Periodic Reporting for period 1 - MediVAC (Bio-sustainable production of natural medicines from Vitex)
Reporting period: 2015-05-01 to 2017-04-30
Vitex agnus-castus is a medicinal plant clinically shown to be an effective treatment for premenstrual syndrome. The bioactive constituents are diterpenoids that can interact with dopamine receptors in the pituitary gland. This specific activity opens up the possibility of other therapeutic applications where dopaminergic drugs are required. The major barrier to the development of V. agnus-castus diterpenoid drugs, and the further exploration of their pharmacological activity, is the lack of a source of pure compounds. MediVAC was a 24 month research project that aimed to investigate the genes involved in the biosynthesis of pharmacologically active diterpenoids in V. agnus-castus and to develop tools that would enable their production in biotechnological platforms.
In this project state-of-the-art imaging mass spectrometry tools were used to identify diterpenoid rich tissues which were targeted for transcriptomics. Through the integration of bioinformatic, molecular biology and analytical chemistry techniques, diterpene synthases and cytochrome P450 enzyme candidates potentially involved in V. agnus-castus diterpenoid biosynthesis were identified and functionally characterised. This work resulted in a molecular toolbox of diterpenoid genes that were expressed in yeast for the production of V. agnus-castus diterpenoids. The engineered host strains hold potential for the future development of an industrial scale production platform able to produce high-purity, bioactive diterpenoids.
The impact of this project on the scientific community has been to provide new knowledge on the biosynthesis of high-value diterpenoids in a widely used medicinal plant. Through this project it could be demonstrated how specific combinations of diterpene synthases from V. agnus-castus can form the large majority of diterpenoid backbones found in this species. In addition, the P450 enzymes described in this work show novel activities that may facilitate further identification of enzymes involved in the formation of diterpenoids with therapeutic activities. The metabolite and transcriptomic resources developed as part of this project will be important additions to the growing catalogue of databases used for identifying new biosynthetic pathways towards valuable pharmaceuticals and nutraceuticals. It is envisioned that the future, wider benefits to society of this and related work will ultimately be access to new pharmaceuticals that are more affordable and more sustainably produced.