Bidirectional Regulation of AdpAch in Controlling the Expression of scnRI and scnRII in the Natamycin Biosynthesis of Streptomyces chattanoogensis L10

Yu, Ping; Bu, Qing-Ting; Yu-qi, Tang; Mao, Xu‐Ming; Li, Yongquan

doi:10.3389/fmicb.2018.00316

Cited by 13 publications

(5 citation statements)

References 39 publications

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“…The role of AdpA in sanG transcription is complicated by the presence of five AdpA-binding sites (I–V) in the upstream region of sanG ; two (I and V) are used for activation of sanG transcription, while the other three (II, III, and IV) lead to repression [ 55 ]. Similar findings have been reported in AdpA regulation of natamycin biosynthesis in S. chattanoogensis [ 56 ]. However, a recent study suggests that AdpA acts as a repressor of oviedomycin biosynthesis by directly inhibiting the transcription of cluster-associated activator ovmZ / ovmW [ 57 ].…”

Section: Cascade Regulation Of Antibiotic Biosynthesis In Actinomycetsupporting

confidence: 90%

Regulation of antibiotic biosynthesis in actinomycetes: Perspectives and challenges

Wei

Niu

2018

Synthetic and Systems Biotechnology

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Actinomycetes are the main sources of antibiotics. The onset and level of production of each antibiotic is subject to complex control by multi-level regulators. These regulators exert their functions at hierarchical levels. At the lower level, cluster-situated regulators (CSRs) directly control the transcription of neighboring genes within the gene cluster. Higher-level pleiotropic and global regulators exert their functions mainly through modulating the transcription of CSRs. Advances in understanding of the regulation of antibiotic biosynthesis in actinomycetes have inspired us to engineer these regulators for strain improvement and antibiotic discovery.

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Section: Cascade Regulation Of Antibiotic Biosynthesis In Actinomycetsupporting

confidence: 90%

Regulation of antibiotic biosynthesis in actinomycetes: Perspectives and challenges

Wei

Niu

2018

Synthetic and Systems Biotechnology

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“…As for another putative AdpA binding sites, we presumed it might recruit RNA polymerase after interacting with AdpA lin and thus the overall effect of AdpA lin on its own promoter appeared to be positive. In the natamycin producer S. chattanoogensis , AdpA ch was an activator of natamycin biosynthesis, and 6 AdpA binding sites were identified in the scnRI-scnRII intergenic region (Du et al, 2011; Yu et al, 2018). It is notable that although the general effect of AdpA ch on the transcription of scnRI is positive, AdpA binding site A and B serve as repression sites.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, AdpA regulates streptomycin biosynthesis positively and indirectly (Tomono et al, 2005). Similarly, for the biosynthesis of grixazone (Higashi et al, 2007), nikkomycin (Pan et al, 2009), and natamycin (Yu et al, 2018), AdpA activates the transcription of CSRs in their BGCs and indirectly regulates antibiotic biosynthesis. On the other hand, AdpA has a negative impact on oviedomycin biosynthesis in S. ansochromogenes by repressing the transcription of CSR (Xu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

AdpAlin, a Pleiotropic Transcriptional Regulator, Is Involved in the Cascade Regulation of Lincomycin Biosynthesis in Streptomyces lincolnensis

et al. 2019

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Lincomycin is one of the most important antibiotics in clinical practice. To further understand the regulatory mechanism on lincomycin biosynthesis, we investigated a pleiotropic transcriptional regulator AdpAlin in the lincomycin producer Streptomyces lincolnensis NRRL 2936. Deletion of adpAlin (which generated ΔadpAlin) interrupted lincomycin biosynthesis and impaired the morphological differentiation. We also found that putative AdpA binding sites were unusually scattered in the promoters of all the 8 putative operons in the lincomycin biosynthetic gene cluster (BGC). In ΔadpAlin, transcript levels of structural genes in 8 putative operons were decreased with varying degrees, and electrophoretic mobility shift assays (EMSAs) confirmed that AdpAlin activated the overall putative operons via directly binding to their promoter regions. Thus, we speculated that the entire lincomycin biosynthesis is under the control of AdpAlin. Besides, AdpAlin participated in lincomycin biosynthesis by binding to the promoter of lmbU which encoded a cluster sited regulator (CSR) LmbU of lincomycin biosynthesis. Results of qRT-PCR and catechol dioxygenase activity assay showed that AdpAlin activated the transcription of lmbU. In addition, AdpAlin activated the transcription of the bldA by binding to its promoter, suggesting that AdpAlin indirectly participated in lincomycin biosynthesis and morphological differentiation. Uncommon but understandable, AdpAlin auto-activated its own transcription via binding to its own promoter region. In conclusion, we provided a molecular mechanism around the effect of AdpAlin on lincomycin biosynthesis in S. lincolnensis, and revealed a cascade regulation of lincomycin biosynthesis by AdpAlin, LmbU, and BldA.

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“…AdpA also activates the transcription of strR, the pathway-specific regulatory gene for streptomycin. Other examples of AdpA positively regulating antibiotic biosynthesis through the control of cluster-situated regulators (CSRs) have been found in Streptomyces clavuligerus (15), Streptomyces avermitilis (16), Streptomyces chattanoogensis (12,17), and Streptomyces roseosporus (10). Since the goal of "one strain-many compounds" is attractive when performing genome mining in Streptomyces (18), the different effects of AdpA on the production of multiple secondary products in a single Streptomyces host have been studied with S. ansochromogenes.…”

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confidence: 99%

A Novel AdpA Homologue Negatively Regulates Morphological Differentiation in Streptomyces xiamenensis 318

Weng

et al. 2019

Appl Environ Microbiol

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The pleiotropic transcriptional regulator AdpA positively controls morphological differentiation and regulates secondary metabolism in most Streptomyces species. Streptomyces xiamenensis 318 has a linear chromosome 5.96 Mb in size. How AdpA affects secondary metabolism and morphological differentiation in such a naturally minimized genomic background is unknown. Here, we demonstrated that AdpASx, an AdpA orthologue in S. xiamenensis, negatively regulates cell growth and sporulation and bidirectionally regulates the biosynthesis of xiamenmycin and polycyclic tetramate macrolactams (PTMs) in S. xiamenensis 318. Overexpression of the adpASx gene in S. xiamenensis 318 had negative effects on morphological differentiation and resulted in reduced transcription of putative ssgA, ftsZ, ftsH, amfC, whiB, wblA1, wblA2, wblE, and a gene encoding sporulation-associated protein (sxim_29740), whereas the transcription of putative bldD and bldA genes was upregulated. Overexpression of adpASx led to significantly enhanced production of xiamenmycin but had detrimental effects on the production of PTMs. As expected, the transcriptional level of the xim gene cluster was upregulated, whereas the PTM gene cluster was downregulated. Moreover, AdpASx negatively regulated the transcription of its own gene. Electrophoretic mobility shift assays revealed that AdpASx can bind the promoter regions of structural genes of both the xim and PTM gene clusters as well as to the promoter regions of genes potentially involved in the cell growth and differentiation of S. xiamenensis 318. We report that an AdpA homologue has negative effects on morphological differentiation in S. xiamenensis 318, a finding confirmed when AdpASx was introduced into the heterologous host Streptomyces lividans TK24. IMPORTANCE AdpA is a key regulator of secondary metabolism and morphological differentiation in Streptomyces species. However, AdpA had not been reported to negatively regulate morphological differentiation. Here, we characterized the regulatory role of AdpASx in Streptomyces xiamenensis 318, which has a naturally streamlined genome. In this strain, AdpASx negatively regulated cell growth and morphological differentiation by directly controlling genes associated with these functions. AdpASx also bidirectionally controlled the biosynthesis of xiamenmycin and PTMs by directly regulating their gene clusters rather than through other regulators. Our findings provide additional evidence for the versatility of AdpA in regulating morphological differentiation and secondary metabolism in Streptomyces.

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Bidirectional Regulation of AdpAch in Controlling the Expression of scnRI and scnRII in the Natamycin Biosynthesis of Streptomyces chattanoogensis L10

Cited by 13 publications

References 39 publications

Regulation of antibiotic biosynthesis in actinomycetes: Perspectives and challenges

Regulation of antibiotic biosynthesis in actinomycetes: Perspectives and challenges

AdpAlin, a Pleiotropic Transcriptional Regulator, Is Involved in the Cascade Regulation of Lincomycin Biosynthesis in Streptomyces lincolnensis

A Novel AdpA Homologue Negatively Regulates Morphological Differentiation in Streptomyces xiamenensis 318

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