title: Disruption of a methyltransferase gene in actinomycin G gene cluster in Streptomyces iakyrus increases the production of phenazinomycin.
abstract: Phenazinomycin is a hybrid natural product consisting of two chemical entities, a phenazine and a cyclic terpenoid. Phenazinomycin exhibits potent activity against murine tumors and adriamycin-resistant P388 leukemia cells. Streptomyces iakyrus DSM 41873 is known to produce five actinomycin G2 -G6 . In the previous study, we identified the gene cluster directing the biosynthesis of actinomycin G2 -G4 . Inactivation of acmG5' gene in the actinomycin G gene cluster in S. iakyrus completely abolished the production of actinomycin G. Metabolic profiling, chemical isolation, and structural elucidation of the resulting mutant SIAΔacmG5' showed a previously unnoticed metabolite phenazinomycin in S. iakyrus. In silico analysis identified a hybrid biosynthetic gene cluster in the genome of S. iakyrus that could be responsible for the biosynthesis of phenazinomycin. It is proposed that the perturbation of actinomycin G to enhance the phenazinomycin production in the mutant may result from the lifted competition of chorismate, the common precursor of the biosynthetic pathways of these two structurally unrelated natural products.
authors.affiliation: Key Laboratory of Combinatory Biosynthesis and Drug Discovery (Ministry of Education), School of Pharmaceutical Sciences, Wuhan University, Wuhan, China; Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Aberdeen, UK.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Qin
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Wang
authors.forename: Mostafa Ezzat
authors.initials: ME
authors.lastname: Rateb
authors.forename: Lina Adnan
authors.initials: LA
authors.lastname: Ass'ad
authors.forename: Marcel
authors.initials: M
authors.lastname: Jaspars
authors.forename: Zixin
authors.initials: Z
authors.lastname: Deng
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.forename: Hai
authors.initials: H
authors.lastname: Deng
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D053898:Biosynthetic Pathways; D003609:Dactinomycin / Q000096:biosynthesis*; D015964:Gene Expression Regulation, Bacterial; D020868:Gene Silencing; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D005810:Multigene Family; D010619:Phenazines / Q000378:metabolism; D013302:Streptomyces / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010619:Phenazines; C586385:actinomycin G; C060454:phenazinomycin; D003609:Dactinomycin; D008780:Methyltransferases
keywords: biosynthesis; gene disruption; phenazinomycin; structural elucidation