This work was supported by grants from the Ministry of Science and Technology of China (grant numbers 2009CB118905 and 2013CB734001) and the National Natural Science Foundation of China (grant number 31030003). (B) Autoregulatory molecules from other streptomycetes. AdpA itself may sense adenine nucleotides: it was very recently shown that AdpA competes with the initiator protein DnaA for binding to the S. coelicolor origin of chromosome replication and that the binding of AdpA to this region was relieved by ATP or ADP (172). Thus, the pathways for different polyethers have different regulatory strategies. Proc. The central line represents the actII-ORF3 to actII-ORF4 region, with the noncoding intergenic region given in white and coding sequences in green. The pseudo-gamma-butyrolactone receptor JadR2 directly represses the transcription of jadR1 in the absence of ethanol and also binds chloramphenicol (Cm) and jadomycins. PubMed  It is repressed both by its own gene product (170) and, in S. coelicolor, by another pleiotropic regulator, BldD (171). U.S.A. 100: 1541–1546. 4: 667–673. 3). (A) The typical two-component system containing a sensor histidine kinase and a cognate response regulator (RR), usually encoded by a pair of adjacent genes. It is notable that the effects of phoP deletion on Streptomyces lividans, a very close relative of S. coelicolor, were quite different: in that organism, in which ACT and RED production is turned off under most conditions, phoP deletion caused strongly increased production of the two antibiotics (73). A suggestion that AfsS might act cooperatively with sigma factors of the ECF subclass, which lack domain 3 (136), seems unlikely given that ECF sigma factors are ubiquitous while AfsS-like proteins are found in only some (not all) streptomycetes. Curr. 6: 617–624. 10). The logic of the two-step negatively acting part of the overall regulatory system is unclear, but in view of the evidence discussed elsewhere in this review, it seems possible that TylQ might be sensitive to a different ligand, perhaps generated by the tylosin pathway, or possibly the product of another biosynthetic pathway in S. fradiae. ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology. Genes associated with the cpk cluster are indicated by large open arrows. Clearly, current knowledge is only the tip of the iceberg. Some reported observations are hard to explain. Other nascent areas expected to generate rapid advances in the near future include chromatin immunoprecipitation (ChIP)-Seq for the analysis of the targets of regulators and nano-DESI analysis of small molecules at the level of individual colonies. Global RegulatorsThe S. coelicolor studies have shown that numerous global regulators transmit various signal inputs, including nutrient availability, translation rates, developmental state, diverse stresses, and other environmental information, to the CSR genes. The regulation of CDA biosynthesis has not been extensively studied, but, by analogy with other gene clusters, it is likely that the SARP CSR encoded by cdaR activates the cda biosynthetic genes. 2): AdpA (a pleiotropic regulator of antibiotic production and development) (30), LexA (a global regulator of the DNA damage response) (28), AbsA2 (a global repressor of antibiotic synthesis [see below]) (31, 32), DasR (mediating the global response to N-acetylglucosamine [see below]) (33), DraR and AfsQ1 (activators responding to nitrogen excess) (34, 35), AtrA (a transcriptional activator, which also binds to targets associated with metabolism of acetyl coenzyme A [acetyl-CoA], an ACT precursor) (32, 36), and the xylose operon repressor ROK7B7 (SCO6008) (37) (Fig. Microbiol. In the three-step CSR cascade controlling daunorubicin production in S. peucetius, the TetR-like product of dnrO activates the diverging gene dnrN, encoding an ARR which then initiates the transcription of dnrI, the SARP product of which turns on daunorubicin (DNR) biosynthesis. 2). These complications are probably partly caused by the complex constellation of other genes affected by PhoP, which include several pleiotropically acting developmental genes that themselves influence antibiotic production (56). Of the 72 SARP genes listed in Table 1, 28 (39%) contain TTA codons, about 10 times more often than the average for all Streptomyces genes, consistent with the notion that UUA codons are significant in regulating antibiotic biosynthesis (see above). At least one global regulator, AfsQ1, directly activates the cdaR promoter (34). 5). Although AfsS is usually thought of as a regulator of antibiotic biosynthetic genes, transcriptome analysis showed that it also has major effects on nutritional starvation genes, which might possibly be responsible for the effects on antibiotic production (136). ScbR has a TetR-like N-terminal helix-turn-helix domain and belongs to a subfamily of such proteins whose founder member, ArpA, senses the gamma-butyrolactone A-factor in Streptomyces griseus (see below). Agents. Activation of Actinorhodin Biosynthesis by Multiple Signal InputsActinorhodin (ACT), a polyketide-derived benzoisochromanequinone (Fig. Other wide-ranging reviews of the topic have also appeared recently (21, 22). Chakraburtty, R. and M. Bibb (1997) The ppGpp synthetase gene (relA) of Streptomyces coelicolor A3(2) plays a conditional role in antibiotic production and morphological differentiation. Another important process involving the production of antibiotics is the symbiosis between Streptomyces and plants, as the antibiotic protects the plant against pathogens, and plant exudates allows the development of Streptomyces. Interestingly, nikkomycin production in a site III mutant is much higher (3-fold) than that in the wild type (179). Comparative genomic analysis of 14 sequenced Streptomyces genomes (G. Chandra and K. F. Chater, unpublished data) has shown that most of the global regulators described in the preceding sections are universal among streptomycetes, with an exception being the whiJ cluster and some of its paralogous clusters. Diverse antibiotics and autoregulator molecules produced by Streptomyces coelicolor A3 (2) and some other streptomycetes. Involvement of other proteases in antibiotic production in other bacteria has been reported (277). This serves as a signaling molecule, binding to the GntR-like regulator DasR and relieving repression of DasR target genes (Fig. Trapezoidal blocks with different colors represent different methods based on gene clusters to activate the possible expression of clusters. For further information and references, see the text. Enter multiple addresses on separate lines or separate them with commas. Its target motif is repeats of the sequence TCGA at 11-bp intervals, which appear in five promoter regions in the act cluster (28, 29). This was the first report that any ARR could be activated by binding to the end product or late biosynthetic intermediates of secondary metabolites. It has proved useful to introduce rpsL and rpoB mutations into strains of S. coelicolor designed to maximize the expression of introduced heterologous sets of biosynthetic genes (255, 256). The jadR1 gene is located upstream of jadJ, the first structural gene of the jadomycin biosynthetic cluster (69). Bacteria of the genus Streptomyces are a particularly abundant source of antibiotics and related compounds, providing more than half of medically important antimicrobial and antitumor agents. The cluster-situated regulator JadR1 activates the biosynthesis of jadomycin B by activating the transcription of biosynthetic structural genes. 82: 501–511. Microbiol. 8: 2013. The influence of AbsC on antibiotic production could possibly be mediated through coelibactin (coelibactin overproduction inhibits sporulation) (115), either in a signaling role or indirectly through changed intracellular zinc levels. Supplementary material, approximately 72.6 KB. Perhaps SARPs sense some physiological parameter that is particularly relevant to polyketide biosynthesis, such as the availability of precursors or the balance between growth-associated fatty acid consumption and starvation-associated lipid degradation. Phosphate Regulation of Antibiotic Production in S. coelicolorUnder laboratory conditions, phosphate limitation of growing cultures activates phosphate scavenging and induces the growth transition that precedes stationary phase and secondary metabolism (70), (71). Two ArpA-like proteins, TylP and TylQ, provide overriding negative control of tylR expression. Mathematical modeling of the scbAR/cpk system has shown that its autoamplifying nature may amount to a developmental commitment to CPK production, by acting as a bistable switch (46, 47). Strains of Streptomyces coelicolor with mutations in the gene ppm1, encoding polyprenol phosphate mannose synthase, and in pmt, encoding a protein O-mannosyltransferase, are resistant to phage ϕC31 and have greatly increased susceptibility to some antibiotics, including vancomycin. The regulatory cascade is complicated by the presence of genes for two ArpA-like proteins (MmyR and MmfR). During coculture, M. xanthus enhanced the production of a siderophore, myxochelin, leading M. xanthus to dominate iron scavenging and S. coelicolor to experience iron-restricted conditions. This work was supported by Research Program to solve social issues of the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2017M3A9E4077234) and National Research Foundation of Korea (NRF) (NRF-2016R1D1A1B03932301), (NRF-2019R1F1A1058805). Very often, there are multiple pathway-associated genes concerned with regulation, permitting signal input at more than one regulatory step. AbsC and Zinc Dependency of Antibiotic ProductionAbout 5% of S. coelicolor proteins are predicted to bind zinc (113). This illuminating study should encourage the use of similar conditions for the activation of antibiotic biosynthesis in other streptomycetes. 3). Microbiology. This, and the TTA codon in adpA (see below), explains why disruption of bldA eliminates biosynthesis of a variety of secondary metabolites in diverse streptomycetes. Bacteria have different types of ATP-dependent proteases, including ClpAP, ClpCP, ClpEP, ClpXP, Lon, FtsH, HslUV, and the recently identified 20S proteasome (274, 275). However, it may be profitable to investigate the possibility that antibiotic production is initiated mainly in compartments that do not have a tip (i.e., are not apical) and in which any AfsK present could therefore not be tip located and might be able to make contact with alternative substrates such as AfsR. K.F.C was supported by a John Innes Foundation Emeritus Fellowship. 6). In two surveys of several two-component systems, the AbrA1A2 system acted negatively on production of ACT, RED, and CDA and the formation of aerial mycelium, while the AbrC1C2C3 system, involving two histidine protein kinases, acted positively on all four aspects (143), and RapA1A2 was shown to stimulate ACT and CPK production (140). However, empirical observations may continue to be useful; for example, it was recently reported that addition of the rare earth scandium to the fermentation medium significantly stimulated the production of actinorhodin in S. coelicolor, of actinomycin in Streptomyces antibioticus, and of streptomycin in S. griseus (247). Liangzhi, L., H. Zheng, and Y. Yingjin (2007) Effect of propionate on streptolydigin production and carbon flux distribution in Streptomyces lydicus AS 4.2501. The Clp complex consists of the proteolytic ClpP subunit and the ATPase regulatory subunit, ClpA, ClpC, ClpE, or ClpX. Bierman, M., R. Logan, K. O’Brien, E. T. Seno, R. N. Rao, and B. E. Schoner (1992) Plasmid cloning vectors for the conjugal transfer of DNA from Escherichia coli to Streptomyces spp. Tax calculation will be finalised during checkout. J. Chem. Chitin is very abundant in soil and is likely to be a major source of carbon and nitrogen for streptomycetes (89). There can be few documented cases of comparably complex regulation of a bacterial promoter, and it will be a challenge for the future to unravel the large number of possible interactions involving regulators binding at separate or overlapping sites. A colony is brought into contact with the droplet, and the solvent-extractable molecules are drawn off and subjected to MS-MS. Covarying fragments are used to identify particular molecular species. Streptomyces coelicolor A3(2) was the first Streptomyces strain to have its genome completely sequenced and is the best-studied Streptomyces strain . S. coelicolor is also the model organism for the actinomycetes, and increasing the level of understanding of the regulation of antibiotic production in this strain may inform new strategies for gaining access to the wide variety of secondary metabolites produced by these organisms. Ryding, N. J., T. B. Anderson, and W. C. Champness (2002) Regulation of the Streptomyces coelicolor calcium-dependent antibiotic by absA, encoding a cluster-linked two-component system. Production of clorobiocin is controlled in part by the cloY gene, and is … Curr. Indeed, there is DNA affinity capture evidence (disputed in reference 114) that AbsC may bind directly to the promoters of actII-ORF4 and redD (38). J. Bacteriol. This approach provides an opportunity to characterize and compare the NAPs associated with the active and repressive portions of the nucleoid (289). No such detailed analysis of the DraRK system has been published. Other regulators also affect CPK biosynthesis. In S. griseus, the adpA promoter is the sole target for the ArpA repressor, which is the sensor for the pleiotropic S. griseus-specific regulatory gamma-butyrolactone molecule A-factor (30). 8: 208–215. This suggests that the coordination of the biosynthesis of disparate antibiotics by receptors of this kind may be widespread in Streptomyces. Sci. About half of them are located very close to genes with homologues in secondary metabolism, and the others are next to diverging genes for medium- or short-chain alcohol dehydrogenases. It is possible that some of the pleiotropic defects of a bldD mutant are attributable to the derepressed expression of nsdA. Streptomyces coelicolor A3 (2) is amongst the best studied representatives of the genus Streptomyces, which is the largest genus within the Actinobacteria. Heterologous Expression in Engineered HostsKnowledge of regulatory factors has informed another method of activating cryptic gene clusters, i.e., heterologous expression of the cluster in different host strains, which is also often used to confirm the integrity of gene clusters synthesizing secondary metabolites (263–265) and for combinatorial biosynthesis to produce novel derivatives of bioactive secondary metabolites. It is therefore not surprising that the timing and levels of production of ACT and RED both depend on the amount of zinc supplied (114). Such studies may suggest ways of increasing production levels, both at the early stages of characterizing new products and at the level of large-scale industrial production. dnrO is repressed by its own product, DnrO, but once daunorubicin or its glycosylated late precursors are produced, they bind to DnrO, derepressing dnrO and apparently activating dnrN (214). After graduation, he worked for 4 years as Associate Research Scholar at The University of Oklahoma Health Sciences Center. Biotechnol Bioproc E 24, 613–621 (2019). - 144.76.157.243. These are among 67 two-component systems encoded in the S. coelicolor chromosome (137). Overexpression of ribosome recycling factor also causes the overproduction of antibiotics, perhaps reflecting enhanced protein synthesis during stationary phase, probably through increased ribosomal stability under amino acid starvation (108). Department of Microbial Engineering, College of Engineering, Konkuk University, Seoul, 05029, Korea, Jong-Min Jeon, Tae-Rim Choi, Bo-Rahm Lee, Hun-Suk Song, Hye-Rim Jung, Soo-Yeon Yang, Jun Young Park & Yung-Hun Yang, Department of Bio and Fermentation Convergence Technology & BK21 Plus Project, Kookmin University, Seoul, 02707, Korea, School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Korea, Institute for Ubiquitous Information Technology and Applications, Konkuk University, Seoul, 05029, Korea, You can also search for this author in This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. 6). These complex data sets will be difficult to interpret until samples are also examined during the antibiotic production phase, and progress has been made on the molecular basis of glucose kinase effects. Streptomyces species produce a vast diversity of secondary metabolites of clinical and biotechnological importance, in particular antibiotics. F1000Res. Curr Microbiol. strain PGA64 resulted in the production of two major angucycline metabolites, UWM6 and rabelomycin, which had not been detected in the parental wild-type strain, and many other metabolites were also produced in the mutant (261). Jeon, J. M., H. Park, H. M. Seo, J. H. Kim, S. K. Bhatia, G. Sathiyanarayanan, H. S. Song, S. H. Park, K. Y. Choi, B. I. A-factor regulates streptomycin biosynthesis in S. griseus (295). Further subtlety is conferred by the ability of TylP to repress both its own gene and that of TylQ. 1), made by a pathway closely similar to that of GBLs (58). Article  The afsR gene is located far from the act and red gene clusters (117, 118), appears to be present in all streptomycetes, and positively regulates the production of diverse antibiotics (119–121). The crystal structure of an MmyB-like protein from a thermophilic Gram-negative organism (purified from an Escherichia coli expression system) revealed that its PAS domain was complexed with a saturated fatty acid, prompting speculation that binding of a fatty acid ligand might be required to confer transcription factor activity on MmyB (61). 6: S9–S14. The UUA codon in adpA mRNA always falls between the segments encoding the two major AdpA domains and accounts largely (but not entirely) for the aerial mycelium-defective phenotype of bldA mutants of S. coelicolor (164, 166). Both genes are part of two-component regulatory systems (DraRK and AfsQ1Q2) that also affect morphological differentiation (35, 64, 65). Interestingly, there are markedly fewer such clusters in S. venezuelae, an organism that grows and sporulates rapidly and produces at least one antibiotic, chloramphenicol (Cm), during vegetative growth (51). In a comprehensive recent paper, AfsQ1 has been revealed as a direct repressor of primary nitrogen assimilation genes and as an activator of several antibiotic biosynthetic regulatory (actII-ORF4, redZ, and cdaR) and structural (cpkA and cpkD) genes, as well as regulating some developmental genes (bldM, whiD, and amfC) (34). It appears to function in the maintenance of C, N, and P balance, as judged by the finding that it also directly represses pstS (phosphate uptake) and binds to promoters of genes for a xylanase (xysA) and a glyceraldehyde 3-phosphate dehydrogenase (gap1) (34) (Fig. It has therefore become necessary to devise methods and strategies to identify physiological signals and regulatory mechanisms that can activate these “cryptic” pathways, thus unleashing the full biosynthetic potential of these prodigious producers of valuable natural products (245, 246). Biotechnol. 7). DasR can also induce transcription of SCO6264, encoding a reductase believed to play a role in modification of the SCB gamma-butyrolactone signaling molecules (88). Microbiol. Since changes of ADP/ATP concentrations significantly affect the binding activity of PolY in vivo, the ATPase domain may sense endogenous ADP/ATP levels. In each case, repressors that sense species-specific gamma-butyrolactones interact with the adpA promoter; and the pleiotropic regulator BldD also represses expression. Similar ATPase domains are also present in CdaR and in two other SARPs of unknown function encoded in the S. coelicolor genome (see below). Keith F. Chater obtained his Ph.D. in Salmonella genetics in 1969 at the University of Birmingham, United Kingdom. Nevertheless, antibiotic production is connected to the S. coelicolor life cycle, and this connection has preoccupied many researchers over several decades. A Special Regulatory Role for the Rare Leucine Codon UUA in Antibiotic ProductionIn Streptomyces genes, with an average GC content of more than 70%, triplets using only T and A residues are rare. Although RED and ACT are very different molecules, ScbR2 structural predictions revealed that its ligand-binding pocket had features reminiscent of QacR and TtgR, other members of the TetR superfamily that possess large helix-rich cavities capable of binding structurally diverse drugs (51, 53, 54). 1) (43). 5, as well as SCO1645, an S. coelicolor protein with unknown function that is very similar to RedZ. However, even though this approach is effective, it is still laborious and obscure. Our preliminary data indicate that a Pup-like protein is a regulator of antibiotic production in S. coelicolor (G. Niu et al., unpublished data). In addition, this work was also supported by polar academic program (PAP, PE18900). In the light of the discovery of the AfsK-DivIVA interaction, the question arises of whether binding of SAM might change the partner choice of AfsK. Deletion of the gene (bldA) for the cognate tRNA does not impair growth but reduces or eliminates the translation of most TTA-containing genes, so it has been assumed that no TTA-containing genes are essential. The initial discovery of SCBs was made possible by their stimulatory effects on pigmented antibiotic production when added exogenously to S. coelicolor cultures, though, paradoxically, eliminating endogenous SCBs by scbA deletion enhanced ACT and RED production (49). Remarkably, AbsA2∼P also binds to and represses the promoters of pathway-specific regulatory genes in some other clusters (actII-ORF4 and redZ, but not cpkO) (31, 32, 65). N-Acetylglucosamine (GlcNAc) released from the cell wall during this process is reimported and phosphorylated by a phosphotransferase-based transport system (PTS) (36, 86). CAS  AfsS may provide some species-specific beneficial modulation of AfsR function by virtue of its (probably mostly indirect) influences on the transcription of various stress response and stationary-phase genes (136). His research focuses on the molecular regulation of secondary metabolites in Streptomyces. Among 236 antibiotic biosynthesis clusters in the sequence database that we collected (Table 1, footnote a), one more strR-like gene was found, at one end of the lankacidin cluster of Streptomyces rochei, but disruption of this gene had no effect on antibiotic production (202). Surprisingly, this motif was also found upstream of some genes unconnected with RED biosynthesis (28). Microbiol. It has been suggested that these clusters may generally determine responses of secondary metabolism and development to environmental signals associated with particular ecological niches (191). Unusually, the A-factor autoregulatory system in S. griseus is determined not by genes close to the streptomycin biosynthetic gene cluster but by scattered genes (afsA and brpA for A-factor biosynthesis and arpA for the A-factor receptor protein ArpA) (177). Ulanova, D., S. Kitani, E. Fukusaki, and T. Nihira (2013) SdrA, a new DeoR family regulator involved in Streptomyces avermitilis morphological development and antibiotic production. Clavulanic acid (Streptomyces clavuligerus ), neomycin (S. marinensis ), chloramphenicol (Streptomyces venezuelae ), the insecticide avermectin (Streptomyces avermitilis ), the immunosuppressant tacrolimus (Streptomyces tsukubaensis ), kanamycin (Streptomyces kanamyceticus ) and potent antitumoral platenolides (Streptomyces platensis ) are only few examples of the 12,400 … Acad. Streptomycetes produce around half of the clinically used antibiotics and other pharmaceutically useful natural products such as anthelmintics, anticancer agents, and immunosuppressives. S. coelicolor produces two pigmented model antibiotics, the red-pigmented antibiotic undecylprodigiosin (RED) and the blue-pigmented antibiotic actinorhodin (ACT) . Regulation of the key pleiotropic regulatory gene adpA. With the newly sequenced genome of Steptomyces coelicolor comes the possibility of deriving still more antibiotics that have so far remained undiscovered.The genes of the unusually large genome of Streptomyces coelicolor are grouped together in clusters, each cluster making a different antibiotic che… Yang, Y. H., E. Song, E. J. Kim, K. Lee, W. S. Kim, S. S. Park, J. S. Hahn, and B. G. Kim (2009) NdgR, an IclR-like regulator involved in amino-acid-dependent growth, quorum sensing, and antibiotic production in Streptomyces coelicolor. Unlike CSR SARPs, these are all present in a significant fraction of streptomycetes. The roles of NanR3 (a putative LacI-like repressor) and the NanT5/NanT3 two-component system (206) remain undetermined. Csrs for carbomycin and spiramycin biosynthesis ( 40 ) including regulatory genes be necessary for transcription of polr by the! Laborious and obscure at this point, but peculiar to, streptomycetes gram-positive. A straightforward strategy, simply to overexpress activators or delete repressors ( 259 ), and directly! Including the whiJ cluster, four of which contain more than one regulatory step least five different antibiotics the... Pseudo-Gbl receptors in S. coelicolor, a few of which will be to. With JadR1 directly in a site III mutant is much higher ( 3-fold ) than that in the field delivering. In 2006 at the University of Oklahoma Health Sciences Center mutant is much (! Shown ) by Streptomyces-triggered fungal histone acetylation modifications ( 251 ) switching between and... 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