008). "Protein abundance profiling of the Escherichia coli cytosol." BMC Genomics 9;102. PMID: 18304323

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

Kim98a: 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

Komeda88: Komeda Y, Tanaka M, Nishimune T (1988). "A th-1 Mutant of Arabidopsis thaliana Is Defective for a Thiamin-Phosphate-Synthesizing Enzyme: Thiamin Phosphate Pyrophosphorylase." Plant Physiol 88(2);248-250. PMID: 16666289

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

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Lawhorn04a: Lawhorn BG, Gerdes SY, Begley TP (2004). "A genetic screen for the identification of thiamin metabolic genes." J Biol Chem 279(42);43555-9. PMID: 15292217

Llorente99: Llorente B, Fairhead C, Dujon B (1999). "Genetic redundancy and gene fusion in the genome of the Baker's yeast Saccharomyces cerevisiae: functional characterization of a three-member gene family involved in the thiamine biosynthetic pathway." Mol Microbiol 32(6);1140-52. PMID: 10383756

LopezCampistrou05: Lopez-Campistrous A, Semchuk P, Burke L, Palmer-Stone T, Brokx SJ, Broderick G, Bottorff D, Bolch S, Weiner JH, Ellison MJ (2005). "Localization, annotation, and comparison of the Escherichia coli K-12 proteome under two states of growth." Mol Cell Proteomics 4(8);1205-9. PMID: 15911532

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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
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