Biosynthesis of Bioactive Diterpenoids: Pathway Discovery and Reconstruction

Plants produce more than 11,000 different diterpenoids which display a wide range of biological activities. Several are used directly as therapeutics for the treatment of human diseases, such as the cyclic AMP booster forskolin or the anti-cancer drugs paclitaxel and ingenol mebutate. Others serve as lead compounds in drug discovery and have been the focus of many medicinal chemistry and therapeutic studies. However, most bioactive diterpenoids have been isolated from non-cultivated medicinal plants or from endangered or red listed species. The lack of a reliable and environmentally benign and stable supply chain thus remains a major obstacle when the need arises to develop specific diterpenoids into medicinal drug. Using forskolin and ingenol mebutate as examples, we provide an account on how production of these plant-derived pharmaceuticals may shift from field acquisition to sustainable manufacturing. To achieve this, knowledge of the enzymes involved in the biosynthetic pathway is essential. Through the strategy consisting of metabolite profiling, transcriptome analysis and enzyme characterization, we have managed to elucidate biosynthetic pathways of several bioactive diterpenoids including forskolin, jolkinol C and vitexilactones^1,2,3. Subsequently, reconstitution of elucidated pathways in microbial hosts like yeast or photosynthetic microalgae offers the sustainable production of targeted plant diterpenoids.

Reference

(1) Luo D. et al., Proc. Natl. Acad. Sci. U. S. A. 2016, 113, E5082.

(2) Pateraki I. et al., eLife 2017, 6, e23001.

(3) Heskes AM. et al., Plant J. 2018, 93, 943.