Exploring and expanding the natural chemical space of bacterial diterpenes

Terpenoids are the largest family of natural products but are relatively rare in bacteria. Genome mining reveals wide- spread prevalence of terpene synthases, the enzymes responsible for constructing the hydrocarbon skeletons, in bacteria. Using an engineered E. coli diterpene production system, we screened 334 diverse terpene synthases from 8 phyla, 17 classes, and 83 genera of bacteria and found that 125 (37%) were active as diterpene synthases. Isolation and structural elucidation of 28 bacterial diterpenes from 31 TSs revealed three new terpene skeletons previously unseen in nature, skeletons of known natural products from other organisms (e.g., coral, sponge, algae) with unknown biosynthetic pathways, diterpenes that are known in other organisms (e.g., fungi, plants) but have not been previously seen in bacteria, and new structural and stereochemical isomers of diterpenes. This study will lead to novel natural products, advances in terpenoid biosynthesis and roles of these natural products.