The quest for large amounts of Thapsigargin

摘要: Since 1978 when Ulla Wagner Smitt together with Søren Brøgger Christensen discovered Thapsigargin in the roots of Thapsia garganica L. the tale has moved forward [1]. Today a cancer drug based on Thapsigargin is progressing through clinical trials and GenSpera Ltd will market the drug under the generic name Mipsagargin [1]. Few have attempted to cultivate Thapsia garganica and currently only the company ThapsIbiza is working on this. With some success though it remains to be shown whether these cultivated species contain Thapsigargin. This is ongoing in our laboratory in collaboration with ThapsIbiza and as part of the EU project MedPlant (www. medplant. eu). Secondly, in the EU project DrugTissueCult (www. drugtissuecult. eu) we will attempt to use tissue culture systems to produce biomass of Thapsia garganica; this is performed in collaboration with Alkion Biopharma in France.The third approach is the elucidation of the biosynthesis of Thapsigargin (www. spotlight. ku. dk) and the product in a heterologous host. Here we published the first step of the pathway in 2012 [2], and can now present the second step. The first step was biosynthesized by a terpene synthase to yield kunzeaol, whereas the following step is mediated by a cytochrome P450. This step establish the lactone ring, and provide the backbone for further modifications. Further steps are currently being elucidated, and we will try to express these in yeast and the moss Physcomitrella patens.