title: 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.
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032.|the University of Chinese Academy of Sciences, Beijing 100049.
authors.forename: Juan-Mei
authors.initials: JM
authors.lastname: He
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032.
authors.forename: Guo-Song
authors.initials: GS
authors.lastname: Zheng
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032.
authors.forename: Pan-Pan
authors.initials: PP
authors.lastname: Liu
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Zhao
authors.affiliation: the College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, yzgqzhu@yzu.edu.cn.
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Zhu
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, whjiang@sibs.ac.cn.|the Jiangsu National Synergetic Innovation Center for Advanced Materials, SICAM, Nanjing 210009, and.
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Jiang
authors.affiliation: From the Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, yhlu@sibs.ac.cn.|the Shanghai Collaborative Innovation Center for Biomanufacturing Technology, Shanghai 200237, China.
authors.forename: Yin-Hua
authors.initials: YH
authors.lastname: Lu
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000378:metabolism; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; C082451:GlnR protein, Streptomyces coelicolor; D015534:Trans-Activators; D007559:Ivermectin; C019264:avermectin
keywords: actinobacteria; gene regulation; nitrogen metabolism; secondary metabolism; transcription regulation