Domesticating deadly carrots: Predicting the biosynthetic pathway of thapsigargins for the treatment of solid tumors
| Autor: | Federico Cozzi, T. Bundgaard Andersen, K Martinez, Christopher Barnes, Henrik Toft Simonsen, Berin A. Boughton, Nina Rønsted |
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| Rok vydání: | 2016 |
| Předmět: |
Pharmacology
chemistry.chemical_classification Apiaceae Thapsigargin biology Organic Chemistry Pharmaceutical Science Cytochrome P450 biology.organism_classification Sesquiterpene lactone Analytical Chemistry Thapsia (plant) Terpene chemistry.chemical_compound Complementary and alternative medicine chemistry Biosynthesis Biochemistry Drug Discovery Vascular cambium biology.protein Molecular Medicine |
| Zdroj: | Planta Medica. 81:S1-S381 |
| ISSN: | 1439-0221 0032-0943 |
| DOI: | 10.1055/s-0036-1596793 |
| Popis: | Thapsigargin, a guaianolide sesquiterpene lactone, is the active component of a pro-drug currently in phase 2 of clinical trials for the treatment of solid tumours. Thapsigargin is currently only being isolated from Thapsia garganica L. (Apiaceae); a member of the taxonomically complex genus Thapsia L. found in the Mediterranean. Thapsia species do not grow well out of their natural habitat and on-going research seeks to solve the potential resource problem for Mipsagargin, a new thapsigargin derived drug, by transferring the biosynthetic pathway to other heterologous hosts for efficient production [1]. Plant material of Thapsia garganica has been collected from around the species' Mediterranean range, as part of a revision of the genus. The amount of thapsigargin and other closely related guaianolides was quantified between individuals across its range, in planta and during the growing season. Secondly the expression levels of the terpene synthases TgTPS1 and TgTPS2, as well as a cytochrome P450, thought to be involved in the biosynthesis of thapsigargin, were investigated. These tests have also been carried out in conjunction with soil analyses to test if fluctuations in the levels of thapsigargin can be linked to environmental factors. Thapsigargin has been found to be extremely variable over its geographical distribution even over small areas. Lastly, to see whether candidates for the biosynthesis of thapsigargin could shed light on where the compound is made within the plant, root sections have been investigated from greenhouse plants provided by ThapsIbiza. Using light microscopy and MALDI-imaging epithelial cells containing thapsigargin and surrounding secretory channels within the vascular cambium were observed, indicating for the first time that this is the localisation of thapsigargin biosynthesis. It is hoped that these results will fast track the discovery of new enzymes involved in the biosynthetic pathway of thapsigargin. |
| Databáze: | OpenAIRE |
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