Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii

Irini Pateraki; Johan Andersen-Ranberg; Nils Bjerg Jensen; Sileshi Gizachew Wubshet; Allison Maree Heskes; Victor Forman; Björn Hallström; Britta Hamberger; Mohammed Saddik Motawie; Carl Erik Olsen; Dan Stærk; Jørgen Hansen; Birger Lindberg Møller; Björn Robert Hamberger

doi:10.7554/eLife.23001

Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii

Irini Pateraki, Johan Andersen-Ranberg, Nils Bjerg Jensen, Sileshi Gizachew Wubshet, Allison Maree Heskes, Victor Forman, Björn Hallström, Britta Hamberger, Mohammed Saddik Motawie, Carl Erik Olsen, Dan Stærk, Jørgen Hansen, Birger Lindberg Møller, Björn Robert Hamberger

Section for Plant Biochemistry

47 Citations (Scopus)

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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

Original language	English
Article number	e23001
Journal	eLife
Volume	6
Number of pages	28
ISSN	2050-084X
DOIs	https://doi.org/10.7554/eLife.23001
Publication status	Published - 14 Mar 2017

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Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohliiFinal published version, 4.46 MBLicence: CC BY

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title = "Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii",

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",

author = "Irini Pateraki and Johan Andersen-Ranberg and Jensen, {Nils Bjerg} and Wubshet, {Sileshi Gizachew} and Heskes, {Allison Maree} and Victor Forman and Bj{\"o}rn Hallstr{\"o}m and Britta Hamberger and Motawie, {Mohammed Saddik} and Olsen, {Carl Erik} and Dan St{\ae}rk and J{\o}rgen Hansen and M{\o}ller, {Birger Lindberg} and Hamberger, {Bj{\"o}rn Robert}",

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T1 - Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii

AU - Pateraki, Irini

AU - Andersen-Ranberg, Johan

AU - Jensen, Nils Bjerg

AU - Wubshet, Sileshi Gizachew

AU - Heskes, Allison Maree

AU - Forman, Victor

AU - Hallström, Björn

AU - Hamberger, Britta

AU - Motawie, Mohammed Saddik

AU - Olsen, Carl Erik

AU - Stærk, Dan

AU - Hansen, Jørgen

AU - Møller, Birger Lindberg

AU - Hamberger, Björn Robert

PY - 2017/3/14

Y1 - 2017/3/14

N2 - 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

AB - 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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DO - 10.7554/eLife.23001

M3 - Journal article

C2 - 28290983

SN - 2050-084X

VL - 6

JO - eLife

JF - eLife

M1 - e23001

ER -

Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii

Abstract

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