Biosynthesis of bioactive diterpenoids in the medicinal plant Vitex agnus-castus

Allison Heskes; Tamil Chelvan Meenakshi Sundram; Berin A. Boughton; Niels Bjerg Jensen; Nikolaj Lervad Hansen; Christoph Crocoll; Federico Cozzi; Simon Rasmussen; Britta Hamberger; Björn Robert Hamberger; Dan Stærk; Birger Lindberg Møller; Irini Pateraki

doi:10.1111/tpj.13822

Biosynthesis of bioactive diterpenoids in the medicinal plant Vitex agnus-castus

Allison Heskes, Tamil Chelvan Meenakshi Sundram, Berin A. Boughton, Niels Bjerg Jensen, Nikolaj Lervad Hansen, Christoph Crocoll, Federico Cozzi, Simon Rasmussen, Britta Hamberger, Björn Robert Hamberger, Dan Stærk, Birger Lindberg Møller, Irini Pateraki

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Abstract

Vitex agnus-castus L. (Lamiaceae) is a medicinal plant historically used throughout the Mediterranean region to treat menstrual cycle disorders, and is still used today as a clinically effective treatment for premenstrual syndrome. The pharmaceutical activity of the plant extract is linked to its ability to lower prolactin levels. This feature has been attributed to the presence of dopaminergic diterpenoids that can bind to dopamine receptors in the pituitary gland. Phytochemical analyses of V. agnus-castus show that it contains an enormous array of structurally related diterpenoids and, as such, holds potential as a rich source of new dopaminergic drugs. The present work investigated the localisation and biosynthesis of diterpenoids in V. agnus-castus. With the assistance of matrix-assisted laser desorption ionisation-mass spectrometry imaging (MALDI-MSI), diterpenoids were localised to trichomes on the surface of fruit and leaves. Analysis of a trichome-specific transcriptome database, coupled with expression studies, identified seven candidate genes involved in diterpenoid biosynthesis: three class II diterpene synthases (diTPSs); three class I diTPSs; and a cytochrome P450 (CYP). Combinatorial assays of the diTPSs resulted in the formation of a range of different diterpenes that can account for several of the backbones of bioactive diterpenoids observed in V. agnus-castus. The identified CYP, VacCYP76BK1, was found to catalyse 16-hydroxylation of the diol-diterpene, peregrinol, to labd-13Z-ene-9,15,16-triol when expressed in Saccharomyces cerevisiae. Notably, this product is a potential intermediate in the biosynthetic pathway towards bioactive furan- and lactone-containing diterpenoids that are present in this species.

Original language	English
Journal	Plant Journal
Volume	93
Pages (from-to)	943-958
Number of pages	16
ISSN	0960-7412
DOIs	https://doi.org/10.1111/tpj.13822
Publication status	Published - Mar 2018

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Biosynthesis of bioactive diterpenoids in the medicinal plant Vitex agnus-castusFinal published version, 1.11 MBLicence: CC BY

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@article{78052b60ba4e4059a5ad083a84a8a31c,

title = "Biosynthesis of bioactive diterpenoids in the medicinal plant Vitex agnus-castus",

abstract = "Vitex agnus-castus L. (Lamiaceae) is a medicinal plant historically used throughout the Mediterranean region to treat menstrual cycle disorders, and is still used today as a clinically effective treatment for premenstrual syndrome. The pharmaceutical activity of the plant extract is linked to its ability to lower prolactin levels. This feature has been attributed to the presence of dopaminergic diterpenoids that can bind to dopamine receptors in the pituitary gland. Phytochemical analyses of V. agnus-castus show that it contains an enormous array of structurally related diterpenoids and, as such, holds potential as a rich source of new dopaminergic drugs. The present work investigated the localisation and biosynthesis of diterpenoids in V. agnus-castus. With the assistance of matrix-assisted laser desorption ionisation-mass spectrometry imaging (MALDI-MSI), diterpenoids were localised to trichomes on the surface of fruit and leaves. Analysis of a trichome-specific transcriptome database, coupled with expression studies, identified seven candidate genes involved in diterpenoid biosynthesis: three class II diterpene synthases (diTPSs); three class I diTPSs; and a cytochrome P450 (CYP). Combinatorial assays of the diTPSs resulted in the formation of a range of different diterpenes that can account for several of the backbones of bioactive diterpenoids observed in V. agnus-castus. The identified CYP, VacCYP76BK1, was found to catalyse 16-hydroxylation of the diol-diterpene, peregrinol, to labd-13Z-ene-9,15,16-triol when expressed in Saccharomyces cerevisiae. Notably, this product is a potential intermediate in the biosynthetic pathway towards bioactive furan- and lactone-containing diterpenoids that are present in this species.",

author = "Allison Heskes and Sundram, {Tamil Chelvan Meenakshi} and Boughton, {Berin A.} and {Bjerg Jensen}, Niels and Hansen, {Nikolaj Lervad} and Christoph Crocoll and Federico Cozzi and Simon Rasmussen and Britta Hamberger and Hamberger, {Bj{\"o}rn Robert} and Dan St{\ae}rk and M{\o}ller, {Birger Lindberg} and Irini Pateraki",

year = "2018",

month = mar,

doi = "10.1111/tpj.13822",

language = "English",

volume = "93",

pages = "943--958",

journal = "Plant Journal",

issn = "0960-7412",

publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Biosynthesis of bioactive diterpenoids in the medicinal plant Vitex agnus-castus

AU - Heskes, Allison

AU - Sundram, Tamil Chelvan Meenakshi

AU - Boughton, Berin A.

AU - Bjerg Jensen, Niels

AU - Hansen, Nikolaj Lervad

AU - Crocoll, Christoph

AU - Cozzi, Federico

AU - Rasmussen, Simon

AU - Hamberger, Britta

AU - Hamberger, Björn Robert

AU - Stærk, Dan

AU - Møller, Birger Lindberg

AU - Pateraki, Irini

PY - 2018/3

Y1 - 2018/3

N2 - Vitex agnus-castus L. (Lamiaceae) is a medicinal plant historically used throughout the Mediterranean region to treat menstrual cycle disorders, and is still used today as a clinically effective treatment for premenstrual syndrome. The pharmaceutical activity of the plant extract is linked to its ability to lower prolactin levels. This feature has been attributed to the presence of dopaminergic diterpenoids that can bind to dopamine receptors in the pituitary gland. Phytochemical analyses of V. agnus-castus show that it contains an enormous array of structurally related diterpenoids and, as such, holds potential as a rich source of new dopaminergic drugs. The present work investigated the localisation and biosynthesis of diterpenoids in V. agnus-castus. With the assistance of matrix-assisted laser desorption ionisation-mass spectrometry imaging (MALDI-MSI), diterpenoids were localised to trichomes on the surface of fruit and leaves. Analysis of a trichome-specific transcriptome database, coupled with expression studies, identified seven candidate genes involved in diterpenoid biosynthesis: three class II diterpene synthases (diTPSs); three class I diTPSs; and a cytochrome P450 (CYP). Combinatorial assays of the diTPSs resulted in the formation of a range of different diterpenes that can account for several of the backbones of bioactive diterpenoids observed in V. agnus-castus. The identified CYP, VacCYP76BK1, was found to catalyse 16-hydroxylation of the diol-diterpene, peregrinol, to labd-13Z-ene-9,15,16-triol when expressed in Saccharomyces cerevisiae. Notably, this product is a potential intermediate in the biosynthetic pathway towards bioactive furan- and lactone-containing diterpenoids that are present in this species.

AB - Vitex agnus-castus L. (Lamiaceae) is a medicinal plant historically used throughout the Mediterranean region to treat menstrual cycle disorders, and is still used today as a clinically effective treatment for premenstrual syndrome. The pharmaceutical activity of the plant extract is linked to its ability to lower prolactin levels. This feature has been attributed to the presence of dopaminergic diterpenoids that can bind to dopamine receptors in the pituitary gland. Phytochemical analyses of V. agnus-castus show that it contains an enormous array of structurally related diterpenoids and, as such, holds potential as a rich source of new dopaminergic drugs. The present work investigated the localisation and biosynthesis of diterpenoids in V. agnus-castus. With the assistance of matrix-assisted laser desorption ionisation-mass spectrometry imaging (MALDI-MSI), diterpenoids were localised to trichomes on the surface of fruit and leaves. Analysis of a trichome-specific transcriptome database, coupled with expression studies, identified seven candidate genes involved in diterpenoid biosynthesis: three class II diterpene synthases (diTPSs); three class I diTPSs; and a cytochrome P450 (CYP). Combinatorial assays of the diTPSs resulted in the formation of a range of different diterpenes that can account for several of the backbones of bioactive diterpenoids observed in V. agnus-castus. The identified CYP, VacCYP76BK1, was found to catalyse 16-hydroxylation of the diol-diterpene, peregrinol, to labd-13Z-ene-9,15,16-triol when expressed in Saccharomyces cerevisiae. Notably, this product is a potential intermediate in the biosynthetic pathway towards bioactive furan- and lactone-containing diterpenoids that are present in this species.

U2 - 10.1111/tpj.13822

DO - 10.1111/tpj.13822

M3 - Journal article

C2 - 29315936

SN - 0960-7412

VL - 93

SP - 943

EP - 958

JO - Plant Journal

JF - Plant Journal

ER -

Biosynthesis of bioactive diterpenoids in the medicinal plant Vitex agnus-castus

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