CS-6-2 - A Solution of the catharanthine/tabersonine pathway and the biochemical assembly of corynanthean, strychnos, iboga and aspidosperma monoterpenoid indole alkaloids
Sunday, July 15
3:38 PM - 3:58 PM
Monoterpenoid indole alkaloids (MIAs) are among the most complex and diverse classes of specialized metabolites found in Nature. Represented by the anticancer drugs vinblastine and vincristine from Catharanthus roseus and camptothecin from Camptotheca acuminata, MIAs are a rich source for bioactive compounds with potential medicinal uses. Decades of research have revealed many aspects of MIA biosynthesis, regulation, and transport using the model plant C. roseus, however the key bio-synthetic pathway from the central precursor strictosidine to various basic MIA skeletons remains essentially undiscovered. By combining targeted bioinformatics and gene silencing to identify candidate genes combined with biochemical characterization of selected ones and in vivo pathway reconstitution, the multi-gene pathway from strictosidine to four fundamental MIA skeletons is described for the first time. A series of highly unstable intermediates that rearrange to other important MIA precursors when not used by appropriate enzymes reveals the plasticity of MIA formation and how this fundamental property led to diverse MIA structures found in nature. This discovery also allows the heterologous production of MIA catharanthine and vindoline, from which the dimeric anticancer drug vinblastine/vincristine is biosynthesized.
Michael Easson – Max Planck Institute for Chemical Ecology; Razvan Simonescu – Brock University; Josef Hajicek – Charles University in Prague; Antje Thamm – Brock University; Vonny Salim – Michigan State University; Vincenzo De Luca – Brock University