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Molecular Breeding of a Fungus Producing a Precursor Diterpene Suitable for Semi-Synthesis by Dissection of the Biosynthetic Machinery

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Title: Molecular Breeding of a Fungus Producing a Precursor Diterpene Suitable for Semi-Synthesis by Dissection of the Biosynthetic Machinery
Authors: Noike, Motoyoshi Browse this author
Ono, Yusuke Browse this author
Araki, Yuji Browse this author
Tanio, Ryo Browse this author
Higuchi, Yusuke Browse this author
Nitta, Hajime Browse this author
Hamano, Yoshimitsu Browse this author
Toyomasu, Tomonobu Browse this author
Sassa, Takeshi Browse this author
Kato, Nobuo Browse this author
Dairi, Tohru Browse this author →KAKEN DB
Issue Date: 1-Aug-2012
Publisher: Public Library of Science
Journal Title: PLoS One
Volume: 7
Issue: 8
Start Page: e42090
Publisher DOI: 10.1371/journal.pone.0042090
Abstract: Many clinically useful pharmaceuticals are semi-synthesized from natural products produced by actinobacteria and fungi. The synthetic protocols usually contain many complicated reaction steps and thereby result in low yields and high costs. It is therefore important to breed microorganisms that produce a compound most suitable for chemical synthesis. For a long time, desirable mutants have been obtained by random mutagenesis and mass screening. However, these mutants sometimes show unfavorable phenotypes such as low viability and low productivity of the desired compound. Fusicoccin (FC) A is a diterpene glucoside produced by the fungus Phomopsis amygdali. Both FC and the structurally-related cotylenin A (CN) have phytohormone-like activity. However, only CN exhibits anti-cancer activity. Since the CN producer lost its ability to proliferate during preservation, a study on the relationship between structure and activity was carried out, and elimination of the hydroxyl group at position 12 of FC was essential to mimic the CN-like activity. Based on detailed dissection of the biosynthetic machinery, we constructed a mutant producing a compound without a hydroxyl group at position 12 by gene-disruption. The mutant produced this compound as a sole metabolite, which can be easily and efficiently converted into an anti-cancer drug, and its productivity was equivalent to the sum of FC-related compounds produced by the parental strain. Our strategy would be applicable to development of pharmaceuticals that are semi-synthesized from fungal metabolites.
Type: article
Appears in Collections:工学院・工学研究院 (Graduate School of Engineering / Faculty of Engineering) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 大利 徹

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