title: Binding of a biosynthetic intermediate to AtrA modulates the production of lidamycin by Streptomyces globisporus.
abstract: The control of secondary production in streptomycetes involves the funneling of environmental and physiological signals to the cluster-situated (transcriptional) regulators (CSRs) of the biosynthetic genes. For some systems, the binding of biosynthetic products to the CSR has been shown to provide negative feedback. Here we show for the production of lidamycin (C-1027), a clinically relevant antitumor agent, by Streptomyces globisporus that negative feedback can extend to a point higher in the regulatory cascade. We show that the DNA-binding activity of the S. globisporus orthologue of AtrA, which was initially described as a transcriptional activator of actinorhodin biosynthesis in S. coelicolor, is inhibited by the binding of heptaene, a biosynthetic intermediate of lidamycin. Additional experiments described here show that S. globisporus AtrA binds in vivo as well as in vitro to the promoter region of the gene encoding SgcR1, one of the CSRs of lidamycin production. The feedback to the pleiotropic regulator AtrA is likely to provide a mechanism for coordinating the production of lidamycin with that of other secondary metabolites. The activity of AtrA is also regulated by actinorhodin. As AtrA is evolutionarily conserved, negative feedback of the type described here may be widespread within the streptomycetes.
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Xingxing
authors: X
authors: Li
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Tengfei
authors: T
authors: Yu
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Qing
authors: Q
authors: He
authors: Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
authors: Kenneth J
authors: KJ
authors: McDowall
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Bingya
authors: B
authors: Jiang
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Zhibo
authors: Z
authors: Jiang
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Linzhuan
authors: L
authors: Wu
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Guangwei
authors: G
authors: Li
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Qinglian
authors: Q
authors: Li
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Songmei
authors: S
authors: Wang
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Yuanyuan
authors: Y
authors: Shi
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Lifei
authors: L
authors: Wang
authors: The Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors: Bin
authors: B
authors: Hong
mesh_terms: D000617:Aminoglycosides / Q000096:biosynthesis*; D000890:Anti-Infective Agents / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis; D001426:Bacterial Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D053281:Enediynes; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013302:Streptomyces / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000617:Aminoglycosides; D000890:Anti-Infective Agents; D000903:Antibiotics, Antineoplastic; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D053281:Enediynes; D014157:Transcription Factors; C058024:C 1027