Distinct mechanisms for spiro-carbon formation reveal biosynthetic pathway crosstalk

Yuta Tsunematsu, Noriyasu Ishikawa, Daigo Wakana, Yukihiro Goda, Hiroshi Noguchi, Hisao Moriya, Kinya Hotta, Kenji Watanabe

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61 Citations (Scopus)

Abstract

Spirotryprostatins, an indole alkaloid class of nonribosomal peptides isolated from Aspergillus fumigatus, are known for their antimitotic activity in tumor cells. Because spirotryprostatins and many other chemically complex spiro-carbon-bearing natural products exhibit useful biological activities, identifying and understanding the mechanism of spiro-carbon biosynthesis is of great interest. Here we report a detailed study of spiro-ring formation in spirotryprostatins from tryprostatins derived from the fumitremorgin biosynthetic pathway, using reactants and products prepared with engineered yeast and fungal strains. Unexpectedly, FqzB, an FAD-dependent monooxygenase from the unrelated fumiquinazoline biosynthetic pathway, catalyzed spiro-carbon formation in spirotryprostatin A via an epoxidation route. Furthermore, FtmG, a cytochrome P450 from the fumitremorgin biosynthetic pathway, was determined to catalyze the spiro-ring formation in spirotryprostatin B. Our results highlight the versatile role of oxygenating enzymes in the biosynthesis of structurally complex natural products and indicate that cross-talk of different biosynthetic pathways allows product diversification in natural product biosynthesis.

Original languageEnglish
Pages (from-to)818-825
Number of pages8
JournalNature Chemical Biology
Volume9
Issue number12
DOIs
Publication statusPublished - Dec 2013

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ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Tsunematsu, Y., Ishikawa, N., Wakana, D., Goda, Y., Noguchi, H., Moriya, H., Hotta, K., & Watanabe, K. (2013). Distinct mechanisms for spiro-carbon formation reveal biosynthetic pathway crosstalk. Nature Chemical Biology, 9(12), 818-825. https://doi.org/10.1038/nchembio.1366