Metabolic engineering of pharmaceutical compounds in plants

Plants produce a wealth of pharmaceutically active compounds and a particularly interesting class of metabolites are the terpenoids.

Examples of terpenoid metabolites that have been developed into drugs are artemisinin, the best anti-malarial drug currently available that is extracted from the annual plant Artemisia annua and the indolalkaloids (half terpenoid, half alkaloid) vincristine/vinblastine two very potent anti-cancer drugs, extracted from Cataranthuds roseus. In addition, there are hundreds and hundreds of additional pharmaceutically active terpenoids reported in plants that can potentially be developed into new drugs, for example in the sesquiterpene lactone and diterpene acid chemical groups.

Our approach:

We study the biosynthesis of these pharamaceutically active terpenoids in plants and isolate and characterise the genes that are involved in this biosynthesis. Hereto we use state-of-the-art technologies such as metabolomics, transcriptomics, 454 sequencing and bioinformatics. The genes we isolate can be used for expression in micro-organisms to characterise their biochemical function but also for microbial production of the corresponding metabolites. In addition, these genes can be used for metabolic engineering where we aim to increase or modify the production of pharmaceutically active terpenoids in homologous or heterologous plant hosts. For this work Arabidopsis and tobacco are used as models but we also work on real production systems. An example of this is our work on the metabolic engineering of artemisinin production. In collaboration with the Belgian pharmaceutical company Dafra, we are engineering industrial chicory for the production of this anti-malarial drug. The aim of this work is to create a better and cheaper supply of this important anti-malarial drug. Other projects on pharmaceutically active terpenoids include gene discovery for the creation of (new) sesquiterpene lactone variants with interesting properties, engineering of the terpenoid branch of indolakaloid biosynthesis and the improvement of transport and storage of terpenoids in (engineered) plants.     

Selected references:

  • Bertea, C.M., J. R. Freije, H. van der Woude, F. W. A. Verstappen, L. Perk, V. Marquez, J-W De Kraker, M. A. Posthumus, B. J. M. Jansen, Ae. de Groot, M. C. R. Franssen and H. J. Bouwmeester, 2005. Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua L. Planta Medica 71: 40-47
  • Bouwmeester, H.J., C.M. Bertea, J-W. de Kraker, F.W.A. Verstappen and M.C.R. Franssen, 2006. Research to improve artemisinin production for use in the preparation of anti-malarial drugs, In: R.J. Bogers, L.E. Craker and D. Langer (eds) Medicinal and Aromatic Plants, Frontis Workshop 17-20 April 2005, Wageningen, the Netherlands, Sprin ger, pp 275-290.