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. 2009 Aug;3(2):10.1128/ecosalplus.3.6.3.7.
doi: 10.1128/ecosalplus.3.6.3.7.

Biosynthesis of Thiamin Pyrophosphate

Christopher T Jurgenson, Steven E Ealick, Tadhg P Begley

Biosynthesis of Thiamin Pyrophosphate

Christopher T Jurgenson et al. EcoSal Plus. 2009 Aug.

Abstract

The biosynthesis of thiamin pyrophosphate (TPP) in prokaryotes, as represented by the Escherichia coli and the Bacillus subtilis pathways, is summarized in this review. The thiazole heterocycle is formed by the convergence of three separate pathways. First, the condensation of glyceraldehyde 3-phosphate and pyruvate, catalyzed by 1-deoxy-D-xylulose 5-phosphate synthase (Dxs), gives 1-deoxy-D-xylulose 5-phosphate (DXP). Next, the sulfur carrier protein ThiS-COO- is converted to its carboxyterminal thiocarboxylate in reactions catalyzed by ThiF, ThiI, and NifS (ThiF and IscS in B. subtilis). Finally, tyrosine (glycine in B. subtilis) is converted to dehydroglycine by ThiH (ThiO in B. subtilis). Thiazole synthase (ThiG) catalyzes the complex condensation of ThiS-COSH, dehydroglycine, and DXP to give a thiazole tautomer, which is then aromatized to carboxythiazole phosphate by TenI (B. subtilis). Hydroxymethyl pyrimidine phosphate (HMP-P) is formed by a complicated rearrangement reaction of 5-aminoimidazole ribotide (AIR) catalyzed by ThiC. ThiD then generates hydroxymethyl pyrimidine pyrophosphate. The coupling of the two heterocycles and decarboxylation, catalyzed by thiamin phosphate synthase (ThiE), gives thiamin phosphate. A final phosphorylation, catalyzed by ThiL, completes the biosynthesis of TPP, the biologically active form of the cofactor. This review reviews the current status of mechanistic and structural studies on the enzymes involved in this pathway. The availability of multiple orthologs of the thiamin biosynthetic enzymes has also greatly facilitated structural studies, and most of the thiamin biosynthetic and salvage enzymes have now been structurally characterized.

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Figures

Figure 1
Figure 1. Prokaryotic thiamin biosynthesis
B. subtilis proteins are labeled in blue, E. coli proteins are labeled in red, and proteins common to both microorganisms are labeled in black. Compound abbreviations are in parentheses.
Figure 2
Figure 2
(A) Reaction catalyzed by DXP synthase (Dxs). (B) X-ray crystal structure of Dxs with individual protomers labeled in blue or green (Protein Data Bank [PDB] accession no. 2O1S). (C) Model of the active site of Dxs showing the environment around the TPP cofactor.
Figure 3
Figure 3. Reactions involved in the formation of ThiS-COSH, the sulfide source for thiazole formation
PLP, pyridoxal 5′-phosphate.
Figure 4
Figure 4
(A) X-ray crystal structure of ThiS with numbered secondary structures (PDB accession no. 1ZUD). (B) NMR structure of ubiquitin (PDB accession no. 1D3Z). Helices are colored blue, and strands are colored magenta.
Figure 5
Figure 5
(A) Reactions catalyzed by ThiS thiocarboxylate synthase (ThiF). (B) X-ray crystal structure of the ThiF-ThiS complex (PDB accession no. 1ZUD). (C) Active-site model for ThiF-ThiS showing the carboxy terminal of ThiS (Gly66) positioned close to the α phosphate of ATP.
Figure 6
Figure 6
(A) Reaction catalyzed by NifS. ThiS posttranslationally modified with an AMP on its C-terminus (ThiS-COAMP) and cysteine react to give thiocarboxylated ThiS (ThiS-COS−) alanine and AMP. (B) X-ray crystal structure of NifS. Protomer 1 is shown with blue helices and magenta strands, and protomer 2 is shown with red helices and yellow strands (PDB accession no. 1KMJ). (C) X-ray crystal structure of the NifS active site showing the environment around the PLP cofactor. PS, perselenocysteine; SC, selenocysteine.
Figure 7
Figure 7
(A) Reaction catalyzed by ThiI. (B) X-ray crystal structure of ThiI (PDB accession no. 2C5S). (C) Model of the active site of ThiI showing the environment around bound AMP.
Figure 8
Figure 8
(A) Reaction catalyzed by glycine oxidase (ThiO). (B) X-ray crystal structure of ThiO with flavin adenine dinucleotide (FAD) and N-acetyl glycine (NAG) bound in the active site (PDB accession no. 1NG3). (C) Model of the active site of ThiO showing the environment around the flavin cofactor and the stable substrate analog N-acetyl glycine.
Figure 9
Figure 9. Current mechanistic proposal for the complex reaction catalyzed by the B. subtilis thiazole synthase
The last step, involving a thiazole aromatization reaction, is catalyzed by a separate thiazole tautomerase (TenI).
Figure 10
Figure 10
(A) Thiazole synthase (ThiG)-catalyzed reaction. (B) X-ray crystal structure of the ThiG-ThiS complex. ThiG protomers are colored with blue helices and magenta strands. ThiS protomers are colored with red helices and yellow strands.
Figure 11
Figure 11
(A) Reaction catalyzed by thiazole tautomerase (TenI). (B) X-ray crystal structure of TenI with thiazole carboxylate bound in the active site (PDB accession no. 1YAD). (C) Model of the active site of TenI showing the residues around the carboxythiazole phosphate reaction product. THC, thiazole carboxylate.
Figure 12
Figure 12. Studies using site-specifically labeled AIR have established the origins of all but one of the atoms of HMP-P and revealed a complex rearrangement reaction involved in the formation of HMP
The colored atoms in HMP-P are derived from the corresponding colored atoms of AIR.
Figure 13
Figure 13
(A) X-ray crystal structure of the pyrimidine synthase (ThiC) with desamino-AIR (IMR) bound in the active site. (B) Model of the active site of ThiC showing the proposed enzyme-IMR-SAM-Fe4S4 complex.
Figure 14
Figure 14
(A) Reactions catalyzed by HMP-P kinase (ThiD). (B) X-ray crystal structure of ThiD (PDB accession no. 1JXI). (C) Model of the active site of ThiD showing the environment around the HMP substrate.
Figure 15
Figure 15
(A) Reaction catalyzed by thiamin phosphate synthase (ThiE). (B) X-ray crystal structure of ThiE (S130A mutant form; PDB accession no. 1G69). (C) Model of the active-site environment showing the pyrimidine carbocation intermediate sandwiched between the pyrophosphate and the thiazole phosphate (THZ-P).
Figure 16
Figure 16
(A) Reaction catalyzed by thiamin phosphate kinase (ThiL). Ad, adenine. (B) X-ray crystal structure of ThiL with the ATP analog AMP-PCP bound in the active site of each protomer (PDB accession no. 3C9T). (C) Model of the active site of ThiL showing the environment around the AMP-PCP and TMP.
Figure 17
Figure 17
(A) Structure of theE. coli periplasmic thiamin binding protein (TbpA) (PDB accession no. 2QRY). (B) Details of the TMP binding site.
Figure 18
Figure 18
Phosphorylation reactions involved in the salvage of stable dephosphorylated TPP biosynthetic intermediates.
Figure 19
Figure 19
New salvage pathway for HMP.
Figure 20
Figure 20
(A) Reaction catalyzed by TenA. (B) X-ray crystal structure of TenA with HMP bound in the active site (PDB accession no. 1YAK). (C) Detailed view of the TenA active site in the vicinity of the bound product.
Figure 21
Figure 21
(A) X-ray crystal structure of the TPP-binding riboswitch with bound TPP (PDB accession no. 2GDI). (B) Detailed view of the TPP binding site with magnesium ions depicted as green spheres and water molecules depicted as red spheres.
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References

    1. Wrenger C, Eschbach ML, Muller IB, Laun NP, Begley TP, Walter RD. Vitamin B1 de novo synthesis in the human malaria parasite Plasmodium falciparum depends on external provision of 4-amino-5-hydroxymethyl-2-methylpyrimidine. Biol Chem. 2006;387:41–51. - PubMed
    1. Lawhorn BG, Mehl RA, Begley TP. Biosynthesis of the thiamin pyrimidine: the reconstitution of a remarkable rearrangement reaction. Org Biomol Chem. 2004;2:2538–2546. - PubMed
    1. Settembre EC, Dorrestein PC, Park JH, Augustine AM, Begley TP, Ealick SE. Structural and mechanistic studies on ThiO, a glycine oxidase essential for thiamin biosynthesis in Bacillus subtilis. Biochemistry. 2003;42:2971–2981. - PubMed
    1. Toms AV, Haas AL, Park JH, Begley TP, Ealick SE. Structural characterization of the regulatory proteins TenA and TenI from Bacillus subtilis and identification of TenA as a thiaminase II. Biochemistry. 2005;44:2319–2329. - PubMed
    1. Himmeldirk K, Sayer BG, Spenser ID. Comparative biogenetic anatomy of vitamin B1: a 13C NMR investigation of the biosynthesis of thiamin in Escherichia coli and in Saccharomyces cerevisiae. J Am Chem Soc. 1998;120:3581–3589.

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