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EcoSal Plus

Domain 3:

Metabolism

Biosynthesis of Thiamin Pyrophosphate

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  • Authors: Christopher T. Jurgenson1, Steven E. Ealick2, and Tadhg P. Begley3
  • Editor: Thomas J. Begley4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853-1301; 2: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853-1301; 3: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853-1301; 4: University at Albany, Rensselear, NY
  • Received 26 April 2006 Accepted 18 July 2006 Published 13 February 2009
  • Address correspondence to Steven E. Ealick see3@cornell.edu and Tadhg P. Begley tpb2@cornell.edu
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  • Abstract:

    The biosynthesis of thiamin pyrophosphate (TPP) in prokaryotes, as represented by the and the 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 ). Finally, tyrosine (glycine in ) is converted to dehydroglycine by ThiH (ThiO in ). 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 (). 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.

  • Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7

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2009-02-13
2017-03-28

Abstract:

The biosynthesis of thiamin pyrophosphate (TPP) in prokaryotes, as represented by the and the 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 ). Finally, tyrosine (glycine in ) is converted to dehydroglycine by ThiH (ThiO in ). 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 (). 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

Image of Figure 1
Figure 1

proteins are labeled in blue, proteins are labeled in red, and proteins common to both microorganisms are labeled in black. Compound abbreviations are in parentheses.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Image of Figure 2
Figure 2

(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.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 3

PLP, pyridoxal 5′-phosphate.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 4

(B) NMR structure of ubiquitin (PDB accession no. 1D3Z). Helices are colored blue, and strands are colored magenta.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 5

(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.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Image of Figure 6
Figure 6

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.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 7

(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.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 8

(B) X-ray crystal structure of ThiO with flavin adenine dinucleotide (FAD) and -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 -acetyl glycine.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 9

The last step, involving a thiazole aromatization reaction, is catalyzed by a separate thiazole tautomerase (TenI).

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 10

(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.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 11

(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.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 12

The colored atoms in HMP-P are derived from the corresponding colored atoms of AIR.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 13

(B) Model of the active site of ThiC showing the proposed enzyme-IMR-SAM-FeS complex.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Image of Figure 14
Figure 14

(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.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Image of Figure 15
Figure 15

(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).

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Image of Figure 16
Figure 16

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.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Image of Figure 17
Figure 17

(B) Details of the TMP binding site.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 18

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 19

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Figure 20

(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.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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Image of Figure 21
Figure 21

(B) Detailed view of the TPP binding site with magnesium ions depicted as green spheres and water molecules depicted as red spheres.

Citation: Jurgenson C, Ealick S, Begley T. 2009. Biosynthesis of Thiamin Pyrophosphate, EcoSal Plus 2009; doi:10.1128/ecosalplus.3.6.3.7
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