The Biogenetic Origin of the Biologically Active Naematolin of Hypholoma Species Involves an Unusual Sesquiterpene Synthase

Suhad A.A. Al-Salihi, Trong Tuan Dao, Katherine Williams, Andy M. Bailey*, Gary D. Foster

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

Naematolin is a biologically active sesquiterpene produced by Hypholoma species. Low titres and complex structure constrain the exploitation of this secondary metabolite. Here, we de novo sequenced the H. fasciculare genome to identify a candidate biosynthetic gene cluster for production of naematolin. Using Aspergillus oryzae as a heterologous host for gene expression, the activity of several sesquiterpene synthases were investigated, highlighting one atypical sesquiterpene synthase apparently capable of catalysing the 1,11 and subsequent 2,10 ring closures, which primes the synthesis of the distinctive structure of caryophyllene derivatives. Co-expression of the cyclase with an FAD oxidase adjacent within the gene cluster generated four oxidised caryophyllene-based sesquiterpenes: 5β,6α,8β-trihydroxycariolan, 5β,8β-dihydroxycariolan along with two previously unknown caryophyllene derivatives 2 and 3. This represents the first steps towards heterologous production of such basidiomycete-derived caryophyllene-based sesquiterpenes, opening a venue for potential novel antimicrobials via combinatorial biosynthesis.

Original languageEnglish
Pages (from-to)754-762
Number of pages9
JournalMolecular Biotechnology
Volume61
Issue number10
Early online date7 Aug 2019
DOIs
Publication statusPublished - 1 Oct 2019

Keywords

  • Caryophyllene synthase
  • Genome mining
  • Hypholoma species
  • Naematolin

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