Withanolides are specialised metabolites from Nightshade plants with potent antiproliferative activity, which possess a long history of human usage as traditional medicine. More than 700 natural withanolides have been isolated so far, and many representatives are biologically active. Little is known, however, how these structurally diverse steroidal lactones are synthesised in plants. In preliminary work, we identified a putative withanolide biosynthetic gene cluster by analysis of all publicly available genome and transcriptome data of withanolide producers. In this project, building on a collaboration between a plant biochemistry group and a bioinformatics group, we want to explore this hypothesis and leverage it for the phylogenomic elucidation of withanolide biosynthesis. Specifically, we will verify our already identified gene candidates by heterologous expression and virus-induced gene silencing. In addition, to further understand the evolution of different withanolide subclasses, we will sequence three additional genomes of the withanolide producers Withania somnifera, Datura innoxia and Nicandra physalodes. From this sequence data, we will select and evaluate gene candidates based on synteny, phylogenetic relationship, and co-expression that might be responsible for the generation of structural subclasses. Based on the sequence data and the biosynthetic genes gained by this approach, we will then be able to reconstruct the evolutionary history of withanolides and their different subclasses. Thus, our project will provide fundamental insights into the molecular basis and evolution of withanolide biosynthesis. On a long term, these findings will help to better harness the medicinal properties of this structurally varied natural product class for drug development.
We are conducting this project with funding from the DFG in coopration with Jakob Franke's reserach group. First results have been published as preprint.