title: A γ-butyrolactone-sensing activator/repressor, JadR3, controls a regulatory mini-network for jadomycin biosynthesis.
abstract: Two regulatory genes, jadR2 and jadR3, in the jadomycin (jad) biosynthetic gene cluster of Streptomyces venezuelae encode homologues of γ-butyrolactone receptor. JadR2 was previously shown to be a pseudo γ-butyrolactone receptor. jadR3 is situated at the upstream of jadW123 encoding putative enzymes for γ-butyrolactone biosynthesis. Disruption of jadR3 resulted in markedly decreased production of jadomycin. Transcriptional analysis revealed that JadR3 represses jadW1, jadR2 and jadR3 but activates jadR1, the key activator gene for jadomycin biosynthesis. DNase I footprinting showed that JadR3 has four binding sites in the intergenic regions of jadR2-jadR1 and jadR3-jadW1. A JadR3 interactive molecule, SVB1, was purified from a large-scale fermentation and its structure found to be the same as SCB3, a γ-butyrolactone from Streptomyces coelicolor, and was absent from a jadW123 mutant lacking jadomycin production. Addition of SVB1 or extract from S. coelicolor to the mutant restored jadomycin production. Overall, our results revealed that the association of JadR3 and SVB1 plays an important role in controlling a regulatory mini-network governing jadomycin biosynthesis, providing new insights into the ways in which γ-butyrolactone/receptor systems modulate antibiotic biosynthesis in Streptomyces.
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Zhengzhong
authors.initials: Z
authors.lastname: Zou
authors.forename: Deyao
authors.initials: D
authors.lastname: Du
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jihui
authors.initials: J
authors.lastname: Zhang
authors.forename: Guoqing
authors.initials: G
authors.lastname: Niu
authors.forename: Huarong
authors.initials: H
authors.lastname: Tan
mesh_terms: D015107:4-Butyrolactone / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001665:Binding Sites; D018983:DNA Footprinting; D004269:DNA, Bacterial / Q000378:metabolism; D021901:DNA, Intergenic / Q000378:metabolism; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D053263:Gene Regulatory Networks; D007546:Isoquinolines / Q000378:metabolism*; D016254:Mutagenesis, Insertional; D009285:Naphthoquinones / Q000378:metabolism*; D011485:Protein Binding; D064210:Secondary Metabolism; D015398:Signal Transduction; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D021901:DNA, Intergenic; D007546:Isoquinolines; D009285:Naphthoquinones; D014157:Transcription Factors; C506597:jadomycin A; D015107:4-Butyrolactone