title: Pleiotropic regulatory genes bldA, adpA and absB are implicated in production of phosphoglycolipid antibiotic moenomycin.
abstract: Unlike the majority of actinomycete secondary metabolic pathways, the biosynthesis of peptidoglycan glycosyltransferase inhibitor moenomycin in Streptomyces ghanaensis does not involve any cluster-situated regulators (CSRs). This raises questions about the regulatory signals that initiate and sustain moenomycin production. We now show that three pleiotropic regulatory genes for Streptomyces morphogenesis and antibiotic production-bldA, adpA and absB-exert multi-layered control over moenomycin biosynthesis in native and heterologous producers. The bldA gene for tRNA(Leu)UAA is required for the translation of rare UUA codons within two key moenomycin biosynthetic genes (moe), moeO5 and moeE5. It also indirectly influences moenomycin production by controlling the translation of the UUA-containing adpA and, probably, other as-yet-unknown repressor gene(s). AdpA binds key moe promoters and activates them. Furthermore, AdpA interacts with the bldA promoter, thus impacting translation of bldA-dependent mRNAs-that of adpA and several moe genes. Both adpA expression and moenomycin production are increased in an absB-deficient background, most probably because AbsB normally limits adpA mRNA abundance through ribonucleolytic cleavage. Our work highlights an underappreciated strategy for secondary metabolism regulation, in which the interaction between structural genes and pleiotropic regulators is not mediated by CSRs. This strategy might be relevant for a growing number of CSR-free gene clusters unearthed during actinomycete genome mining.
authors.affiliation: Department of Genetics and Biotechnology, Ivan Franko National University of Lviv, Hrushevskoho st. 4, Lviv 79005, Ukraine.
authors.forename: Roman
authors.initials: R
authors.lastname: Makitrynskyy
authors.forename: Bohdan
authors.initials: B
authors.lastname: Ostash
authors.forename: Olga
authors.initials: O
authors.lastname: Tsypik
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Rebets
authors.forename: Emma
authors.initials: E
authors.lastname: Doud
authors.forename: Timothy
authors.initials: T
authors.lastname: Meredith
authors.forename: Andriy
authors.initials: A
authors.lastname: Luzhetskyy
authors.forename: Andreas
authors.initials: A
authors.lastname: Bechthold
authors.forename: Suzanne
authors.initials: S
authors.lastname: Walker
authors.forename: Victor
authors.initials: V
authors.lastname: Fedorenko
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D003062:Codon; D003198:Computer Simulation; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D005809:Genes, Regulator; D016680:Genome, Bacterial; D009154:Mutation; D009844:Oligosaccharides / Q000096:biosynthesis*; D046928:Peptidoglycan Glycosyltransferase / Q000037:antagonists & inhibitors; D011401:Promoter Regions, Genetic; D012329:RNA, Bacterial; D012356:RNA, Transfer, Leu / Q000235:genetics / Q000378:metabolism; D064210:Secondary Metabolism / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003062:Codon; D009844:Oligosaccharides; D012329:RNA, Bacterial; D012356:RNA, Transfer, Leu; D015534:Trans-Activators; D046928:Peptidoglycan Glycosyltransferase; C419802:moenomycin
keywords: Streptomyces; absB; adpA; bldA; moenomycin A; pleiotropic regulators