Engineering the Production of Medicinal Natural Products from Plant Tissue Cultures

Plants have developed elaborate mechanisms for responding rapidly and specifically to changes in their environment. For instance, in response to attack by pathogens, insects, or herbivores, plants strategically redirect their metabolic resources from growth and development towards the production of defense-related specialized metabolites. This induction of specialized metabolism is also carefully controlled to limit the costly expenditure of resources. The overall vision of our research is to elucidate how plants rapidly and efficiently coordinate and control this defense response. Our model system for studying the regulation of defense-related specialized metabolism is the Madagascar periwinkle or the Catharanthus roseus. We chose C. roseus since it produces medicinally-valuable terpenoid indole alkaloids (TIAs) upon herbivory and deploys sophisticated mechanisms for the transcriptional regulation of TIA biosynthesis. TIA biosynthesis consists of ~30 enzymatic steps distributed across multiple cell types. The regulation of TIA biosynthesis is similarly complex as multiple transcription factors are required to coordinate the expression of multiple branches of the TIA pathway. This network is difficult to dissect since activators (like MYC2) not only induce the expression of the TIA pathway genes but also that of repressors (like JAZ). In the case of MYC2, its role in the regulatory network was obscured by JAZ until recently. Similarly, other relationships are likely masked by repressors since the overexpression of activators alone had a limited effect on TIA accumulation. In this talk, I will present the role of repressors in the regulatory network and how we can devise strategies to reprogram the regulation to enhance specialized metabolism.