Expanding the “Terpenome”: Diterpene Synthases Accept GGPP-Ether Substrates

Three geranylgeranyl pyrophosphate derivatives carrying an ether group at different positions within geranylgeranyl pyrophosphate were employed in biotransformations with five diterpene synthases (CotB2, PvHVS, PaFS, Bnd4 and TXS) derived from plants, bacteria and fungi. A total of six new oxygen-containing diterpenoids were isolated and characterized, deepening our knowledge on the substrate promiscuity of diterpene synthases. In addition, the diterpene synthase PvHVS also accepts an ether derivative of farnesyl pyrophosphate and converts it to the same tetrahydrofuran core as found for the analogous extended GGPP substrate. This result further demonstrates that diterpene synthases also exhibit promiscuity toward truncated unnatural substrates.