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. In 1992, he started to work on the molecular regulation of differentiation and secondary metabolites in Streptomyces. These small, redox- and nitric oxide-sensitive iron-sulfur proteins are widespread in actinobacteria and are absent from all other bacteria (195). It is very common for a TTA codon to be present in cluster-situated regulatory genes: among 143 secondary metabolic biosynthetic gene clusters, 109 included TTA-containing genes, most of which encoded regulators (159). This enhanced production is mediated at least partially at the level of regulation of the relevant biosynthetic genes and their CSR regulatory genes. Phosphorylation of PhoP presumably enhances DNA binding. ATP or GTP is used for autophosphorylation by the histidine kinase, and the phosphoryl group is transferred to the RR, which then controls the transcription of target genes. PubMed  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). Such layered regulation has been called “pyramidal” or “cascade” regulation, though neither term seems apposite for systems in which multiple inputs drive a process forward (“confluent regulation” might be more accurate). PhoR is a membrane-bound sensor kinase that senses phosphate deprivation and then phosphorylates PhoP, its target response regulator, which binds to specific sequences in target promoters (Streptomyces PHO boxes, which are degenerate versions of consensus GTTCACC usually repeated at 11-bp intervals), to influence their expression (56, 78). The feasibility of this concept was first exemplified by the activation of ACT production in S. lividans, in which the act genes are normally not expressed (107). Chitin is very abundant in soil and is likely to be a major source of carbon and nitrogen for streptomycetes (89). Abstract. In this comparative genomic analysis, apparent orthologues of many of the global regulatory genes were also found in actinomycetes other than streptomycetes, often including morphologically and metabolically simple genera with small genomes. The authors equally contributed to this study. Likewise, bialaphos production in Streptomyces hygroscopicus (99) and production of clavulanic acid and cephalomycin in Streptomyces clavuligerus (100) were reported to be stimulated by (p)ppGpp accumulation. Biotechnol Bioproc E 24, 613–621 (2019). Therefore, miniaturized high-throughput screening methods need to be used. J. Biotechnol. His research focuses mainly on the regulation of microbial antibiotic production. 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. PubMed  We evaluated the relative frequencies of the three SARP classes and their association with different classes of antibiotics (Table 1). It was found that AfsK is almost entirely located at hyphal tips, where DivIVA is concentrated, as part of a “polarisome” that controls tip extension (Fig. 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. MmyB can then activate the MM biosynthetic genes. Remarkably, S. coelicolor AfsK is also implicated in the phosphorylation of a key determinant of mycelial polar growth, DivIVA (129). Mol Microbiol 21: 385–396. Virginiae butanolides (VBs) induce the coordinated production of virginiamycin M and virginiamycin S, synergistically acting but biosynthetically distinct antibiotics in S. virginiae (235). AfsR (993 amino acids [aa]) has an N-terminal SARP domain, a central NB-ARC-like ATPase domain that may act as a molecular switch (122), and a C-terminal possible tetratricopeptide repeat (TPR) domain suggesting protein-protein interaction (SMART database) (123). Similarly, the activation of the cryptic cpk gene cluster and production of a novel antibiotic followed the deletion of scbR2 in S. coelicolor (41), and transcription of cpk genes was also markedly increased in a mutant lacking the master regulator DasR (33). Google Scholar. Of course, some of the wide-ranging effects may be indirect, ranging from the consequences of draining pools of precursors to physicochemical properties of the end products such as redox activity (27). Streptomycetes have a remarkably complex developmental life cycle and the capacity to produce a plethora of natural products. Although there is not enough evidence to confirm that changes to ribosome structure contribute to the onset of antibiotic production, it has been reported that ribosome structure determines translation accuracy and speed (110). 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). The specific sequences recognized by SARPs generally overlap the −35 regions of their targets, but sometimes the sequences are far from the transcriptional start point (tsp) of their target genes. A complex role for the g-butyrolactone SCB1 in regulating antibiotic production in Streptomyces coelicolor A3(2) ErikoTakano,1*RekhaChakraburtty,1† TakuyaNihira,2 Yashuhiro Yamada2‡ and Mervyn J. Bibb1† 1Department of Molecular Microbiology, John … A Survey of SARPsAs shown above, SARPs are the most frequently encountered CSRs in S. coelicolor and are associated with antibiotic biosynthetic clusters in many other streptomycetes. The N-terminal winged helix-turn-helix (HTH) DNA-binding motif of SARPs binds repeated motifs (often heptamers) at an 11-nt spacing, and the adjacent transcriptional activation domain switches on the expression of target antibiotic production genes (29). RedZ belongs to the NarL family ARRs, which include DnrN, which is required for daunorubicin (DNR) biosynthesis in S. peucetius (209) (Fig. nagE2 is also subject to repression by the GlcNAc-sensing pleiotropic regulator DasR (20, 36). Thus, JdB interacts with JadR1 directly in a dose-dependent manner (Fig. Article  It is not in use pharmaceutically at this point, but it may be used as a starting material to make new antibiotics. It is therefore possible that depletion of adenine nucleotides may affect the autoregulation of adpA expression, consistent with the observation that intracellular ATP levels are low at the onset of antibiotic production (173). atrA is regulated by the PhoRP system, providing a link with phosphate availability, and a further nutritional link is provided by the activation by AtrA of nagE2, encoding the GlcNAc permease. Both genes are part of two-component regulatory systems (DraRK and AfsQ1Q2) that also affect morphological differentiation (35, 64, 65). Biotechnology and Bioprocess Engineering The angucycline antibiotic jadomycin B (JdB) produced by Streptomyces venezuelae has been found here to induce complex survival responses in Streptomyces coelicolor at subinhibitory concentration. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. https://doi.org/10.1007/s12257-019-0084-8. End product-mediated feedback regulation has also been found with CSRs of a different type. 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). Natl. The regulatory cascade is complicated by the presence of genes for two ArpA-like proteins (MmyR and MmfR). StrR does not resemble other characterized proteins, except in possessing a likely ATPase domain like those of ParA partitioning proteins. A further role in cross talk between the CPK, ACT, and RED pathways is played by ScbR2, the gene for which is located close to the SARP gene cpkO. Strategies for the activation of cryptic secondary metabolic gene clusters in Streptomyces. In 1994, he was appointed as Full Professor in molecular microbiology at the Institute of Microbiology, Chinese Academy of Sciences (CAS), and in 1999 to 2008, he was the Deputy Director of the Institute of Microbiology, CAS. Cascade Regulation of Methylenomycin BiosynthesisThe methylenomycin (MM) biosynthetic pathway of S. coelicolor is encoded by the mmy genes on a large linear plasmid, SCP1, which can remain autonomous or integrate into the chromosome (4). Only one of the paralogues, SCO4944, is widely conserved in other streptomycetes, and in S. griseus this gene is just one gene away from the biosynthetic gene for A-factor and is regulated by A-factor (61). From this point of view, relatively simple regulatory interfaces of gene clusters for antibiotic production with the ubiquitous global regulatory systems might be sufficient to ensure appropriate timing of antibiotic production in any host that the gene cluster enters through horizontal gene transfer, at least under some conditions in which production has a selective advantage. Streptomyces coelicolor A3(2) was the first Streptomyces strain to have its genome completely sequenced and is the best-studied Streptomyces strain . Slowing of translation speed when growth slows may enhance folding of nascent antibiotic biosynthetic proteins, thus enhancing antibiotic production (Y. Pan et al., unpublished data). 7) (112). In the case of ACT, the effect of NsdA is exerted, directly or indirectly, via actII-ORF4 (188). There appears to be no information about whether endogenous SAM levels increase as growth comes to a stop (for example, if methionine is shunted to SAM biosynthesis when protein synthesis slows down). pp. It is repressed both by its own gene product (170) and, in S. coelicolor, by another pleiotropic regulator, BldD (171). This illuminating study should encourage the use of similar conditions for the activation of antibiotic biosynthesis in other streptomycetes. It has been pointed out that all the examples of large SARP CSRs are in pathways for antifungal antibiotics, leading to the suggestion that such SARPs might recognize a common signal related to this antifungal activity (220). Bioprocess Biosyst. Microbiology. This gene is repressed both directly and indirectly by HpdR, an IclR-type protein encoded by a nearby gene (111) (Fig. Article  Tax calculation will be finalised during checkout. JadR1 also represses the production of Cm by binding to the promoters of the structural genes (51). However, it is not known whether any of the KbpA paralogues interact with protein kinases. These ActII-ORF4-like SARPs are referred to here as “small SARPs.” Members of a second class of SARP CSRs (“medium SARPs”) resemble CdaR in being around 600 aa long, and these all show end-to-end similarity to each other (229). 10). 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. Gene. This results in cross-recognition of some sites (especially those in the promoters of nitrogen assimilation genes), leading to actual competition between GlnR activation and AfsQ1 repression (34). F1000Res. 128: 635–659. The pleiotropic effects of A-factor in S. griseus are manifested entirely via AdpA. Some of the conserved clusters determine the production of metabolites with roles in the physiology or development of the host, including metal-binding siderophores, spore pigments, and volatile odor compounds (notably geosmin, which is responsible for the earthy smell of streptomycetes). strain TP-A0584 (257, 258), and desferrioxamine E, a siderophore secreted by S. griseus (257, 258). polR itself is activated by another large SARP, PolY, the product of the adjacent gene (232). Some ARRs can be activated by binding to the end product or late biosynthetic intermediates of secondary metabolites, such as antibiotics (see the text). 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