Molecular Breeding of a Fungus Producing a Precursor Diterpene Suitable for Semi-Synthesis by Dissection of the Biosynthetic Machinery 英文参考文献.docVIP

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Molecular Breeding of a Fungus Producing a Precursor Diterpene Suitable for Semi-Synthesis by Dissection of the Biosynthetic Machinery 英文参考文献.doc

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Molecular Breeding of a Fungus Producing a Precursor Diterpene Suitable for Semi-Synthesis by Dissection of the Biosynthetic Machinery 英文参考文献

MolecularBreedingofaFungusProducingaPrecursor DiterpeneSuitableforSemi-SynthesisbyDissectionof theBiosyntheticMachinery MotoyoshiNoike1*,YusukeOno1,YujiAraki1,RyoTanio1,YusukeHiguchi2,HajimeNitta2, YoshimitsuHamano3,TomonobuToyomasu4,TakeshiSassa4,NobuoKato2,TohruDairi1* 1Graduate School of Engineering, Hokkaido University, Hokkaido, Japan, 2The institute of Scientific and Industrial Research, Osaka University, Osaka, Japan, 3DepartmentofBioscience,FukuiPrefecturalUniversity,Fukui,Japan,4DepartmentofBioresourceEngineering,YamagataUniversity,Yamagata,Japan Abstract Manyclinicallyusefulpharmaceuticalsaresemi-synthesizedfromnaturalproductsproducedbyactinobacteriaandfungi. Thesyntheticprotocolsusuallycontainmanycomplicatedreactionstepsandtherebyresultinlowyieldsandhighcosts.Itis thereforeimportanttobreedmicroorganismsthatproduceacompoundmostsuitableforchemicalsynthesis.Foralong time, desirable mutants have been obtained by random mutagenesis and mass screening. However, these mutants sometimesshowunfavorablephenotypessuchaslowviabilityandlowproductivityofthedesiredcompound.Fusicoccin (FC)AisaditerpeneglucosideproducedbythefungusPhomopsisamygdali.BothFCandthestructurally-relatedcotylenin A(CN)havephytohormone-likeactivity.However,onlyCNexhibitsanti-canceractivity.SincetheCNproducerlostitsability 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 dissectionofthebiosyntheticmachinery,weconstructedamutantproducingacompoundwithoutahydroxylgroupat 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- synthes