Abstract
Comparative transcriptional profiling of a ΔbldM mutant of Streptomyces venezuelae with its unmodified progenitor revealed that the expression of a cryptic biosynthetic gene cluster containing both type I and type III polyketide synthase genes is activated in the mutant. The 29.5 kb gene cluster, which was predicted to encode an unusual biaryl metabolite, which we named venemycin, and potentially halogenated derivatives, contains 16 genes including one—vemR—that encodes a transcriptional activator of the large ATP‐binding LuxR‐like (LAL) family. Constitutive expression of vemR in the ΔbldM mutant led to the production of sufficient venemycin for structural characterisation, confirming its unusual biaryl structure. Co‐expression of the venemycin biosynthetic gene cluster and vemR in the heterologous host Streptomyces coelicolor also resulted in venemycin production. Although the gene cluster encodes two halogenases and a flavin reductase, constitutive expression of all three genes led to the accumulation only of a monohalogenated venemycin derivative, both in the native producer and the heterologous host. A competition experiment in which equimolar quantities of sodium chloride and sodium bromide were fed to the venemycin‐producing strains resulted in the preferential incorporation of bromine, thus suggesting that bromide is the preferred substrate for one or both halogenases.
Highlights
Polyketides are structurally diverse natural products from plants and microorganisms that exhibit a broad range of biological activities.[1,2,3] They are assembled through a process similar to fatty acid biosynthesis, involving one or more rounds of [d] Prof
We propose that the biosynthesis of venemycin begins with the formation of 3,5-dihydroxybenzoic acid catalysed by the enzymes encoded by vemA, vemB, vemC, vemD, vemE and vemF
By combining microarray analysis of a S. venezuelae DbldM mutant with bioinformatics analysis of its genome sequence, we were able to identify a biosynthetic gene cluster encoding an unusual combination of modular type I and type III PKSs that was predicted to assemble a new biaryl natural product— which we named venemycin—along with halogenated derivatives
Summary
Anyarat Thanapipatsiri,[a, b] Juan Pablo Gomez-Escribano,[b] Lijiang Song,[c] Maureen J. Bibb,[b] Mahmoud Al-Bassam,[b, e] Govind Chandra,[b] Arinthip Thamchaipenet,*[a, d] Gregory L. Comparative transcriptional profiling of a DbldM mutant of Streptomyces venezuelae with its unmodified progenitor revealed that the expression of a cryptic biosynthetic gene cluster containing both type I and type III polyketide synthase genes is activated in the mutant. Constitutive expression of vemR in the DbldM mutant led to the production of sufficient venemycin for structural characterisation, confirming its unusual biaryl structure. Co-expression of the venemycin biosynthetic gene cluster and vemR in the heterologous host Streptomyces coelicolor resulted in venemycin production. The gene cluster encodes two halogenases and a flavin reductase, constitutive expression of all three genes led to the accumulation only of a monohalogenated venemycin derivative, both in the native producer and the heterologous host. A competition experiment in which equimolar quantities of sodium chloride and sodium bromide were fed to the venemycin-producing strains resulted in the preferential incorporation of bromine, suggesting that bromide is the preferred substrate for one or both halogenases
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