A new biosynthetic route enlarges the terpene portfolio of bacteria

Introduction: The class of terpenoids remain one of the largest groups of natural products (ca. 80,000 compounds, 1), which are structurally and functionally diverse (e.g. rubber, cholesterin, carotenoides, gibberellin, caryophyllene, geraniol, limonene), and many have pharmacological activities (e.g. artemisinin, taxol). Their biosyntheses are based on the reactions of C5 building blocks through head-to-tail, head-to-head, head-to-middle to generate terpene backbones (prenylpyrophosphates) of C10, C15, C20 etc. (2, 3). These backbones can be further rearranged and cyclized by terpene synthases. Furthermore, the regular length compounds can be modified by tailoring enzymes, e.g. methylations, hydroxylation, oxygenation or degradation to reveal irregulare terpenes.

Recently we could show that in bacteria an alternative biosynthetic pathway produces irregulare, non-canonical terpenes via C16 and C17 prenylpyrophosphates (terpene backbones). Two enzyme classes with unusual catalytic capacities and substrate specificities are required to synthesize these non-canonical homo- and bishomo-sesquiterpenes, e.g., sodorifen, chlororaphen (4, 5). The first enzyme is a SAM-dependent bifunctional FPP-methyltransferase with cyclization activity, the second enzyme is a species-specific terpene synthase that accepts (only) cyclic prenylpyrophosphates as substrates.

Results and Discussion: Here we present the state of the art of this new biosynthetic route and demonstrate its presence in α-, β- and γ-proteobacteria and a Streptomyces species. Alltogether this biosynthetic pathway contributes to the diversity of the microbial natural terpenomes and we propose that the 136-year-old isoprene dogma should be modified. Furthermore, this non-canonical terpene biosynthesis inspires potential applications (6).

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