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• W2110347270 abstract "Vitamin B1 in its active form thiamin pyrophosphate is an essential coenzyme that is synthesized by coupling of pyrimidine (hydroxymethylpyrimidine; HMP) and thiazole (hydroxyethylthiazole) moieties in bacteria. Using comparative analysis of genes, operons, and regulatory elements, we describe the thiamin biosynthetic pathway in available bacterial genomes. The previously detected thiamin-regulatory element,thi box (Miranda-Rios, J., Navarro, M., and Soberon, M. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 9736–9741), was extended, resulting in a new, highly conserved RNA secondary structure, the THI element, which is widely distributed in eubacteria and also occurs in some archaea. Search for THIelements and analysis of operon structures identified a large number of new candidate thiamin-regulated genes, mostly transporters, in various prokaryotic organisms. In particular, we assign the thiamin transporter function to yuaJ in theBacillus/Clostridium group and the HMP transporter function to an ABC transporter thiXYZ in some proteobacteria and firmicutes. By analogy to the model of regulation of the riboflavin biosynthesis, we suggest thiamin-mediated regulation based on formation of alternative RNA structures involving theTHI element. Either transcriptional or translational attenuation mechanism may operate in different taxonomic groups, dependent on the existence of putative hairpins that either act as transcriptional terminators or sequester translation initiation sites. Based on analysis of co-occurrence of the thiamin biosynthetic genes in complete genomes, we predict that eubacteria, archaea, and eukaryota have different pathways for the HMP and hydroxyethylthiazole biosynthesis. Vitamin B1 in its active form thiamin pyrophosphate is an essential coenzyme that is synthesized by coupling of pyrimidine (hydroxymethylpyrimidine; HMP) and thiazole (hydroxyethylthiazole) moieties in bacteria. Using comparative analysis of genes, operons, and regulatory elements, we describe the thiamin biosynthetic pathway in available bacterial genomes. The previously detected thiamin-regulatory element,thi box (Miranda-Rios, J., Navarro, M., and Soberon, M. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 9736–9741), was extended, resulting in a new, highly conserved RNA secondary structure, the THI element, which is widely distributed in eubacteria and also occurs in some archaea. Search for THIelements and analysis of operon structures identified a large number of new candidate thiamin-regulated genes, mostly transporters, in various prokaryotic organisms. In particular, we assign the thiamin transporter function to yuaJ in theBacillus/Clostridium group and the HMP transporter function to an ABC transporter thiXYZ in some proteobacteria and firmicutes. By analogy to the model of regulation of the riboflavin biosynthesis, we suggest thiamin-mediated regulation based on formation of alternative RNA structures involving theTHI element. Either transcriptional or translational attenuation mechanism may operate in different taxonomic groups, dependent on the existence of putative hairpins that either act as transcriptional terminators or sequester translation initiation sites. Based on analysis of co-occurrence of the thiamin biosynthetic genes in complete genomes, we predict that eubacteria, archaea, and eukaryota have different pathways for the HMP and hydroxyethylthiazole biosynthesis. Thiamin pyrophosphate (vitamin B1) is an essential cofactor for several important enzymes of the carbohydrate metabolism (1Schowen R.L. Sinnott M.L. Comprehensive Biological Catalysis. 2. Academic Press, London1998: 217-266Google Scholar). Many microorganisms, as well as plants and fungi, synthesize thiamin, but it is not produced by vertebrates. The thiamin biosynthetic (TBS) 1The abbreviations used are: TBS, thiamin biosynthesis; HMP, hydroxymethylpyrimidine; HET, hydroxyethylthiazole; TMS, transmembrane segment; SD, Shine-Dalgarno. pathway of bacteria is outlined in Fig. 1. Thiamin monophosphate is formed by coupling of two independently synthesized moieties, HMP-PP and HET-P. In Escherichia coliand Salmonella typhimurium, this enzymatic step is mediated by the ThiE protein. At the next step, thiamin monophosphate is phosphorylated by ThiL to form thiamin pyrophosphate. The pyrimidine moiety of thiamin, HMP-PP, is synthesized from aminoimidazole ribotide, an intermediate of the purine biosynthesis pathway. ThiC produces HMP-P, which is then phosphorylated by the bifunctional HMP kinase/HMP-P kinase ThiD. The thiazole moiety of thiamin in E. coli is derived from tyrosine, cysteine, and 1-deoxy-d-xylulose phosphate in an unresolved chain of reactions involving the thiF, thiS,thiG, thiH, and thiI gene products. 1-Deoxy-d-xylulose phosphate, whose production is catalyzed by the dxs gene product, the latter utilizing thiamin pyrophosphate as a co-factor, is also used in the nonmevalonate pathway and the pyridoxal biosynthesis (2Begley T.P. Downs D.M. Ealick S.E. McLafferty F.W. Van Loon A.P. Taylor S. Campobasso N. Chiu H.J. Kinsland C. Reddick J.J. Xi J. Arch. Microbiol. 1999; 171: 293-300Google Scholar). ThiF catalyzes adenylation of the sulfur carrier protein ThiS by ATP. In addition, ThiI and IscS, enzymes shared by the thiamin and 4-thiouridine biosynthetic pathways, may play a role in the sulfur transfer chemistry. Three distinct kinases, ThiM, ThiD, and ThiK, are involved in the salvage of HET, HMP, and thiamin, respectively, from the culture medium. Thiamin, thiamin phosphate, and thiamin pyrophosphate are actively transported in enteric bacteria using the ABC transport system ThiBPQ (3Webb E. Claas K. Downs D.M. J. Bacteriol. 1997; 179: 4399-4402Google Scholar). No other thiamin transporters, neither HET nor HMP transport systems, have been identified in bacteria. A gene for the thiamin kinase ThiK has not yet been identified in the complete genome of E. coli, although the genes for other mentioned proteins are known. A similar TBS pathway exists in Bacillus subtilis, but instead of thiH it involves another probable thiazole biosynthesis gene, yjbR, which is most similar to thethiO gene from Rhizobium etli (4Perkins J.B. Pero J.G. Sonenshein A.L. Hoch J.A. Losick R. Bacillus subtilis and Its Relatives: From Genes to Cells. American Society for Microbiology, Washington, D. C.2001: 279-293Google Scholar). It has been proposed that ThiO may have the amino acid oxidase activity in the thiazole biosynthesis (5Miranda-Rios J. Morera C. Taboada H. Davalos A. Encarnacion S. Mora J. Soberon M. J. Bacteriol. 1997; 179: 6887-6893Google Scholar). The traditional gene names are different inE. coli and B. subtilis (Table I). HMP biosynthesis protein ThiC, thiamin-phosphate pyrophosphorylase ThiE, and hydroxyethylthiazole kinase ThiM from E. coli have their counterparts in B. subtilis named ThiA, ThiC, and ThiK, respectively. Moreover, the bifunctional gene thiD fromE. coli has two orthologs in B. subtilis,yjbV and ywdB, which separately could encode the biosynthetic and salvage HMP kinases (4Perkins J.B. Pero J.G. Sonenshein A.L. Hoch J.A. Losick R. Bacillus subtilis and Its Relatives: From Genes to Cells. American Society for Microbiology, Washington, D. C.2001: 279-293Google Scholar). For consistency, unless specified otherwise, we use the E. coli gene names throughout.Table IThe thiamin biosynthetic genes of E. coli (EC) and their counterparts in B. subtilis (BS)ECBSFunctionSimilarity%thiCthiAHMP biosynthesis76thiDyjbVPhosphomethylpyrimidine kinase43thiGyjbTThiazole biosynthesis protein ThiG52thiHThiazole biosynthesis protein ThiHyjbRThiazole biosynthesis protein ThiOthiIytbJThiazole biosynthesis protein ThiI33thiFyjbUAdenylyltransferase37thiSyjbSSulfur carrier protein ThiS31thiMthiKHydroxyethylthiazole kinase43thiEthiCThiamin-phosphate synthase39thiLydiAThiamin-monophosphate kinase37 Open table in a new tab No thiamin-regulatory genes have been identified in bacteria, but it has been shown that thiamin pyrophosphate is an effector molecule involved in the regulation of TBS genes. In S. typhimurium, the TBS operons thiCEFSGH and thiMD and the thiamin transport operon thiBPQ are transcriptionally regulated by thiamin pyrophosphate, whereas the thiI andthiL genes are not (3Webb E. Claas K. Downs D.M. J. Bacteriol. 1997; 179: 4399-4402Google Scholar, 6Petersen L.A. Downs D.M. J. Bacteriol. 1997; 179: 4894-4900Google Scholar, 7Webb E. Downs D. J. Biol. Chem. 1997; 272: 15702-15707Google Scholar, 8Webb E. Claas K. Downs D. J. Biol. Chem. 1998; 273: 8946-8950Google Scholar, 9Webb E. Febres F. Downs D.M. J. Bacteriol. 1996; 178: 2533-2538Google Scholar). B. subtilis has a thiamin-regulated gene, thiA, and the ywbI-thiKCoperon whose transcription is partially repressed by thiazole but not by thiamin (10Zhang Y. Begley T.P. Gene (Amst.). 1997; 198: 73-82Google Scholar, 11Zhang Y. Taylor S.V. Chiu H.J. Begley T.P. J. Bacteriol. 1997; 179: 3030-3035Google Scholar). Recently, a new thiamin-regulated operon,tenA-tenI-yjbR-thiSGF-yjbV, was detected in B. subtilis by the expression microarray analysis (12Lee J.M. Zhang S. Saha S. Santa Anna S. Jiang C. Perkins J. J. Bacteriol. 2001; 183: 7371-7380Google Scholar). Sequence analysis revealed the existence of putative Rho-independent transcriptional terminator sites in the upstream regions of theB. subtilis thiamin-regulated operons (4Perkins J.B. Pero J.G. Sonenshein A.L. Hoch J.A. Losick R. Bacillus subtilis and Its Relatives: From Genes to Cells. American Society for Microbiology, Washington, D. C.2001: 279-293Google Scholar). Deletion of one such site located upstream of the tenA-tenI-yjbR-thiSGF-yjbVoperon increased the expression level of tenA (13Pang A.S. Nathoo S. Wong S.L. J. Bacteriol. 1991; 173: 46-54Google Scholar). The 5′-untranslated region of the R. etli thiCOGE operon contains a 39-bp sequence, thi box, that is highly conserved in the upstream regions of the TBS genes from several bacterial genomes, and an additional stem-loop structure that would mask the ribosome binding site of thiC (5Miranda-Rios J. Morera C. Taboada H. Davalos A. Encarnacion S. Mora J. Soberon M. J. Bacteriol. 1997; 179: 6887-6893Google Scholar). Involvement of these two RNA structural elements in the thiamin-mediated translational regulation of the R. etli TBS operon has been demonstrated using deletion analysis (14Miranda-Rios J. Navarro M. Soberon M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9736-9741Google Scholar). The exact mechanism by which thiamin inhibits translation initiation of the thiC gene remains to be determined. RNA elements similar to the thi box ofR. etli have been observed upstream of the thiCgenes from E. coli, S. typhimurium, B. subtilis, Mycobacterium tuberculosis,Synechocystis sp., and the thiMD operon fromS. typhimurium (5Miranda-Rios J. Morera C. Taboada H. Davalos A. Encarnacion S. Mora J. Soberon M. J. Bacteriol. 1997; 179: 6887-6893Google Scholar). Comparative analysis of many bacterial genomes is a powerful approach to reconstruction of metabolic pathways and their DNA or RNA regulation (for a review, see Ref. 15Gelfand M.S. Novichkov P.S. Novichkova E.S. Mironov A.A. Brief. Bioinform. 2000; 1: 357-371Google Scholar). In particular, analysis of the regulation of the riboflavin and biotin biosynthesis has shown that these vitamin regulons are highly conserved among unrelated bacteria (16Vitreshchak A. Rodionov D. Mironov A.A. Gelfand M.S. Nucleic Acids Res. 2002; 30: 3141-3151Google Scholar, 17Rodionov D. Mironov A.A. Gelfand M.S. Genome Res. 2002; 12: 1507Google Scholar). In the former study, a model for the riboflavin-mediated regulation based on formation of alternative RNA structures involving the RFNelements has been suggested. To construct a single conserved structure of an RNA regulatory element, analysis of complementary substitutions in aligned sequences is used (18Eddy S.R. Durbin R. Nucleic Acids Res. 1994; 22: 2079-2088Google Scholar). In addition, analysis of positional clustering of genes on the chromosome helps in detection of functionally coupled genes (19Overbeek R. Fonstein M. D'Souza M. Pusch G.D. Maltsev N. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 2896-2901Google Scholar). Simultaneous analysis of probable operon structures and regulatory elements is the most effective theoretical method of functional annotation when the standard homology-based methods are insufficient. In this study, we analyzed the TBS pathway and the thiamin regulon in all available bacterial genomes by the comparative genomics approach. After extension of the thi box, we found a new RNA structure, the THI element, which is highly conserved on the sequence and structural levels. A possible mechanism of theTHI-element-mediated regulation involving either transcriptional or translational attenuation was proposed for different groups of bacteria. Analysis of the candidateTHI elements and positional clustering of the TBS genes resulted in identification of new thiamin-related genes, most of which are hypothetical transport systems. Finally, using metabolic reconstruction of the TBS pathway, we described some radical differences of the HET and HMP biosynthetic pathways in eubacteria, archaea, and eukaryota. Complete and partial sequences of bacterial genomes were downloaded from GenBankTM (20Benson D.A. Karsch-Mizrachi I. Lipman D.J. Ostell J. Rapp B.A. Wheeler D.L. Nucleic Acids Res. 2000; 28: 15-18Google Scholar). Preliminary sequence data were also obtained from the World Wide Web sites of the Institute for Genomic Research (www.tigr.org) the University of Oklahoma's Advanced Center for Genome Technology (www.genome.ou.edu/), the Wellcome Trust Sanger Institute (www.sanger.ac.uk/), the DOE Joint Genome Institute (jgi.doe.gov), and the ERGO data base (ergo.integratedgenomics.com/ERGO/) (21Overbeek R. Larsen N. Pusch G.D. D'Souza M. Selkov Jr., E. Kyrpides N. Fonstein M. Maltsev N. Selkov E. Nucleic Acids Res. 2000; 28: 123-125Google Scholar). Gene identifiers from the ERGO data base and GenBankTM are used throughout. The RNA-PATTERN program (22Vitreshchak A. Mironov A.A. Gelfand M.S. Proceedings of the 3rd International Conference on “Complex Systems: Control and Modeling Problems,” Samara, Russia, September 4–9, 2001. The Institute of Control of Complex Systems, Samara, Russia2001: 623-625Google Scholar) was used to search for conserved RNA regulatory elements. The input RNA pattern included both the RNA secondary structure and the sequence consensus motifs. The RNA secondary structure was described as a set of the following parameters: the number of helices, the length of each helix, the loop lengths, and the description of the topology of helix pairs. The initial RNA pattern of the thi box was constructed using the training set of eight thi boxes (5Miranda-Rios J. Morera C. Taboada H. Davalos A. Encarnacion S. Mora J. Soberon M. J. Bacteriol. 1997; 179: 6887-6893Google Scholar). Each genome was scanned with thethi-box pattern, resulting in detection of ∼150 newthi boxes. Using multiple alignment of these thiboxes with flanking regions, additional conserved helices and sequence motifs were revealed, resulting in an extended RNA secondary structure, named the THI element. The RNA secondary structures of theTHI elements, antiterminators, and antisequestors were predicted using Zuker's algorithm of free energy minimization (23Lyngso R.B. Zuker M. Pedersen C.N. Bioinformatics. 1999; 15: 440-445Google Scholar) implemented in the Mfold program (available on the World Wide Web at bioinfo.math.rpi.edu/∼mfold/rna). Protein similarity search was done using the Smith-Waterman algorithm implemented in the GenomeExplorer program (24Mironov A.A. Vinokurova N.P. Gelfand M.S. Mol. Biol. 2000; 34: 222-231Google Scholar). Orthologous proteins were initially defined by the best bidirectional hits criterion (25Tatusov R.L. Galperin M.Y. Natale D.A. Koonin E.V. Nucleic Acids Res. 2000; 28: 33-36Google Scholar) and, if necessary, confirmed by construction of phylogenetic trees. The phylogenetic trees were created by the maximum likelihood method implemented in PHYLIP (26Felsenstein J. J. Mol. Evol. 1981; 17: 368-376Google Scholar) and drawn using the GeneMaster program. 2A. Mironov, unpublished results. Distant homologs were identified using PSI-BLAST (27Altschul S. Madden T. Schaffer A. Zhang J. Zhang Z. Miller W. Lipman D. Nucleic Acids Res. 1997; 25: 3389-3402Google Scholar). Transmembrane segments (TMSs) were predicted using the TMpred program (www.ch.embnet.org/software/TMPRED_form.html). Multiple sequence alignments were constructed using ClustalX (28Thompson J.D. Gibson T.J. Plewniak F. Jeanmougin F. Higgins D.G. Nucleic Acids Res. 1997; 25: 4876-4882Google Scholar). Orthologs of the thiamin biosynthesis and transport genes fromE. coli and B. subtilis have been identified in all available bacterial genomes by similarity search (TableI). We have not considered thedxs, iscS, and thiI genes because they are shared between the TBS and other pathways. Then we scanned 103 genomic sequences by the RNA-PATTERN program and found 170THI elements in 78 genomes. It has been demonstrated that the thiamin biosynthesis is a widely distributed metabolic pathway in bacteria and it is usually regulated by the THI element. Note that the fact of gene absence is reliable only for complete genomes. Among all complete genomes, only spirochetes, mycoplasmas, chlamydiae, and rickettsiae have neither TBS genes nor THIelements. Two streptococci lack the TBS genes but have THIelements. In contrast, Aquifex aeolicus, Helicobacter pylori, Lactococcus lactis, Legionella pneumophila, Magnetococcus sp., and almost all archaeal genomes lack THI elements but have the TBS genes. The detailed phylogenetic and positional analysis of the TBS genes and theTHI elements is given below. At the first step, we have considered genomes that have no genes for the initial steps of the TBS pathway, namely thiC for the HMP biosynthesis and thiS-thiG-thiH (orthiS-thiG-thiO) for the HET biosynthesis. Most Gram-positive pathogens from the Bacillus/Clostridium group, all Pasteurellaeceae, and H. pylori lack both HMP and HET biosynthetic genes but have the thiM, thiD, andthiE genes. Thus, the TBS pathway in these organisms is incomplete and possibly uses exogenously supplied HET and HMP. Using analysis of the THI elements, we tried to identify candidate genes for the HMP and HET transport (see below). Homologs of genes for the HET biosynthesis are absent in all archaeal genomes as well as in the genome of Thermotoga maritima. However, all of these microorganisms except for Aeropyrum pernix andThermoplasma sp. have the HMP biosynthetic genethiC. In this work, we predict that archaea and T. maritima, like eukaryota, have a different pathway of HET biosynthesis (see below). The similarities between the ThiF/ThiS and MoeB/MoaD proteins involved in the initial steps of TBS and molybdopterin biosynthesis, respectively, have already been described (29Taylor S.V. Kelleher N.L. Kinsland C. Chiu H.J. Costello C.A. Backstrom A.D. McLafferty F.W. Begley T.P. J. Biol. Chem. 1998; 273: 16555-16560Google Scholar). In bacterial genomes containing the HET biosynthetic genes, we have identified either one or two ThiF/MoeB homologs per genome. Interestingly, all of these genes have been found in the loci containing either TBS or molybdopterin biosynthesis genes. However, the phylogenetic tree of the ThiF/MoeB family (data not shown) has several branches represented by both TBS-linked proteins (ThiF) and molybdopterin biosynthesis-linked proteins (MoeB). Thus, it is likely that the sulfur transfer chemistry of these two biosynthetic pathways can be shared in bacteria with only one ThiF/MoeB homolog. Alternatively, these organisms could have an unidentified ThiS-activating enzyme. Because of that, we do not consider thiF during analysis of the HET biosynthetic genes. Two distinct enzymes, ThiH and ThiO, are involved in the HET biosynthesis in E. coli and B. subtilis, respectively. Similarity search in bacterial genomes has showed that aerobic microorganisms including α- and β-proteobacteria, pseudomonads, bacilli, actinomycetes, members of theThermus/Deinococcus group, A. aeolicus, L. pneumophila, and Magnetococcus sp. have ThiO, whereas enterobacteria, clostridia, bacteria of the CFB group, Shewanella putrefaciens, Campylobacter jejuni, Chlorobium tepidum, and Fusobacterium nucleatum, which are mostly anaerobic microorganisms, have ThiH. This diversity in one enzyme of the HET biosynthesis can be explained by the use of different substrates for the synthesis of the thiazole moiety of thiamin by aerobes and anaerobes. Indeed, in two experimentally studied cases, an aerobe B. subtilis and a facultative anaerobe E. coli require glycine and tyrosine, respectively (30Tazuya K. Morisaki M. Yamada K. Kumaoka H. Saiki K. Biochem. Int. 1987; 14: 153-160Google Scholar). The thiE gene, which is required for coupling of the HET and HMP moieties of thiamin, has been identified in almost all organisms containing the TBS pathway except T. maritima and seven archaebacteria. The thiD gene encoding HMP kinase is the most widely distributed TBS gene, which is absent only inSynechocystis sp. Interestingly, the ThiD proteins fromT. maritima and most archaea have an additional C-terminal domain of ∼130 amino acids, whereas this domain is encoded by a separate gene in Methanobacterium thermoautotrophicum. The additional ThiD domain, named here ThiN, is not similar to any known protein and contains no conserved motifs. In all cases when ThiE is absent and ThiD is present, there is the ThiN domain, although in many cases ThiN and ThiE co-exist. We suggest that this conserved domain is somehow involved in the TBS, possibly replacing the ThiE function in the genomes of some archaea and T. maritima. The least common gene of the TBS pathway is the thiM gene encoding HET kinase from the thiazole salvage pathway. thiM was found only in the Bacillus/Clostridium group, enterobacteria, Pasteurellaecae, Vibrio fischeri, H. pylori, Agrobacterium tumefaciens, Rhodobacter sphaeroides, Corynebacterium glutamicum, and some archaea. The operon structures of the TBS genes are quite diverse (TableII). Some genomes (e.g. Corynebacterium diphtheriae) have all TBS genes clustered in one putative operon, whereas the genomes of A. aeolicus,Caulobacter crescentus, Magnetococcus sp., andXylella fastidiosa contain single TBS genes.Table IIThiamin biosynthesis and transport genes and THI elements in bacteria Open table in a new tab The thiM, thiD, and thiE genes, encoding adjacent enzymatic steps of the TBS pathway, often form clusters (probably operons) in a bacterial chromosome or can even be fused. The fused thiE-thiD genes were found in three bacteria, C. glutamicum, L. pneumophila, and Porphyromonas gingivalis, and one eukaryote, plantBrassica napus. In addition, several yeast genomes contain a single gene encoding the fused protein ThiE-ThiM. Another frequently occurring gene cluster includes genes of the HET biosynthesis: thiF, thiS, thiG, andthiH (or thiO). Again, we have observed a single gene encoding the fused protein ThiO-ThiG in two cyanobacteria. A search for THI elements upstream of TBS genes showed that the TBS pathways of all eubacteria, except A. aeolicus,H. pylori, L. pneumophila, L. lactis, and Magnetococcus sp., are regulated by THIelements (Table II). Moreover, the TBS pathways in about half of these bacteria seem to be completely regulated, since all TBS operons have upstream THI elements; about one-fourth of the genomes contain only one THI element-regulated gene thiC, and the remaining bacteria apparently have partially regulated TBS pathways. The thiC gene is the most tightlyTHI-regulated gene of the TBS pathway, since onlyClostridium botulinum has THI regulation, but not of thiC. Finally, the archaeal TBS operons apparently are not regulated by THI elements. The thiB-thiP-thiQ operon encoding an ATP-dependent transport system for thiamin has been identified in most α- and γ-proteobacteria and Streptomyces coelicolor, and in all of these cases it is preceded byTHI elements. In addition, bacteria from theThermus/Deinococcus group and Petrotoga miothermahave incomplete thiB-thiP loci, which are alsoTHI-regulated (cf. discussion of the ThiX-ThiY-ThiZ system below). The thiB-thiP-thiQ loci without THI elements were detected in several archaea, namely Halobacterium sp., Pyrobaculum aerophilum, and Pyrococcus species. The thiB-thiP-thiQ genes never cluster with TBS genes. Comparison of TBS protein phylogenetic trees with the standard trees for ribosomal proteins reveals some unusual branches. The most interesting observation is a likely horizontal transfer of thethiM-thiD-thiE genes from Listeria species to three Pasteurellaeceae. For instance, the ThiD proteins fromHemophilus influenzae, Pasteurella multocida, andMannheimia hemolytica are close to ThiD from theBacillus/Clostridium group, showing the highest similarity to Listeria species, and the same holds for other phylogenetic trees (data not shown). Among γ-proteobacteria, only Pasteurellaeceae have an incomplete TBS pathway (i.e.ThiM-ThiD-ThiE), which is widely distributed in Gram-positive pathogens from the Bacillus/Clostridium group. Another example of possible horizontal transfer is thethiM-thiD-thiE operon of H. pylori. Again, the TBS proteins of this bacterium are similar to the proteins from the Bacillus/Clostridium group. A search for THI elements in bacterial genomes complemented by analysis of the putative operon structure of the TBS genes has allowed us to detect a number of new thiamin-related genes. Most of these genes encode new transport systems. The single THI-regulated gene yuaJ (the B. subtilis name) was found in all complete genomes of theBacillus/Clostridium group except Staphylococcus aureus and Streptococcus pneumoniae (Table II). It is always preceded by a THI element with only one exception inEnterococcus faecalis and is never clustered with TBS genes.Clostridium perfringes has two yuaJ paralogs, with and without an upstream THI element. YuaJ has six predicted transmembrane segments (TMSs) and is not similar to any known protein. yuaJ is the only thiamin-regulated gene in the complete genomes of Streptococcus mutans andStreptococcus pyogenes, which have no genes for the TBS pathway. These observations strongly suggest that YuaJ is a thiamin transporter, which, in contrast to ThiB-ThiP-ThiQ, is obviously not ATP-dependent. In support of this prediction, the thiamin uptake in Bacillus cereus, which has yuaJ, is coupled to the proton movement (31Toburen-Bots I. Hagedorn H. Arch. Microbiol. 1977; 113: 23-31Google Scholar). A hypothetical thiamin-related ABC transporter, named herethiX-thiY-thiZ, was identified in bacteria from various taxonomic divisions, such as α- and γ-proteobacteria, theBacillus/Clostridium group, and Thermotogales. The first gene, thiX, encodes the transmembrane component of the ABC transport system, whereas the second (thiY) and the third (thiZ) genes encode the substrate- and ATP-binding components, respectively. These genes have upstream THIelements in all cases with only one exception in T. maritima. In A. tumefaciens, R. sphaeroides,B. melitensis, Pasteurella multocida, V. fischeri, and B. cereus, the thiX-thiY-thiZgenes are clustered with the thiD gene that encodes HMP kinase. In contrast to yuaJ, the thiX-thiY-thiZoperon is not found in the genomes without TBS genes, but sometimes it occurs in genomes with the incomplete TBS pathway. The need of HMP and HET moiety for the thiamin biosynthesis is obvious. However, pathways other than TBS that could supply these compounds are not known. The putative substrate-binding protein ThiY is similar to enzymes for the HMP biosynthesis from yeasts, namely Thi3 of Schizosaccharomyces pombe and Thi5 of Saccharomyces cerevisiae. All found ThiY orthologs are predicted to have an N-terminal transmembrane segment, which is common for substrate-binding components of ABC transporters. Thus, we predict that ThiX-ThiY-ThiZ is a HMP transport system that substitutes for missing HMP biosynthesis in some bacteria. Unusually, Brucella melitensis and A. tumefacienshave ThiX-ThiY but miss the ATPase component ThiZ. A similar situation with incomplete ThiB-ThiP systems in some bacteria has been described above. Based on the experimental fact that ATPases of different ABC transport systems can be functionally exchangeable (32Hekstra D. Tommassen J. J. Bacteriol. 1993; 175: 6546-6552Google Scholar), we suggest that the incomplete ThiXY and ThiBP systems could use another ATPase component. The HMP specificity of the ThiXYZ system is further supported by the observation that B. melitensis lacks the HMP pathway but not the HET pathway. In some Gram-positive bacteria, we have found another thiamin-related ABC transporter, YkoE-YkoD-YkoC. It consists of two transmembrane components (YkoE and YkoC) and an ATPase component (YkoD). We could not identify a substrate-binding component for this system. Similarly tothiX-thiY-thiZ, the ykoE-ykoD-ykoC genes always co-occur with the TBS genes and are preceded by a THIelement. They have also been found in genomes with the incomplete TBS pathway. In B. subtilis, the first gene of theTHI-regulated ykoF-ykoE-ykoD-ykoC operon is not similar to any known protein and has only one ortholog inMesorhizobium loti, where it clusters with the above described candidate HMP transporter, forming a THI-regulated cluster, ykoF-thiX-thiY-thiZ. Thus, the new ABC transport system YkoE-YkoD-YkoC is obviously thiamin-related and most likely is involved in the HMP transport for TBS. This prediction is based on positional clustering and on the follow" @default.
• W2110347270 created "2016-06-24" @default.
• W2110347270 creator A5016957787 @default.
• W2110347270 creator A5041084611 @default.
• W2110347270 creator A5048046634 @default.
• W2110347270 creator A5072879495 @default.
• W2110347270 date "2002-12-01" @default.
• W2110347270 modified "2023-10-18" @default.
• W2110347270 title "Comparative Genomics of Thiamin Biosynthesis in Procaryotes" @default.
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