A widespread metabolic gene cluster family in metazoans

Abstract

Octocorals are unique among metazoans in their prolific production of bioactive terpenoid natural products that rival the chemical diversity of plants and microbes. We recently established that these cnidarians uniformly express terpene cyclases and that their encoding genes often reside within putative biosynthetic gene clusters (BGCs), a feature uncommon in animal genomes. In this work, we report the discovery and characterization of a widespread gene cluster family for the biosynthesis of briarane diterpenoids that number over 700 molecules specific to the Scleralcyonaceans, one of the two octocoral orders. We sequenced five genomes from evolutionarily distinct families of briarane-producing octocorals to complement three publicly available briarane-producing coral genomes, enabling the discovery of a conserved five-gene cluster composed of a terpene cyclase, three cytochrome P450s, and a short-chain dehydrogenase. Using Escherichia coli and Saccharomyces cerevisiae as hosts and homologous briarane biosynthesis genes from eight corals, we reconstituted the biosynthesis of cembrene B γ-lactone, which contains the γ-lactone structural feature distinctive of briarane diterpenoids. The discovery of the genomic basis of briarane biosynthesis establishes that animals, like microbes and plants, employ gene cluster families to produce specialized metabolites. Further, the presence of BGCs in octocoral proves that the formation and maintenance of BGCs over evolutionary time is a more widespread phenomenon in specialized metabolite biosynthesis than previously realized.