Planta Med 2011; 77 - PB15
DOI: 10.1055/s-0031-1282269

SPOTLight: Sustainable Production of Thapsigargin using Light – turning moss into a terpenoid producer

T Manczak 1, C Weitzel 1, AH Klem 1, X Pan 1, D Ro 2, C Lunde 1, HT Simonsen 1
  • 1Dept. of Plant Biology and Biotechnology, VKR Research Centre Pro-Active Plants, Faculty of Life Sciences, University of Copenhagen, Denmark
  • 2Dept. of Biological Sciences, University of Calgary, Canada

Terpenoids is the biggest group of secondary metabolites among plants. Their accumulation in species belonging to the Apiaceae and Asteraceae family is the reason why several of these plants possess biological activities that are used in the treatment of various diseases [1,2]. Thapsigargin's ability to induce apoptosis by inhibiting the endo/sarcoplasmatic calcium ATPase (SERCA) makes it a promising agent for the therapy of cancer. The development of a pro-drug targeted to prostate cancer cells allows its selective use [3].

Comparison with related sesquiterpenes for which biosynthetic enzymes have been identified has enabled us to propose an enzymatic pathway by which thapsigargin could be generated from farnesyl diphosphate via several intermediates [1]. Large scale High Throughput Sequencing of expressed mRNAs from Thapsia species was undertaken to provide contig database of gene fragments, to date we have identified and cloned several genes of interest, which are undergoing characterization. Our first targets are two sesquiterpene synthases. Secondly, we have cloned 12 P450's in the CYP71 clade, which is believed to be involved in secondary metabolism. These are currently undergiong characterization in yeast.

To optimize Physcomitrella as a production host for thapsigargin we aim at constitutively upregulate the expression of enzymes involved in the upstream part of the isopentenyl diphosphate (IPP) biosynthesis [4]. These metabolic modifications will increase the pool of the terpenoid precursor IPP that is available for sesquiterpene biosynthesis. We aim at establishing the moss Physcomitrella patents as the system of choice for the production of all kinds of terpenoids [4].

Acknowledgement: We would like to thank The Danish Council for Strategic Research for their financial support.

References: 1. Drew DP et al. (2009) Phytochem Rev 8: 581–599

2. Drew DP et al. (2011) Phytochem Anal In press

3. Søhoel H et al. (2006) Bioorg Med Chem 14: 2810–2815

4. Simonsen HT et al. (2009) Perspec Med Chem 3: 1–6