1. Biochemistry and Chemical Biology
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Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii

  1. Irini Pateraki  Is a corresponding author
  2. Johan Andersen-Ranberg
  3. Niels Bjerg Jensen
  4. Sileshi Gizachew Wubshet
  5. Allison Maree Heskes
  6. Victor Forman
  7. Björn Hallström
  8. Britta Hamberger
  9. Mohammed Saddik Motawia
  10. Carl Erik Olsen
  11. Dan Staerk
  12. Jørgen Hansen
  13. Birger Lindberg Møller
  14. Bjoern Hamberger
  1. University of Copenhagen, Denmark
  2. University of California, Berkeley, United States
  3. Evolva, Denmark
  4. Nofima, Norway
  5. KTH - Royal Institute of Technology, Sweden
  6. Michigan State University, United States
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Cite this article as: eLife 2017;6:e23001 doi: 10.7554/eLife.23001

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

  1. Irini Pateraki

    Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark
    For correspondence
    eipa@plen.ku.dk
    Competing interests
    Irini Pateraki, Filed international patent600 applications (PCT/DK2015/050020) covering 'Biosynthesis of forskolin and related compounds.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7526-2334
  2. Johan Andersen-Ranberg

    Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    Johan Andersen-Ranberg, Filed international patent600 applications (PCT/DK2015/050020) covering 'Biosynthesis of forskolin and related compounds.
  3. Niels Bjerg Jensen

    Evolva, Copenhagen, Denmark
    Competing interests
    Niels Bjerg Jensen, Filed international patent600 applications (PCT/DK2015/050020) covering 'Biosynthesis of forskolin and related compoundsEmployee of Evolva SA.
  4. Sileshi Gizachew Wubshet

    Nofima, Osloveien, Norway
    Competing interests
    No competing interests declared.
  5. Allison Maree Heskes

    Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2732-5185
  6. Victor Forman

    Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  7. Björn Hallström

    Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  8. Britta Hamberger

    Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, United States
    Competing interests
    No competing interests declared.
  9. Mohammed Saddik Motawia

    Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  10. Carl Erik Olsen

    Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  11. Dan Staerk

    Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  12. Jørgen Hansen

    Evolva, Copenhagen, Denmark
    Competing interests
    Jørgen Hansen, Employee of Evolva SA.
  13. Birger Lindberg Møller

    Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    Birger Lindberg Møller, Filed international patent600 applications (PCT/DK2015/050020) covering 'Biosynthesis of forskolin and related compounds.
  14. Bjoern Hamberger

    Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, United States
    Competing interests
    Bjoern Hamberger, Filed international patent600 applications (PCT/DK2015/050020) covering 'Biosynthesis of forskolin and related compounds'.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1249-1807

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

  1. Joerg Bohlmann, University of British Columbia, Canada

Publication history

  1. Received: November 5, 2016
  2. Accepted: March 9, 2017
  3. Accepted Manuscript published: March 14, 2017 (version 1)
  4. Accepted Manuscript updated: March 21, 2017 (version 2)
  5. Accepted Manuscript updated: March 21, 2017 (version 3)
  6. Version of Record published: April 11, 2017 (version 4)
  7. 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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