If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
Synonyms: superpathway of thiamin diphosphate biosynthesis (E .coli), superpathway of vitamin B1 biosynthesis (E .coli)
|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
The thiamin biosynthesis pathway illustrated here has been most extensively studied in Escherichia coli K-12 and Salmonella enterica enterica serovar Typhimurium. There are several differences between the pathways employed by Bacillus subtilis and by Escherichia coli (see superpathway of thiamin diphosphate biosynthesis II).
Thiamin biosynthesis in bacteria is composed of the separate formation of the pyrimidine and thiazole moieties, which are subsequently coupled to form thiamin phosphate. A final phosphorylation reaction yields the biologically active form, thiamin diphosphate.
The process begins when IscS, a protein that is also involved in the biosynthesis of iron-sulfur clusters, catalyzes the transfer of a sulfur atom from cysteine to a ThiI sulfur-carrier protein, generating a an S-sulfanyl-[ThiI sulfur-carrier protein]. In a parallel route, a ThiF protein catalyzes a two step process: First, the activation of a ThiS sulfur-carrier protein by adenylation of its carboxy terminus, generating a carboxy-adenylated-[ThiS sulfur-carrier protein], and second, the subsequent exchange of the adenylate with the ThiI persulfide, generating a ThiS-ThiI acyl-disulfide. The next step is a disulfide interchange, where a ThiF sulfur-carrier protein replaces the ThiI moiety, resulting in a ThiS-ThiF acyl-disulfide.
This dual-protein disulfide finally acts as the sulfur donor for thiazole formation, in a reaction that also involves 1-deoxy-D-xylulose 5-phosphate and 2-iminoacetate, and is catalyzed by the ThiG protein. 2-iminoacetate is formed in Escherichia coli from L-tyrosine by tyrosine lyase (ThiH), which forms a complex with ThiG [Taylor98, Xi01, Lehmann06].
The biosynthesis of the pyrimidine moiety of thiamin is not simple either. Starting with 5-amino-1-(5-phospho-β-D-ribosyl)imidazole, an intermdiate in purine biosynthesis, two enzymatic steps, catalyzed by HMP-P synthase and ThiD, produce 4-amino-2-methyl-5-diphosphomethylpyrimidine. The first of these reactions is one of the most complex rearrangement reactions known.
Created in MetaCyc 01-Feb-1995 by Riley M , Marine Biological Laboratory
Revised in MetaCyc 07-Oct-2008 by Caspi R , SRI International
Revised in MetaCyc 14-Sep-2011 by Caspi R , SRI International
Imported from MetaCyc 18-Sep-2013 by Fulcher CA , SRI International
Lehmann06: Lehmann C, Begley TP, Ealick SE (2006). "Structure of the Escherichia coli ThiS-ThiF complex, a key component of the sulfur transfer system in thiamin biosynthesis." Biochemistry 45(1);11-9. PMID: 16388576
Taylor98: Taylor SV, Kelleher NL, Kinsland C, Chiu HJ, Costello CA, Backstrom AD, McLafferty FW, Begley TP (1998). "Thiamin biosynthesis in Escherichia coli. Identification of this thiocarboxylate as the immediate sulfur donor in the thiazole formation." J Biol Chem 273(26);16555-60. PMID: 9632726
Xi01: Xi J, Ge Y, Kinsland C, McLafferty FW, Begley TP (2001). "Biosynthesis of the thiazole moiety of thiamin in Escherichia coli: identification of an acyldisulfide-linked protein--protein conjugate that is functionally analogous to the ubiquitin/E1 complex." Proc Natl Acad Sci U S A 98(15);8513-8. PMID: 11438688
Begley99: Begley TP, Downs DM, Ealick SE, McLafferty FW, Van Loon AP, Taylor S, Campobasso N, Chiu HJ, Kinsland C, Reddick JJ, Xi J (1999). "Thiamin biosynthesis in prokaryotes." Arch Microbiol 1999;171(5);293-300. PMID: 10382260
Herz00: Herz S, Wungsintaweekul J, Schuhr CA, Hecht S, Luttgen H, Sagner S, Fellermeier M, Eisenreich W, Zenk MH, Bacher A, Rohdich F (2000). "Biosynthesis of terpenoids: YgbB protein converts 4-diphosphocytidyl-2C-methyl-D-erythritol 2-phosphate to 2C-methyl-D-erythritol 2,4-cyclodiphosphate." Proc Natl Acad Sci U S A 97(6);2486-90. PMID: 10694574
Kambampati00: Kambampati R, Lauhon CT (2000). "Evidence for the transfer of sulfane sulfur from IscS to ThiI during the in vitro biosynthesis of 4-thiouridine in Escherichia coli tRNA." J Biol Chem 2000;275(15);10727-30. PMID: 10753862
MartinezGomez11: Martinez-Gomez NC, Palmer LD, Vivas E, Roach PL, Downs DM (2011). "The Rhodanese Domain of ThiI Is Both Necessary and Sufficient for Synthesis of the Thiazole Moiety of Thiamine in Salmonella enterica." J Bacteriol 193(18);4582-7. PMID: 21724998
Miller00: Miller JR, Busby RW, Jordan SW, Cheek J, Henshaw TF, Ashley GW, Broderick JB, Cronan JE, Marletta MA (2000). "Escherichia coli LipA is a lipoyl synthase: in vitro biosynthesis of lipoylated pyruvate dehydrogenase complex from octanoyl-acyl carrier protein." Biochemistry 39(49);15166-78. PMID: 11106496
Mueller98: Mueller EG, Buck CJ, Palenchar PM, Barnhart LE, Paulson JL (1998). "Identification of a gene involved in the generation of 4-thiouridine in tRNA." Nucleic Acids Res 26(11);2606-10. PMID: 9592144
Ryals82: Ryals J, Hsu RY, Lipsett MN, Bremer H (1982). "Isolation of single-site Escherichia coli mutants deficient in thiamine and 4-thiouridine syntheses: identification of a nuvC mutant." J Bacteriol 151(2);899-904. PMID: 6178725
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