Metabolic engineering of terpenoid indole alkaloid pathway in Catharanthus roseus

Eukaryotes such as higher plants have evolved to produce a diverse range of low-molecular-weight secondary compounds that can be used as food and feed additives, flavours, fragrances, cosmetics, agrochemicals and pharmaceuticals. The dominant role of secondary metabolites in the pharmaceutical industry is demonstrated by the fact that approximately 50% of novel anticancer drugs have been discovered from nature including blockbusters such as taxanes (paclitaxel), Catharanthus alkaloids and camptothecin. The chemical synthesis of plant-derived compounds is usually challenging and uneconomical because the complex stereospecific structures are difficult to replicate. Sustainable and cost-effective production systems must therefore be developed, and the best outcome can be achieved by integrating biotechnology-based approaches into more sustainable production chains featuring cutting-edge innovative technologies. Spectacular advances in characterizing plant metabolic pathways using functional genomics and through the development of large-scale cultivation processes have offered for the first time unprecedented opportunities to explore the extraordinary complexity of the biochemical capacity of plants in entirely new ways. State-of-the-art genomics tools can now be used to improve the production of known natural compounds or to synthesize entirely novel plant constituents by combinatorial biochemistry in cultivated plants and cells1. Therefore, the utilization of plants and cells as green production factories is becoming more realistic and more attractive also from a commercial point of view. Metabolic engineering aspects to discover bottlenecks in the biosynthetic pathways and direct the selected pathway towards the desired end-product will be discussed using examples of our large EU-project consortium SmartCell which focuses on terpenoid indole alkaloids.