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Curr Opin Microbiol. Author manuscript; available in PMC 2009 April 1. Published in final edited form as: doi: 10.1016/j.mib.2008.02.005. | PMCID: PMC2387123 NIHMSID: NIHMS49053 |
Evolution of bacterial trp operons and their regulation Enrique Merino,1 Roy A Jensen,2 and Charles Yanofsky3 1Department of Molecular Microbiology, Instituto de Biotecnologia, Universidad Nacional Autonoma de Mexico, Cuernavaca, Morelos 62271, México (Email: merino/at/ibt.unam.mx) 2Emerson Hall, PO Box 110700, University of Florida, Gainesville, FL 32611, USA (Email: rjensen/at/ufl.edu) 3Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA (Email: yanofsky/at/stanford.edu) Survival and replication of most bacteria require the ability to synthesize the amino acid L-tryptophan whenever it is not available from the environment. In this article we describe the genes, operons, proteins, and reactions involved in tryptophan biosynthesis in bacteria, and the mechanisms they use in regulating tryptophan formation. We show that although the reactions of tryptophan biosynthesis are essentially identical, gene organization varies among species - from whole-pathway operons to completely dispersed genes. We also show that the regulatory mechanisms used for these genes vary greatly. We address the question - what are some potential advantages of the gene organization and regulation variation associated with this conserved, important pathway? Extensive knowledge exists for the genes, enzymes, operons, and reactions of L-tryptophan (Trp) biosynthesis of bacteria, and on the mechanisms they use in regulating Trp formation [ **1- 5]. All organisms with this pathway use structurally similar enzymes, suggesting that the genes for this pathway evolved just once, probably late in the evolution of genes for amino acid biosynthesis. Trp is one of the rarest amino acids in most proteins, and it is the most costly to synthesize. It is generally encoded by a single codon, UGG, which may have served as a stop codon in early codon evolution. The 3D structures of all seven of the Trp biosynthetic enzymes are known, and most resemble structures of proteins catalyzing similar reactions in other pathways. The organization of trp genes within operons and the regulatory mechanisms used to control trp operon expression both vary greatly, undoubtedly reflecting organismal divergence in relationship to different metabolic contexts of Trp biosynthesis. Various trans-acting proteins and cis-acting sites and regions are used to regulate trp operon expression. The variety of mechanisms used suggests that groups of organisms experienced differing selective pressures in response to differing capabilities and needs. Intracellular concentrations of Trp and of charged and uncharged tRNA Trp are the cues most often sensed in trp operon regulation. In this article we review and update knowledge on the distribution of the genes, enzymes, and regulatory mechanisms used by bacteria in Trp biosynthesis. Phylogenetic distribution of trp gene organization and associated regulatory factors, elements, and mechanisms portrays a 16S rRNA tree of selected organisms that are color-coded according to major phylogenetic groupings in the Bacteria. Although some studies on trp gene regulation in Archaea have appeared recently [ 6- 9], these are outside the scope of this review. Shown to the right are the trp-gene clustering, trp-gene fusions, and regulatory features. trp genes that have specialized functional roles other than primary Trp biosynthesis and which therefore are not regulated by Trp are not shown. A few pathogens ( Haemophilus, Coxiella, and Propionibacterium) that appear to be in the process of losing the Trp pathway [ 4] are also shown. The extensive variation in trp gene arrangements within operons and the repertoire of alternative mechanisms used in regulating transcription of these genes (), illustrate the plasticity that bacteria must have had for optimization of Trp biosynthesis. Sensing Trp and tRNATrp in Gram-negative bacteria, Actinobacteridae, and Deinococci Not surprisingly, particular gene arrangements and regulatory strategies are often present in related phylogenetic groupings. For example, in Escherichia coli and other lower-Gammaproteobacteria the seven trp biosynthetic genes are organized within a single transcriptional unit, the trp operon, which always has a trpCF gene fusion and which, in a smaller group, has a trpGD fusion (). In this group of bacteria two principal mechanisms are used for transcriptional regulation - one sensing Trp and a second sensing uncharged tRNA Trp. Initiation of transcription of the trp operon is regulated by repression by the Trp-activated TrpR repressor protein () [ 10, 11]. Regulation by TrpR in Psychrobacter and Coxiella has been predicted by bioinformatic analysis, and regulation by TrpR has been demonstrated experimentally [ 12] in the phylogenetically distant Chlamydiales (which are not Gram-negative bacteria). Thus far, trpR generally appears to be autoregulated, and it exists predominantly in a monocistronic operon (). However, in some organisms trpR is co-transcribed with other trp genes, allowing coordinate expression, e.g., in the trpREG, trpRBA, and trpRDCFBA operons of Psychrobacter cryohalolentis, Chlamydia trachomatis and Chlamydophila caviae, respectively (). Uncharged tRNA Trp is also sensed by transcription attenuation mechanisms as a regulatory signal () [ 11, *13, 14]. Interestingly, although trp operons containing all the trp genes are commonly subject to regulation by transcription attenuation, in some organisms this mechanism is used to regulate only a subset of the trp genes (). Thus, transcription attenuation is used to regulate the trpE and trpGDC operons of Pseudomonas aeruginosa, the trpEG operon of some Alphaproteobacteria (e.g., Rhizobium etli) and Actinobacteridae (e.g., Streptomyces coelicolor), as well as the monocistronic trpE operon of Deinococci (e.g., Deinococcus radiodurans) (). In P. aeruginosa (and P. entomophila) transcription of the trpBA operon is activated by the TrpI protein in response to the accumulation of indoleglycerol phosphate (InGP), a Trp biosynthetic intermediate [ 15, 16] (). InGP accumulates whenever the cellular Trp concentration is low. The trpI and trpBA operons of these organisms are divergently transcribed () and their transcription is regulated by the binding of TrpI at their overlapping regulatory regions (). When the Trp concentration is high, the InGP concentration is low, and TrpI binds near its promoter and autoregulates its own synthesis. When the Trp concentration is low and InGP accumulates, two molecules of activated TrpI are bound near the trpBA promoter, activating trpBA transcription () [ 15, 16]. Sensing Trp and tRNATrp in Gram-positive bacteria Although Gram-positive bacteria also sense both the intracellular level of free Trp and the availability of charged tRNA Trp as regulatory signals, quite different strategies are used by these organisms in regulating the trp biosynthetic operon (). For example, in B. subtilis and some of its close relatives, coordinate expression of all seven trp genes is required for Trp biosynthesis. Six of these genes are clustered in the trp operon, trpEDCFBA, which is transcribed as part of a supraoperon also containing genes involved in the common aromatic pathway, and in phenylalanine, tyrosine, and histidine biosynthesis. The seventh trp gene, trpG, (also functioning as pabA) is located in the unlinked folate operon. Transcription of the trp operon of B. subtilis is regulated by attenuation by the Trp-activated trp RNA-binding attenuation protein, TRAP [ 17, 18] (). In the presence of excess Trp, TRAP-mediated transcription termination predominates, but those few transcripts that escape termination are subject to translational regulation via formation of a secondary structure that blocks ribosome access to the trpE ribosome-binding site [ 19]. Expression of trpG is coordinately regulated with the other trp genes by Trp-activated TRAP, which binds at the trpG mRNA ribosome-binding site, inhibiting its translation [ 20]. TRAP regulation of the trp operon also occurs in some Clostridia, although here trp operon organization varies significantly from that of B. subtilis. For example, in Syntrophomonas wolfei and Carboxydothermus hydrogenoformans all the trp genes are transcribed as part of a common operon. In the former, trpE and trpG are fused and located at the end of the operon while in the latter, the operon begins with the aroF gene, followed by unfused trpE and trpG genes (). In B. subtilis the availability of uncharged tRNA Trp is also sensed, and accumulation of uncharged tRNA Trp regulates synthesis of AT, an anti-TRAP protein. AT binds to Trp-activated TRAP, inhibiting its function [ 21, 22]. (). The structural gene for AT, rtpA, is transcriptionally regulated by the T box mechanism (see below), in response to the accumulation of uncharged tRNA Trp [ 22]. AT synthesis is also regulated translationally by uncharged tRNA Trp [ 21]. AT appears to have evolved very recently since it has only been identified in B. subtilis and the closely related B. licheniformis (). In the other TRAP-containing organisms it is not known whether some other regulatory mechanism is used to sense uncharged tRNA Trp accumulation. In the vast majority of Gram-positive bacteria, TRAP is not present. Transcription of the trp operon is regulated in response to uncharged tRNA Trp accumulation, by the T box mechanism [ 23] (). This mechanism involves leader RNA recognition of uncharged tRNA Trp - targeted with great specificity and affinity in the absence of any protein factors. The T box was originally identified as the regulatory element used for many aminoacyl-tRNA synthetase operons in Gram-positive bacteria [ 23]. It was later found to be associated with many other operons of amino acid metabolism, such as those containing transporter genes and biosynthesis genes. The T box elements regulating trp biosynthetic genes are often tandemly arranged in the upstream transcribed region of the trp operon. However, in some species only a single T box element is present [ **1, **24] ). In organisms that use the T box mechanism to sense uncharged tRNA Trp in regulating trp operon expression, the existence of a free-Trp sensing mechanism is unknown. In organisms with tandem T box elements, the quantitative advantages derived from employing tandem T boxes might compensate for the lack of a separate regulatory mechanism for sensing Trp [ **1, **24]. Regulation of the trp operon by the T box mechanism is almost exclusively confined to the Firmicutes. Possible reasons for differences in operon organization and regulatory mechanisms The Trp pathway requires the products of four other pathways for completion of Trp biosynthesis. Chorismate is the common precursor of all three aromatic amino acids, as well as a precursor of other essential metabolites, e.g., folic acid. Glutamine provides an essential amino group during anthranilate formation, PRPP is the source of several carbons of the indole ring of Trp, and L-serine provides the side-chain of Trp. PRPP, an important high-energy metabolite, must be used efficiently. If exogenous anthranilate were to enter the cell and generate unneeded Trp, this could decrease the availability of PRPP for L-histidine synthesis (and for other functions). This likely explains why anthranilate phosphoribosyl transferase is a second target in addition to anthranilate synthase (AS) for Trp feedback inhibition in enteric bacteria [ 25]. Bacillus subtilis employs an alternative - and indirect - mechanism whereby its AS is activated by histidine [ 26]. Beyond the fate of Trp as a substrate for protein synthesis, some intermediates in Trp biosynthesis – and Trp itself – can serve other functions, and these functions are highly individualistic in nature. In view of this, it is perhaps not surprising that trp operon organization varies appreciably in different bacterial species, and that different mechanisms are used in regulating its expression. (i) Organisms such as P. aeruginosa use anthranilate for several purposes. (See the later discussion of quinolone biosynthesis in the LGT section). Thus, the overall need for AS here may not be coordinated with the need for synthesis of other Trp pathway enzymes. These relationships may partially explain the split operon () [ 4] and the differential regulation of Trp enzymes seen in this species and its close relatives. (ii) In plant-associated organisms such as Azospirillum brasilense [ 27] Trp assists plant growth by serving as precursor of indole-3-acetic acid. This organism possesses two AS enzymes, one sensitive to feedback inhibition by Trp and controlled by a TrpL leader peptide region. The second AS is neither sensitive to feedback inhibition by Trp, nor known to be subject to repression by Trp, suggestive of its specialized role in auxin synthesis [ 28]. (iii) Chromobacterium violaceum produces large quantities of the pigment, violacein, which is derived from two molecules of Trp [ 29]. The trp genes of this organism (not shown in ) are mostly scattered and present as single copies. It would be interesting to know what control strategies dictate the two fates of Trp in C. violaceum. (iv) Streptomyces coelicolor possesses a large gene cluster associated with formation of a calcium-dependent antibiotic containing Trp. The cluster includes copies of four of the trp genes (not shown in ), implying their specialized participation in the antibiotic pathway (4). Hence, the remaining three trp genes which are present as single copies are uniquely used for two different pathway functions. (v) species of Cytophaga, Polaribacter, Xanthomonas, and Gemmata (not shown in ) synthesize quinolinate from Trp and use it as a precursor of niacin [ 30]. In some of these organisms only single trp genes are present, implying that regulatory mechanisms exist that do not depend upon differential regulation of multiple copies of trp genes. An interesting alteration of metabolic context for the Trp pathway is exemplified by the mosaic trp operon of Chlamydophila caviae (), an intracellular pathogen which recycles Trp-derived kynurenine of the mammalian host back to pathogen-available Trp [ 2]. The trp operon of this organism lacks genes encoding AS, but possesses the remaining trp-pathway genes. Its mosaic trp operon also contains genes encoding PRPP synthase (not otherwise present in Chlamydia) and kynureninase (required for conversion of host kynurinine to pathogen anthranilate). The repressor gene, trpR, is also within the operon, indicating that it is auto-regulated (). The reactions of Trp biosynthesis are invariant, but the enzymes that catalyze them often exhibit distinct characteristics. Many different gene-fusion combinations exist in different lineages [ 4], and such fusions are reliable markers of phylogenetic relatedness. Anthranilate synthase (AS) The TrpE polypeptide, in complex with the TrpG polypeptide, catalyzes anthranilate formation from chorismate and glutamine [ 31]. p-aminobenzoate (PABA) synthase, a close homolog of AS, performs a similar reaction to generate PABA for folate synthesis [ 32]. Both enzymes use an amidotransferase subunit to deliver glutamine-derived ammonia to the active site. AS, but not PABA synthase, is feedback inhibited by Trp. Since PABA synthase nevertheless has a Trp-binding pocket, this is consistent with an evolutionary scenario whereby the PABA synthase gene evolved from trpE by gene duplication, followed by loss of Trp feedback inhibition. PABA is not derived from chorismate in some organisms [ *33]. Anthranilate phosphoribosyl transferase TrpD is a highly conserved enzyme, which together with nucleoside phosphorylase and thymidine phosphorylase represent one of three types of phosphotransferase folds [ 34]. Interestingly, under certain conditions, TrpD supplies phosphoribosyl amine for thiamine biosynthesis [ 35]. The TrpF, TrpC, and TrpA polypeptides These three enzymes are of similar size and all have αβ barrel structures. All three may have originated via gene duplication from an ancestral gene encoding an enzyme that may have been capable of catalyzing all three reactions. In some Actinomycetes the trpF-encoded isomerase polypeptide is missing, and its function is provided by the similar histidine-pathway isomerase, denoted PriA [ 36]. The group of organisms lacking trpF include all of the Actinobacteridae subclass, except a small group within the Family Corynebacteriaceae () in which the entire trp operon (except for a trpC remnant) has been replaced via LGT (see later section). TrpB Some organisms have two TrpB proteins, one of which complexes with TrpA and functions in Trp formation, while the other (a clearly distinct subhomolog) may act as a serine deaminase [ *37, 38]. It has been proposed that TrpB and the enzyme catalyzing the final step in threonine biosynthesis have a common origin [ 39]. The transfer of whole-pathway and partial-pathway trp operons to other organisms via LGT has been extensively reviewed recently [ 3, 40]. Even where LGT origin of a given operon is clearly evident, it is rare that both the donor and the recipient have been studied experimentally in order to deduce the evolution of altered functional roles and altered regulation. It is exciting that recent publications now allow a comprehensive understanding of trp-operon LGT in the following two examples. Whole-pathway LGT in Corynebacterium A common ancestor of some of the species within the genus Corynebacterium received a complete trp operon from a member of the enteric lineage [ 3, 4]. Genes having the functional role of primary Trp biosynthesis in the recipient have been replaced by genes having the same functional role in the donor. The recipient genome can be pinpointed to an ancestor that existed quite recently at a time after the divergence of C. jeikeium (which does not have the LGT operon; ) but before the divergence of C. glutamicum, C. efficiens, and C. diptheriae (which all have the LGT operon). It is quite interesting that acquisition of the LGT operon has provided the isomerase encoded by trpF, a gene that is otherwise missing from a large group of actinomycete bacteria, as previously discussed. Thus, like most actinomycetes, C. jeikeium relies on the histidine-pathway isomerase (PriA) for dual function in two pathways, whereas the three sister species possess specialized isomerases (one for the Trp pathway and one for the histidine pathway). The transferred operon has the trpC/trpF fusion that is typical of the enteric lineage. cis elements of regulation that were transferred include a leader peptide associated with an attenuator region, as well as an internal promoter. The structural gene for the trpR repressor was not transferred, as might be expected of a regulatory gene unlinked to the biosynthetic structural genes. However, a recent publication shows that this has been compensated for by conscription of LtbR, an IclR-type transcriptional repressor [ **41] that has a highly conserved role in regulation of leucine biosynthesis in actinomycete bacteria. Thus, the Trp pathway of C. glutamicum can be appreciated as a novel evolutionary jump that resulted from a combination of LGT from a distant donor and conscription of a native regulatory gene. Partial-pathway LGT in Pseudomonas aeruginosa P. aeruginosa is a very recent recipient of a trpEG operon from a donor within the enteric lineage, i.e., the proximal fragment of the seven-gene trp operon. As shown by a recent publication [ **42], this exemplifies a case where the genes, which in the donor were dedicated to primary biosynthesis, were recruited for a new specialized function in the recipient (and hence not shown in where only trp genes participating in primary tryptophan biosynthesis are illustrated). The control elements ahead of AS were either not transferred or were discarded. Sensitivity to feedback inhibition by Trp was also lost. The trpEG operon was placed adjacent to the pqsABCDE operon. Together these seven genes encode the gene products which produce 2-heptyl-3-hydroxy-4-quinolone (PQS), a quorum-sensing signaling compound and virulence factor. The two operons are controlled positively by PqsR, and the gene products are primarily expressed during stationary-phase metabolism. Hence, the alien trp genes were assimilated into a different functional context and placed under a completely different control regimen. This represents an extremely recent innovation at the species level since the LGT operon is not present in very close relatives of P. aeruginosa. The LGT event is sufficiently recent that one could deduce that the trpEG donor species might perhaps have been from Vibrio. The genes and operons of the Trp biosynthetic pathway are organized differently in various bacterial species. These differences reflect evolutionary divergence as well as adjustment to unique metabolic capabilities and environmental interactions. Associated with these differences in operon organization are the use of a variety of cis-acting sites and trans-acting proteins in regulating operon transcription. In addition, some organisms may have acquired, in one step, via LGT, an operon that has experienced evolutionary modifications that allow it to provide a new function and/or new regulation. Thus LGT must have also contributed to the operon diversity we now observe. The authors wish to express their appreciation to each other, for their contributions to this article. We also thank the various organizations that provide support for our investigations. E. Merino receives support from the Consejo Nacional de Ciencia y Tecnología (CONACyT 60127-Q) and the Universidad Nacional Autónoma de México (DGAPA IN212708). R. Jensen's research is partially funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services (Contract HHSN266200400042C). C, Yanofsky receives support from the National Science Foundation (MCB-061539). References and recommended reading Papers of particular interest, published recently, have been highlighted as: * of special interest ** of outstanding interest **1. Gutierrez-Preciado A, Jensen RA, Yanofsky C, Merino E. New insights into regulation of the tryptophan biosynthetic operon in Gram-positive bacteria. Trends Genet. 2005;21:432–436. 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Lateral gene transfer and ancient paralogy of operons containing redundant copies of tryptophan-pathway genes in Xylella species and in heterocystous cyanobacteria. Genome Biol. 2003;4:R14. [PubMed] **41. Brune I, Jochmann N, Brinkrolf K, Huser AT, Gerstmeir R, Eikmanns BJ, Kalinowski J, Puhler A, Tauch A. The IclR-type transcriptional repressor LtbR regulates the expression of leucine and tryptophan biosynthesis genes in the amino acid producer Corynebacterium glutamicum. J Bacteriol. 2007;189:2720–2733. [PubMed]The whole-pathway trp operon of C. glutamicum originated via lateral gene transfer, and the key information in this paper completes one of the two best examples that exist for any experimental system where functional roles and regulation are known in both the donor and recipient organisms. **42. Farrow JM, 3rd, Pesci EC. Two distinct pathways supply anthranilate as a precursor of the Pseudomonas quinolone signal. J Bacteriol. 2007;189:3425–3433. 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