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Production of Podophyllotoxin in Transgenic Anthriscus sylvestris.

Podophyllotoxin (POD) is a lignan, which is used as educt for the semisynthesis of etoposide and tenoposide. Both antineoplastic drugs are of importance for the therapie and today and in the future will be a high demand for the commercial drug and its precursors for the treatment of leukemia [1,2]. For the production of podophyllotoxin three different routes are known:

  1. Extraction and isolation from Podophyllum hexandrum and other Linum species
  2. Production in plant cell cultures
  3. Organic synthesis 

Extraction and isolation of podophyllotoxin from Indian Podophyllum hexandrum species is not economic and characterised by a high price for the final product. Another problem is cultivation of the plant, why mostly the natural product is extracted from wild cllected species. Main reason for this is the limited growth rate and not optimised culture conditions for accelarated growth. As a consequence from wild collection P. hexandrum is actually endangered in India, especially in the Himalaya region. Working with plant cell cultures as described in the past or obtaining the drug by organic synthesis is difficult, the yield is limited and the price can not compete with wild collection.  

To overcome this problem an alternative has been worked out by the group of Prof. Dr. Kayser and the applicant at the Department of Pharmaceutical Biology that is known as combinatorial biosynthesis approach. In recent work that has been submitted for publication [4] the combinatorial biosynthesis of podophyllotoxin has been demonstrated for deoxypodophyllotoxin (DOP). DOP is a precursor in the biosynthesis and can be converted to POD by hydroxylation at the position C7. This metabolic reaction is catalysed in plants by a plant Cytochrom P450. Until now the gene is not known in Podophyllum species why a combinatorial conversion with a human Cytochrom P 450 3A4 in a heterologous E. coli line has been conducted. This reaction in a genetically modified E. coli host allows stereospecific metabolisation of DOP to Epipodophyllotoxin (ePOD) which is the synthetic precursor for industrial production. Main advantage of this metabolisation is that a production of ePOD is economically now of interest and Podophyllum hexandrum species can protected from extinction.

In contrast to conventional species as discussed above the biosynthetic precursor DOP can be isolated from a plant sources which is well known in Northern parts of Europe and which is not at the risk of extinction. The Apiaceae species Anthriscus sylvestris L. Hoffman, is known as a poison plant because of the high content of the toxic deoxypodophyllotoxin. DOP can be found at concentrations between 0.2 and 0.5% in all parts of the plant. As a disadvantage we do not have a clear picture of the lignan profile of the plant and we do not know if other species may contain higher concentrations of the desired product.

Laatst gewijzigd:11 oktober 2012 09:50