title: Heterologous Production of the Marine Myxobacterial Antibiotic Haliangicin and Its Unnatural Analogues Generated by Engineering of the Biochemical Pathway.
abstract: Despite their fastidious nature, marine myxobacteria have considerable genetic potential to produce novel secondary metabolites. The marine myxobacterium Haliangium ochraceum SMP-2 produces the antifungal polyketide haliangicin (1), but its productivity is unsatisfactory. The biosynthetic gene cluster hli (47.8 kbp) associated with 1 was identified and heterologously expressed in Myxococcus xanthus to permit the production of 1 with high efficiency (tenfold greater amount and threefold faster in growth speed compared with the original producer), as well as the generation of bioactive unnatural analogues of 1 through gene manipulation. A unique acyl-CoA dehydrogenase was found to catalyse an unusual γ,δ-dehydrogenation of the diketide starter unit, leading to the formation of the terminal alkene moiety of 1. Biological evaluation of the analogues obtained through this study revealed that their bioactivities (anti-oomycete and cytotoxic activities) can be modified by manipulating the vinyl epoxide at the terminus opposite the β-methoxyacrylate pharmacophore.
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Tomura
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuge
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Mori
authors.affiliation: Center for Nutraceutical and Pharmaceutical Materials, Department of Bioscience and Bioinformatics, Myongji University, Yongin, Gyeonggido 449-728, Korea.
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Suh
authors.affiliation: Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Kanagawa 210-8681, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Iizuka
authors.affiliation: R&D Planning Department, Ajinomoto Co., Inc., Chuo-ku, Tokyo 104-8315, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Fudou
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ojika
mesh_terms: D000935:Antifungal Agents; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis / Q000235:genetics*; D009231:Myxococcales / Q000378:metabolism*; D019076:Transgenes
chemical_list: D000935:Antifungal Agents; D005231:Fatty Acids, Unsaturated; C424925:haliangicin