With 12,000+ known structures, diterpenoids are a prime example of bio-active natural products produced by plants. Many are used as highly valuable pharmaceuticals, fragrances, natural plant growth promoters and food ingredients. Unfortunately, they are typically produced in minute amounts in plants and their structural complexity render them difficult to prepare from fossil resources using organic chemical synthesis. Terpene synthases, cytochrome P450s and acyl transferases are key multienzyme families involved in diterpenoid synthesis. Using state-of-the-art technologies, elucidation of even highly complex biosynthetic pathways is now possible within a reasonably short time frame (1). Terpenoid metabolism is modular right from assembly of the C5 building blocks to the final structurally complex diterpenoid. Using the approaches of synthetic biology for combinatorial biosynthesis, the functional modules may be assembled in new combinations to expand the landscape of diterpenoid structural diversity into new-to-nature structures (2). We recently elucidated the entire biosynthetic pathway for forskolin (1). Forskolin is a cyclic AMP booster approved for treatment of glaucoma but also used as a weight loss aid. Heterologous expression of the forskolin pathway in yeast was accomplished. Based on our successful targeting of the entire cytochrome P450-driven pathway for the cyanogenic glucoside dhurrin to tobacco chloroplasts (3), the forskolin pathway is now used as a test model for direct light driven production of high value diterpenoids following targeting of the pathway to the photosynthetic thylaloid membrane using micro algae, cyanobacteria or moss as photosynthetic production hosts grown in contained photo-bioreactors (4, 5).

References
(1)
I. Pateraki, J. Andersen-Ranberg, N.B. Jensen, S. GizachewWubshet, A.M. Heskes, V. Forman, B. Hallström, B. Hamberger, M.S. Motawia, C.E. Olsen, D. Staerk, J. Hansen, B.L. Møller, B. Hamberger. Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii. eLIFE (2017) 6:e23001. DOI: 10.7554/eLife.23001
2:
J. Andersen-Ranberg, K.T. Kongstad, M.T. Nielsen, N.B. Jensen, I. Pateraki, S.S. Bach, B. Hamberger, P. Zerbe, D. Stærk, J. Bohlmann, B.L. Møller, and B. Hamberger: Expanding the Landscape of Diterpene Structural Diversity through Stereochemically Controlled Combinatorial Biosynthesis. Angewandte Chemie (2016)128: 2182-2186
3:
T. Laursen, J. Borch, C. Knudsen, K. Bavishi, F. Torta, H.J. Martens, D. Silvestro, N.S. Hatzakis, M.R. Wenk, T.R. Dafforn, C.E. Olsen, M.S. Motawia, B. Hamberger, B.L. Møller, J.E. Bassard: Characterization of a dynamic metabolon producing the defense compound dhurrin in sorghum. Science (2016) 354: 890-893
4.
A. Wlodarczyk, T. Gnanasekaran , A.Z. Nielsen, N.N. Zulu, S.B. Mellor, M. Luckner, J.F.B. Thøfner, C.E. Olsen, M.S. Mottawie, M. Burrow, M. Pribil, I. Feussner, B.L. Møller, P.E. Jensen: Metabolic engineering of light-driven cytochrome P450 dependent pathways into Synechocystis sp. PCC 6803. Metabolic Engineering (2016) 33: 1-11
5:
S.B. Mellor, A.Z. Nielsen, M. Burow, M.S. Motawia, D. Jakubauskas, B.L. Møller, P.E. Jensen: Fusion of Ferredoxin and Cytochrome P450 Enables Direct Light-Driven Biosynthesis. ACS Chemical Biology (2016) 11: 1862-1869