Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii
Irini Pateraki, Johan Andersen-Ranberg, Niels Bjerg Jensen, Sileshi Gizachew Wubshet, Allison Maree Heskes, Victor Forman, Björn Hallström, Britta Hamberger, Mohammed Saddik Motawia, Carl Erik Olsen, Dan Staerk, Jørgen Hansen, Birger Lindberg Møller, Bjoern Hamberger
University of Copenhagen, Denmark; University of California, Berkeley, United States; Evolva, Denmark; Nofima, Norway; KTH – Royal Institute of Technology, Sweden; Michigan State University, United States
Forskolin is a unique structurally complex labdane type diterpenoid used in the treatment of glaucoma and heart failure based on its activity as a cyclic AMP booster. Commercial production of forskolin relies exclusively on extraction from its only known natural source,
the plant Coleus forskohlii, in which forskolin accumulates in the root cork. Here we report the discovery of five cytochrome P450s and two acetyltransferases which catalyze a cascade of reactions converting the forskolin precursor 13R-manoyl oxide into forskolin and a diverse array of additional labdane-type diterpenoids. A minimal set of three P450s in combination with a single acetyl transferase was identified that catalyzes the conversion of 13R-manoyl oxide into forskolin as demonstrated by transient expression in Nicotiana benthamiana. The entire pathway for forskolin production from glucose encompassing expression of nine genes was stably integrated into Saccharomyces cerevisiae and afforded forskolin titers of 40 mg/L.
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