Biosynthesis of Thiamin Pyrophosphate

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The biosynthesis of thiamin pyrophosphate (TPP) in prokaryotes, as represented by the Escherichia coli and the Bacillus subtilis pathways, is summarized in this review (Fig. 1).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 5phosphate 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 5aminoimidazole 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. ENZYMES INVOLVED IN THIAZOLE BIOSYNTHESIS DXP SynthaseDXP synthase (Dxs) catalyzes the formation of DXP from glyceraldehyde 3-phosphate and pyruvate (Fig. 2A).Remarkably, this thiamin biosynthetic enzyme requires TPP as a cofactor.The crystal structure of Dxs has been solved (1) (Fig. 2B andC). Sulfide Carrier ProteinThiS-COSH is the sulfide donor for the thiazole biosynthesis.The enzymes involved in its formation are shown in Fig. 3, and the properties of each protein are summarized below.The structure of ThiS-COOH has been determined (2,3,4).ThiS-COOH is structurally and functionally similar to ubiquitin (Fig. 4), suggesting that ubiquitin may have evolved from a

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