Reconstitution of biosynthetic machinery for the synthesis of the highly elaborated indole diterpene penitrem

Chengwei Liu, Koichi Tagami, Atsushi Minami, Tomoyuki Matsumoto, Jens Christian Frisvad, Hideyuki Suzuki, Jun Ishikawa, Katsuya Gomi, Hideaki Oikawa

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

Abstract

Penitrem A is one of the most elaborated members of the fungal indole diterpenes. Two separate penitrem gene clusters were identified using genomic and RNA sequencing data, and 13 out of 17 transformations in the penitrem biosynthesis were elucidated by heterologous reconstitution of the relevant genes. These reactions involve 1) a prenylation-initiated cationic cyclization to install the bicyclo[3.2.0]heptane skeleton (PtmE), 2) a two-step P450-catalyzed oxidative processes forming the unique tricyclic penitrem skeleton (PtmK and PtmU), and 3) five sequential oxidative transformations (PtmKULNJ). Importantly, without conventional gene disruption, reconstitution of the biosynthetic machinery provided sufficient data to determine the pathway. It was thus demonstrated that the Aspergillus oryzae reconstitution system is a powerful method for studying the biosynthesis of complex natural products. The gene cluster that is responsible for the biosynthesis of the indole diterpene penitrem A has been identified. Thirteen out of the seventeen involved transformations were elucidated by heterologous reconstitution of the relevant genes and found to feature a prenylation-initiated cationic cyclization (PtmE) and two successive P450-catalyzed oxidative reactions to install the bicyclo[4.2.0]octane skeleton.

Original languageEnglish
Pages (from-to)5748-5752
Number of pages5
JournalAngewandte Chemie - International Edition
Volume54
Issue number19
DOIs
Publication statusPublished - 2015 May 4

Keywords

  • biosynthesis
  • heterologous expression
  • indole diterpenes
  • natural products
  • penitrem

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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