A novel TetR family transcriptional regulator, SAV576, negatively controls avermectin biosynthesis in Streptomyces avermitilis

• Published in: PloS one Vol. 8; no. 8; p. e71330
• Main Authors: Guo, Jia, Zhang, Xuan, Luo, Shuai, He, Fei, Chen, Zhi, Wen, Ying, Li, Jilun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.08.2013; Public Library of Science (PLoS)
• Subjects: Agriculture; Animal health; Antibiotics; Avermectin; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Base Sequence; Binding Sites; Biology; Biosynthesis; Biotechnology; Chromosome Mapping; Chromosomes, Bacterial; Cloning; Conserved sequence; Cytochrome; Cytochrome P450; Deoxyribonuclease; Deoxyribonucleic acid; DNA; DNA, Intergenic; E coli; Footprinting; Gene Deletion; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Gene Order; Genes; Genetic aspects; Genetic engineering; Genetic transcription; Genomes; Health aspects; Health care; Ivermectin - analogs & derivatives; Ivermectin - metabolism; Laboratories; Metabolites; Molecular Sequence Data; Mutagenesis; Mutation; NADP; NADPH-ferrihemoprotein reductase; Nucleases; Physiological aspects; Plasmids; Promoter Regions, Genetic; Protein Binding; Regulators; Streptomyces; Streptomyces - genetics; Streptomyces - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription; Transcription, Genetic; Beijing China; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0071330

Avermectins produced by Streptomyces avermitilis are potent anti-parasitic agents that are useful in animal health care, agriculture, and the treatment of human infections. In a search for novel regulators that affect avermectin biosynthesis, comparative transcriptome analysis was performed between wild-type strain ATCC31267 and avermectin overproducing strain 76-02-e, revealing some differentially expressed genes. SAV576, which is downregulated in 76-02-e and encodes a TetR family transcriptional regulator (TFR), was shown to inhibit avermectin production by indirectly affecting the expression of ave genes. SAV576 directly repressed the transcription of its gene SAV576 and of adjacent genes SAV575 (encodes cytochrome P450/NADPH-ferrihemoprotein reductase) and SAV574. The SAV576-binding sites within the bidirectional SAV575-SAV576 promoter region were determined by DNase I footprinting assays. A consensus 15-bp palindromic sequence CCRTACRVYGTATGS was found in these binding sites and shown to be important for SAV576-binding activity. SAV575, an important target gene of SAV576, was shown to exert a positive effect on avermectin production. The study findings extend our limited knowledge of the complex regulation of avermectin biosynthesis and provide a basis for rational genetic manipulation of S. avermitilis to improve avermectin production through control of SAV576 and its target gene.