title: Generation of new compounds through unbalanced transcription of landomycin A cluster.
abstract: The biosynthetically well-studied landomycin A cluster has been used to demonstrate the unbalancing of gene transcription as an efficient method for the generation of new compounds. Landomycin A structural genes were decoupled from the native regulators LanI and LanK and placed under the control of a single synthetic promoter and expressed in a heterologous host Streptomyces albus J1074. In contrast to their native quantitative and temporal regulation, these genes were transcribed as a single polycistronic mRNA leading to the production of four novel and two known compounds. No glycosylated landomycins were detected though the entire biosynthetic cluster was transcribed, showing the crucial role of the balanced gene expression for the production of landomycin A. Two new compounds, fridamycin F and G, isolated in this study were shown to originate from the interplay between the expressed biosynthetic pathway and metabolic network of the heterologous host. Structure activity studies of the isolated compounds as well as results of transcriptome sequencing are discussed in this article.
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University Campus, Building C2.3, 66123, Saarbrücken, Germany.
authors.forename: Maksym
authors.initials: M
authors.lastname: Myronovskyi
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University Campus, Building C2.3, 66123, Saarbrücken, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Brötz
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University Campus, Building C2.3, 66123, Saarbrücken, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Rosenkränzer
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University Campus, Building C2.3, 66123, Saarbrücken, Germany.
authors.forename: Niko
authors.initials: N
authors.lastname: Manderscheid
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University Campus, Building C2.3, 66123, Saarbrücken, Germany.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Tokovenko
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University Campus, Building C2.3, 66123, Saarbrücken, Germany.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Rebets
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University Campus, Building C2.3, 66123, Saarbrücken, Germany. andriy.luzhetskyy@helmholtz-hzi.de.|Department of Pharmaceutical Biotechnology, Helmholtz-Institute for Pharmaceutical Research Saarland, Actinobacteria Metabolic Engineering Group, Saarland University, UdS Campus, C2 3, 66123, Saarbrücken, Germany. andriy.luzhetskyy@helmholtz-hzi.de.
authors.forename: Andriy
authors.initials: A
authors.lastname: Luzhetskyy
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism*; D000880:Anthraquinones / Q000378:metabolism*; D001688:Biological Products / Q000378:metabolism; D015870:Gene Expression; D005810:Multigene Family; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D000617:Aminoglycosides; D000880:Anthraquinones; D001688:Biological Products; D011994:Recombinant Proteins; C064648:landomycin A
keywords: Angucyclines; Landomycin A; Natural product discovery; Streptomyces albus; Synthetic promoters; Transcriptional unbalancing