title: Insights into a divergent phenazine biosynthetic pathway governed by a plasmid-born esmeraldin gene cluster.
abstract: Phenazine-type metabolites arise from either phenazine-1-carboxylic acid (PCA) or phenazine-1,6-dicarboxylic acid (PDC). Although the biosynthesis of PCA has been studied extensively, PDC assembly remains unclear. Esmeraldins and saphenamycin, the PDC originated products, are antimicrobial and antitumor metabolites isolated from Streptomyces antibioticus Tü 2706. Herein, the esmeraldin biosynthetic gene cluster was identified on a dispensable giant plasmid. Twenty-four putative esm genes were characterized by bioinformatics, mutagenesis, genetic complementation, and functional protein expressions. Unlike enzymes involved in PCA biosynthesis, EsmA1 and EsmA2 together decisively promoted the PDC yield. The resulting PDC underwent a series of conversions to give 6-acetylphenazine-1-carboxylic acid, saphenic acid, and saphenamycin through a unique one-carbon extension by EsmB1-B5, a keto reduction by EsmC, and an esterification by EsmD1-D3, the atypical polyketide sythases, respectively. Two transcriptional regulators, EsmT1 and EsmT2, are required for esmeraldin production.
authors.affiliation: Department of Biological Science, Louisiana State University, Baton Rouge, LA 70803, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Rui
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.forename: Shuoguo
authors.initials: S
authors.lastname: Wang
authors.forename: Kaori
authors.initials: K
authors.lastname: Fujikawa
authors.forename: Bankole
authors.initials: B
authors.lastname: Akerele
authors.forename: May
authors.initials: M
authors.lastname: Aung
authors.forename: Heinz G
authors.initials: HG
authors.lastname: Floss
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.forename: Tin-Wein
authors.initials: TW
authors.lastname: Yu
mesh_terms: D053898:Biosynthetic Pathways / Q000235:genetics*; D003001:Cloning, Molecular; D003998:Dicarboxylic Acids / Q000737:chemistry / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005816:Genetic Complementation Test; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010619:Phenazines / Q000737:chemistry / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics*; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D013303:Streptomyces antibioticus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism
chemical_list: D003998:Dicarboxylic Acids; D010619:Phenazines; D048630:Polyketide Synthases