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The Structural and Biochemical Foundations of Thiamin Biosynthesis

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The Structural and Biochemical Foundations of Thiamin Biosynthesis ANRV378-BI78-20 ARI 5 May 2009 14:27 The Structural and Biochemical Foundations of Thiamin Biosynthesis Christopher T. Jurgenson,1 Tadhg P. Begley,2 and Steven E. Ealick2 1Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520; email: [email protected] 2Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853; email: [email protected], [email protected] Annu. Rev. Biochem. 2009. 78:569–603 Key Words First published online as a Review in Advance on degradation, salvage, transport, vitamin B1 April 6, 2009 The Annual Review of Biochemistry is online at Abstract biochem.annualreviews.org Thiamin is synthesized by most prokaryotes and by eukaryotes such as This article’s doi: yeast and plants. In all cases, the thiazole and pyrimidine moieties are 10.1146/annurev.biochem.78.072407.102340 by Texas A&M University - College Station on 08/11/09. For personal use only. synthesized in separate branches of the pathway and coupled to form Copyright c 2009 by Annual Reviews. Annu. Rev. Biochem. 2009.78:569-603. Downloaded from arjournals.annualreviews.org thiamin phosphate. A final phosphorylation gives thiamin pyrophos- All rights reserved phate, the active form of the cofactor. Over the past decade or so, bio- 0066-4154/09/0707-0569$20.00 chemical and structural studies have elucidated most of the details of the thiamin biosynthetic pathway in bacteria. Formation of the thiazole requires six gene products, and formation of the pyrimidine requires two. In contrast, details of the thiamin biosynthetic pathway in yeast are only just beginning to emerge. Only one gene product is required for the biosynthesis of the thiazole and one for the biosynthesis of the pyrimidine. Thiamin can also be transported into the cell and can be salvaged through several routes. In addition, two thiamin degrading en- zymes have been characterized, one of which is linked to a novel salvage pathway. 569 ANRV378-BI78-20 ARI 5 May 2009 14:27 INTRODUCTION Contents When Christiaan Eijkman received the 1929 INTRODUCTION .................. 570 Nobel Prize in Medicine (see “The Eijkman THIAZOLE BIOSYNTHESIS Nobel Prize” sidebar) “for his discovery of IN PROKARYOTES .............. 571 the antineuritic vitamin” (1) dubbed thiamin Deoxy-D-Xylulose 5-Phosphate through the work of Casimir Funk (2), it seemed Synthase........................ 571 unlikely that nearly 80 years later thiamin would Sulfur Carrier Protein .............. 573 still be the subject of active research, produc- Adenylyltransferase ................ 574 ing exciting advances in chemistry and biology. Sulfur Transfer .................... 576 We now know that the elaborate process of Glycine Oxidase ................... 576 thiamin biosynthesis utilizes many previously Thiazole Synthase ................. 577 unprecedented biochemical mechanisms. Even Aromatization of the Thiazole the regulation of thiamin was shown to use Ring ........................... 579 a sophisticated method of transcriptional con- HYDROXYMETHYL PYRIMIDINE trol through the use of the thiamin riboswitch BIOSYNTHESIS ................. 580 (3, 4). Hydroxymethyl Pyrimidine In all organisms, the thiazole and pyrimidine Phosphate Synthase ............. 580 moieties of thiamin monophosphate (ThMP) 4-Amino-5-hydroxymethyl-2- are generated in separate branches of the path- methylpyrimidine Phosphate way and then joined by a coupling enzyme. Kinase.......................... 580 ThMP is converted to the active form of the THIAMIN PYROPHOSPHATE cofactor thiamin diphosphate (ThDP) by a spe- BIOSYNTHESIS ................. 582 cific kinase. The best-studied thiamin biosyn- Thiamin Phosphate Synthase ....... 582 thetic pathways are those of Escherichia coli and Thiamin Phosphate Kinase ......... 583 Bacillus subtilis, which utilize very similar path- THIAMIN DEGRADATION ........ 584 ways, yet differ in some notable ways. The Thiaminase I ...................... 585 enzymes involved in the thiamin biosynthe- Thiaminase II ..................... 585 sis pathways for prokaryotes are illustrated in THIAMIN SALVAGE ................ 587 Figure 1. Table 1 gives the gene and enzyme Thiazole Kinase ................... 587 names. Although at one time the gene names Thiamin Pyrophosphokinase ....... 588 varied between E. coli and B. subtilis, the cur- THIAMIN TRANSPORT ............ 590 rently accepted standards, which are the same Thiamin-Binding Protein .......... 590 for both species, are used here. YkoF Protein ...................... 591 Collaboration between chemists, enzymol- by Texas A&M University - College Station on 08/11/09. For personal use only. THIAMIN REGULATION .......... 592 ogists, and structural biologists has produced Annu. Rev. Biochem. 2009.78:569-603. Downloaded from arjournals.annualreviews.org THI-Box Riboswitch............... 592 a clear understanding of how prokaryotes pro- EUKARYOTIC THIAMIN duce this essential cofactor. The X-ray crystal BIOSYNTHESIS ................. 593 structures and biochemical functions of nearly Hydroxymethylpyrimidine every enzyme in this pathway have been deter- Kinase/Thiamin Phosphate mined. Studies on the formation of the thiazole, Synthase........................ 594 the pyrimidine, and thiamin itself, along with Thiazole Synthase ................. 594 a variety of required kinases, are an important CONCLUSIONS AND contribution to the vast array of biochemical FUTURE ISSUES ................ 596 knowledge in the field of vitamin biosynthesis. In this review, we highlight the enzymological and structural studies that have elucidated thi- amin biosynthesis in prokaryotes. Mechanisms 570 Jurgenson · Begley · Ealick ANRV378-BI78-20 ARI 5 May 2009 14:27 and protein structures, where possible, are de- scribed for each step. Thiamin salvage, trans- THE EIJKMAN NOBEL PRIZE port, and regulation of thiamin biosynthetic genes are also discussed. The final section high- Christiaan Eijkman’s pioneering work from 1890 to 1900 showed lights a divergent thiazole biosynthetic path- that a component of rice hulls could reverse the effects of beriberi way in Saccharomyces cerevisiae. The conclusion in animals; however, it was not until 1933 that R.R. Williams pu- presents areas of further thiamin biochemical rified thiamin. Prior to this discovery, Umetaro Suzuki identified research in both bacteria and higher organisms. rice hull isolates that contained the active ingredient. This work was first published in Japanese and then republished in German in 1912 (5). THIAZOLE BIOSYNTHESIS The active ingredient called oryzanine, and later patented un- IN PROKARYOTES der the names aberic acid and orizanin, was shown to be an essen- The thiazole moiety (4-methyl-5-β- tial dietary component. Dogs fed on a thiamin-deficient diet of hydroxyethylthiazole or THZ) is made polished rice and boiled meat would succumb to beriberi in weeks through three distinct steps (Figure 1). First, but would recover quickly when given small amounts of oryza- glyceraldehyde 3-phosphate and pyruvate nine. This discovery was published about the time Casimir Funk are coupled together by 1-deoxy-d-xylulose was able to obtain crystals of a substance preventing polyneuritis, 5-phosphate synthase (Dxs) to give 1-deoxy-d- dubbing it “vitamine”—as it was a vital amine—although it was xylulose 5-phosphate (DXP). Next, the sulfur later shown that Funk most likely crystallized nicotinic acid (6). carrier protein ThiS undergoes an adenylyla- Eijkman further advanced his work after initially attributing the tion by ThiF, followed by a sulfur transfer step cause of beriberi to poisoning or microbial effects. He won the using ThiI (E. coli ) and IscS (NifS) to yield a Nobel Prize in Physiology or Medicine in 1929, “for his discov- thiocarboxy at its C terminus. It is this sulfur ery of the antineuritic vitamin” (1), also dubbed thiamin through atom that is incorporated into the THZ ring of the work of Funk (2). thiamin. Finally, glycine (by ThiO in B. subtilis) or tyrosine (by ThiH in E. coli ) is converted to dehydroglycine. The thiocarboxy C terminus pyrophosphate (PP) (8–11), so it is possible that of ThiS, along with DXP and dehydroglycine, the function of DXP synthase may have evolved are all coupled together by thiazole synthase, during a time when bacteria produced thiamin ThiG, to give thiazole phosphate carboxylate through a more ancient pathway. tautomer. The enzyme TenI (B. subtilis) then Dxs exists as a dimer, with the majority of aromatizes the thiazole tautomer to the thiazole the 3900-A˚ 2 protomer interface consisting of phosphate carboxylate. The key enzymes of hydrophobic residues. The crystal structures THZ formation are discussed in the following of Dxs from E. coli and Deinococcus radiodurans by Texas A&M University - College Station on 08/11/09. For personal use only. sections. show that the monomer contains three distinct domains (Figure 2a) (12). Domains I (residues Annu. Rev. Biochem. 2009.78:569-603. Downloaded from arjournals.annualreviews.org 1–319), II (residues 320–495), and III (residues Deoxy-D-Xylulose 5-Phosphate 496–629) contain five-, six- and five-stranded Synthase β-sheets, respectively. All β-sheets are parallel The first step in thiazole biosynthesis uti- with the exception of domain III, which has the lizes Dxs to produce DXP from glyceraldehyde first β-strand antiparallel to the other four. Dxs 3-phosphate and pyruvate. Paradoxically, de- is most structurally similar to transketolase (13), spite being required for the biosynthesis of thi- pyruvate
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