Total Biosynthesis of Diterpene Aphidicolin, a Specific Inhibitor of DNA Polymerase .ALPHA.: Heterologous Expression of Four Biosynthetic Genes in Aspergillus oryzae

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  • FUJII Ryuya
    Division of Chemistry, Graduate School of Science, Hokkaido University
  • MINAMI Atsushi
    Division of Chemistry, Graduate School of Science, Hokkaido University
  • TSUKAGOSHI Tae
    Division of Chemistry, Graduate School of Science, Hokkaido University
  • SATO Natsuko
    Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)
  • SAHARA Takehiko
    Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)
  • OHGIYA Satoru
    Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)
  • GOMI Katsuya
    Graduate School of Agricultural Science, Tohoku University
  • OIKAWA Hideaki
    Division of Chemistry, Graduate School of Science, Hokkaido University

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  • Total biosynthesis of diterpene aphidicolin, a specific inhibitor of DNA polymerase α: heterologous expression of four biosynthetic genes in Aspergillus oryzae
  • Total biosynthesis of diterpene aphidicolin a specific inhibitor of DNA polymerase a heterologous expression of four biosynthetic genes in Aspergillus oryzae
  • Total Biosynthesis of Diterpene Aphidicolin, a Specific Inhibitor of DNA Polymerase α: Heterologous Expression of Four Biosynthetic Genes in<i>Aspergillus oryzae</i>

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Abstract

Clustering of biosynthetic genes for producing fungal secondary metabolites, which frequently consist of less than ten genes, has been recognized with numerous genomes. The heterologous expression of whole genes in the clusters will therefore produce various types of natural products when using a suitable fungal host. We introduced the whole gene cluster for the biosynthesis of diterpene aphidicolin into the fungal quadruple auxotrophic host, Aspergillus oryzae, by using four different vectors (pTAex3, pPTRI, pUSA and pAdeA) which harbor a starch-inducible promoter/terminator to examine the expression conditions. The resulting quadruple transformant carrying the genes of geranylgeranyl diphosphate synthase PbGGS, terpene synthase PbACS, and two monooxygenases (PbP450-1 and PbP450-2) produced aphidicolin. The double and triple transformants also respectively produced aphidicolan-16β-ol and 3-deoxyaphidicolin. Alternative host Saccharomyces cerevisiae carrying the genes, PbGGS and PbACS, produced key intermediate aphidicolan-16β-ol. This is the first example of a total biosynthesis of terpenoids using fungal hosts.

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