Enhancing production of the antitumor compound astin by a novel fungal endophyte of Aster tataricus

- Jutta Ludwig-Müller - Technische Universität Dresden - Germany
- Didier Allaer - Diagenode - Belgium (Wallonia)
- Arnaud Delecroix - Lipofabrik Belgium SPRL - Belgium (Wallonia)
- Phillipe Jacques - Université de Liège - Belgium (Wallonia)
- Willem van Berkel - Wageningen University - Netherlands
- Karl-Heinz van Pee - Technische Universität Dresden - Germany
- Luc Willems - Université de Liège - Belgium (Wallonia)

Extracts of dried roots of the plant Aster tataricus are successfully used in traditional Chinese medicine. Astins, secondary metabolites isolated from these root extracts, show promising antitumor activities. Astins are cyclic pentapeptides and ca 20 different astins have been now isolated from aster roots. For antitumor activity, cyclization and a rarely observed dichlorinated proline residue are necessary. Since astins have been isolated from dried aster roots, they were assumed to being produced by the plant itself. However, we showed that the producer of astins is not the plant but a novel, not yet described fungus that we named Pelliciarosea asterica. We detected at least three astins in fermentation broths of the new fungus, among them astin C, which has been one of the active compounds in antitumor studies. We have sequenced the genome of the astin-producing fungus and we could detect nonribosomal peptide synthetase gene clusters likely to code for the synthesis of the cyclic pentapeptide core and additional genes for the formation of nonproteinogenic amino acids required for astin biosynthesis. The discovery that astins can be produced biotechnologically by fermentation of the new fungus now offers the possibility for large-scale production in microorganisms. This will save valuable resources and will be less
time-consuming. In addition, microbial production systems also enable the engineering of product formation via feeding of specific precursors such as amino acids or other halides than chloride. Moreover, the fungus and heterologous expression hosts can be optimized in their astin production rates by genetic engineering. Still, astin production needs to be further improved to make these compounds available in large scale for extensive bioactivity and pharmacological studies. Finally, we will assess the bioactivities of a variety of astin derivatives using, among others, different tumor cell lines as models.