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Direct Involvement of the Master Nitrogen Metabolism Regulator GlnR in Antibiotic Biosynthesis in Streptomyces.

ABSTRACT: GlnR, an OmpR-like orphan two-component system response regulator, is a master regulator of nitrogen metabolism in the genus Streptomyces In this work, evidence that GlnR is also directly involved in the regulation of antibiotic biosynthesis is provided. In the model strain Streptomyces coelicolor M145, an in-frame deletion of glnR resulted in markedly increased actinorhodin (ACT) production but reduced undecylprodigiosin (RED) biosynthesis when exposed to R2YE culture medium. Transcriptional analysis coupled with DNA binding studies revealed that GlnR represses ACT but activates RED production directly via the pathway-specific activator genes actII-ORF4 and redZ, respectively. The precise GlnR-binding sites upstream of these two target genes were defined. In addition, the direct involvement of GlnR in antibiotic biosynthesis was further identified in Streptomyces avermitilis, which produces the important anthelmintic agent avermectin. We found that S. avermitilis GlnR (GlnRsav) could stimulate avermectin but repress oligomycin production directly through the respective pathway-specific activator genes, aveR and olmRI/RII To the best of our knowledge, this report describes the first experimental evidence demonstrating that GlnR regulates antibiotic biosynthesis directly through pathway-specific regulators in Streptomyces Our results suggest that GlnR-mediated regulation of antibiotic biosynthesis is likely to be universal in streptomycetes. These findings also indicate that GlnR is not only a master nitrogen regulator but also an important controller of secondary metabolism, which may help to balance nitrogen metabolism and antibiotic biosynthesis in streptomycetes.

SUBMITTER: He JM

PROVIDER: S-EPMC5159505 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Direct Involvement of the Master Nitrogen Metabolism Regulator GlnR in Antibiotic Biosynthesis in Streptomyces.

He Juan-Mei JM Zhu Hong H Zheng Guo-Song GS Liu Pan-Pan PP Wang Jin J Zhao Guo-Ping GP Zhu Guo-Qiang GQ Jiang Wei-Hong WH Lu Yin-Hua YH

The Journal of biological chemistry 20161108 51

GlnR, an OmpR-like orphan two-component system response regulator, is a master regulator of nitrogen metabolism in the genus Streptomyces In this work, evidence that GlnR is also directly involved in the regulation of antibiotic biosynthesis is provided. In the model strain Streptomyces coelicolor M145, an in-frame deletion of glnR resulted in markedly increased actinorhodin (ACT) production but reduced undecylprodigiosin (RED) biosynthesis when exposed to R2YE culture medium. Transcriptional an ...[more]

PMID: 27875313

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Project description:Regulation of antibiotic production by Streptomyces is complex. We report that the response regulator MtrA is a master regulator for antibiotic production in Streptomyces Deletion of MtrA altered production of actinorhodin, undecylprodigiosin, calcium-dependent antibiotic, and the yellow-pigmented type I polyketide and resulted in altered expression of the corresponding gene clusters in S. coelicolor Integrated in vitro and in vivo analyses identified MtrA binding sites upstream of cdaR, actII-orf4, and redZ and between cpkA and cpkD MtrA disruption also led to marked changes in chloramphenicol and jadomycin production and in transcription of their biosynthetic gene clusters (cml and jad, respectively) in S. venezuelae, and MtrA sites were identified within cml and jad MtrA also recognized predicted sites within the avermectin and oligomycin pathways in S. avermitilis and in the validamycin gene cluster of S. hygroscopicus The regulator GlnR competed for several MtrA sites and impacted production of some antibiotics, but its effects were generally less dramatic than those of MtrA. Additional potential MtrA sites were identified in a range of other antibiotic biosynthetic gene clusters in Streptomyces species and other actinobacteria. Overall, our study suggests a universal role for MtrA in antibiotic production in Streptomyces and potentially other actinobacteria.IMPORTANCE In natural environments, the ability to produce antibiotics helps the producing host to compete with surrounding microbes. In Streptomyces, increasing evidence suggests that the regulation of antibiotic production is complex, involving multiple regulatory factors. The regulatory factor MtrA is known to have additional roles beyond controlling development, and using bioassays, transcriptional studies, and DNA-binding assays, our study identified MtrA recognition sequences within multiple antibiotic pathways and indicated that MtrA directly controls the production of multiple antibiotics. Our analyses further suggest that this role of MtrA is evolutionarily conserved in Streptomyces species, as well as in other actinobacterial species, and also suggest that MtrA is a major regulatory factor in antibiotic production and in the survival of actinobacteria in nature.

Project description:Paenibacillus polymyxa WLY78, a N2-fixing bacterium, has great potential use as a biofertilizer in agriculture. Recently, we have revealed that GlnR positively and negatively regulates the transcription of the nif (nitrogen fixation) operon (nifBHDKENXhesAnifV) in P. polymyxa WLY78 by binding to two loci of the nif promoter according to nitrogen availability. However, the regulatory mechanisms of nitrogen metabolism mediated by GlnR in the Paenibacillus genus remain unclear. In this study, we have revealed that glutamine synthetase (GS) and GlnR in P. polymyxa WLY78 play a key role in the regulation of nitrogen metabolism. P. polymyxa GS (encoded by glnA within glnRA) and GS1 (encoded by glnA1) belong to distinct groups: GSI-α and GSI-β. Both GS and GS1 have the enzyme activity to convert NH4+ and glutamate into glutamine, but only GS is involved in the repression by GlnR. GlnR represses transcription of glnRA under excess nitrogen, while it activates the expression of glnA1 under nitrogen limitation. GlnR simultaneously activates and represses the expression of amtBglnK and gcvH in response to nitrogen availability. Also, GlnR regulates the expression of nasA, nasD1D2, nasT, glnQHMP, and glnS. IMPORTANCE In this study, we have revealed that Paenibacillus polymyxa GlnR uses multiple mechanisms to regulate nitrogen metabolism. GlnR activates or represses or simultaneously activates and inhibits the transcription of nitrogen metabolism genes in response to nitrogen availability. The multiple regulation mechanisms employed by P. polymyxa GlnR are very different from Bacillus subtilis GlnR which represses nitrogen metabolism under excess nitrogen. Both GS encoded by glnA within the glnRA operon and GS1 encoded by glnA1 in P. polymyxa WLY78 are involved in ammonium assimilation, but only GS is required for regulating GlnR activity. The work not only provides significant insight into understanding the interplay of GlnR and GS in nitrogen metabolism but also provides guidance for improving nitrogen fixation efficiency by modulating nitrogen metabolism.

Dataset Information

Direct Involvement of the Master Nitrogen Metabolism Regulator GlnR in Antibiotic Biosynthesis in Streptomyces.

Publications

Direct Involvement of the Master Nitrogen Metabolism Regulator GlnR in Antibiotic Biosynthesis in Streptomyces.

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