title: Characterization of Giant Modular PKSs Provides Insight into Genetic Mechanism for Structural Diversification of Aminopolyol Polyketides.
abstract: Polyketides form many clinically valuable compounds. However, manipulation of their biosynthesis remains highly challenging. An understanding of gene cluster evolution provides a rationale for reprogramming of the biosynthetic machinery. Herein, we report characterization of giant modular polyketide synthases (PKSs) responsible for the production of aminopolyol polyketides. Heterologous expression of over 150 kbp polyketide gene clusters successfully afforded their products, whose stereochemistry was established by taking advantage of bioinformatic analysis. Furthermore, phylogenetic analysis of highly homologous but functionally diverse domains from the giant PKSs demonstrated the evolutionary mechanism for structural diversification of polyketides. The gene clusters characterized herein, together with their evolutionary insights, are promising genetic building blocks for de novo production of unnatural polyketides.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Lihan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Bin
authors.initials: B
authors.lastname: Qin
authors.affiliation: Japan Biological Informatics Consortium, 2-4-7 Aomi, Koto-ku, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Hashimoto
authors.affiliation: Japan Biological Informatics Consortium, 2-4-7 Aomi, Koto-ku, Tokyo, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Kozone
authors.affiliation: Japan Biological Informatics Consortium, 2-4-7 Aomi, Koto-ku, Tokyo, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Kawahara
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okada
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Awakawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihama, Yamashirocho, Tokushima, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Ito
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihama, Yamashirocho, Tokushima, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Asakawa
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ueki
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Wakimoto
authors.affiliation: Laboratory of Microbial Engineering, Kitasato Institute for Life Sciences, Kitasato University, Kanagawa, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shin-Ya
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Ikuro
authors.identifier: 0000-0002-3640-888X
authors.initials: I
authors.lastname: Abe
mesh_terms: D000586:Amination; D016680:Genome, Bacterial; D005810:Multigene Family; D010802:Phylogeny; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism*; D061065:Polyketides / Q000737:chemistry / Q000378:metabolism*; D013302:Streptomyces / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*
chemical_list: D061065:Polyketides; D048630:Polyketide Synthases
keywords: bioengineering; biosynthesis; polyketides; protein structures