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Plant J. 2018 Mar;93(5):943-958. doi: 10.1111/tpj.13822. Epub 2018 Feb 14.

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

Author information

1
Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Thorvaldsensvej 40, DK-1871, Frederiksberg C, Denmark.
2
Center for Synthetic Biology 'bioSYNergy', Department of Plant and Environmental Sciences, University of Copenhagen, Thorvaldsensvej 40, DK-1871, Frederiksberg C, Denmark.
3
VILLUM Center for Plant Plasticity, Department of Plant and Environmental Sciences, University of Copenhagen, Thorvaldsensvej 40, DK-1871, Frederiksberg C, Denmark.
4
Department of Plant Science, Kulliyyah of Science, International Islamic University Malaysia, 50728, Kuala Lumpur, Malaysia.
5
Metabolomics Australia, School of BioSciences, The University of Melbourne, Vic., 3010, Australia.
6
Evolva A/S, Lersø Parkallé 42-44, DK-2100, Copenhagen Ø, Denmark.
7
DynaMo Center, Department of Plant and Environmental Sciences, University of Copenhagen, Thorvaldsensvej 40, DK-1871, Frederiksberg C, Denmark.
8
Department of Bio and Health Informatics, Technical University of Denmark, DK-2800, Lyngby, Denmark.
9
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100, Copenhagen, Denmark.

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.

KEYWORDS:

Vitex agnus-castus ; Lamiaceae; MALDI-MS imaging; bioactive diterpenoid; cytochrome P450; terpene synthase

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