Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii
- 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
Abstract
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.
Article and author information
Author details
Allison Maree Heskes
Funding
Villum Fonden
- Birger Lindberg Møller
Novo Nordisk
- Birger Lindberg Møller
European Commission
- Irini Pateraki
DOE Office of Science (BER DE-FC02-07ER64494)
- Bjoern Hamberger
Strategic Partnership Grant (15-SPG-Full-3101)
- Bjoern Hamberger
MSU Foundation
- Bjoern Hamberger
Michigan State University (startup funding from the Department of Molecular Biology and Biochemistry)
- Bjoern Hamberger
Michigan State University (AgBioResearch - MICL02454)
- Bjoern Hamberger
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Joerg Bohlmann, University of British Columbia, Canada
Version history
- Received: November 5, 2016
- Accepted: March 9, 2017
- Accepted Manuscript published: March 14, 2017 (version 1)
- Accepted Manuscript updated: March 21, 2017 (version 2)
- Accepted Manuscript updated: March 21, 2017 (version 3)
- Version of Record published: April 11, 2017 (version 4)
- Version of Record updated: April 13, 2017 (version 5)
Copyright
© 2017, Pateraki et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii
eLife 6:e23001.
https://doi.org/10.7554/eLife.23001
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