title: Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics.
abstract: Quinomycin antibiotics, represented by echinomycin, are an important class of antitumor antibiotics. We have recently succeeded in identification of biosynthetic gene clusters of echinomycin and SW-163D, and have achieved heterologous production of echinomycin in Escherichia coli. In addition, we have engineered echinomycin non-ribosomal peptide synthetase to generate echinomycin derivatives. However, the biosynthetic pathways of intercalative chromophores quinoxaline-2-carboxylic acid (QXC) and 3-hydroxyquinaldic acid (HQA), which are important for biological activity, were not fully elucidated. Here, we report experiments involving incorporation of a putative advanced precursor, (2S, 3R)-[6'-(2)H]-3-hydroxy-L-kynurenine, and functional analysis of the enzymes Swb1 and Swb2 responsible for late-stage biosynthesis of HQA. On the basis of these experimental results, we propose biosynthetic pathways for both QXC and HQA through the common intermediate 3-hydroxy-L-kynurenine.
authors.affiliation: Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hirose
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Minami
authors.forename: Takemichi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Oguri
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oikawa
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis*; D003001:Cloning, Molecular; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D004448:Echinomycin / Q000031:analogs & derivatives* / Q000096:biosynthesis; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D005798:Genes, Bacterial; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D005810:Multigene Family; D009904:Optical Rotation; D010453:Peptide Synthases / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011810:Quinoxalines / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: C533875:3-hydroxyquinaldic acid; D000903:Antibiotics, Antineoplastic; D004269:DNA, Bacterial; D011810:Quinoxalines; C010777:quinomycin; D007737:Kynurenine; D004448:Echinomycin; D010453:Peptide Synthases; D007736:Kynurenic Acid; C042218:quinoxaline-2-carboxylic acid