Antitumor astins originate from the fungal endophyte Cyanodermella asteris living within the medicinal plant Aster tataricus

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Thomas Schafhauser - , Chair of Biochemistry, Chair of Plant Physiology, University of Tübingen (Author)
  • Linda Jahn - , Chair of Plant Physiology (Author)
  • Norbert Kirchner - , University of Tübingen (Author)
  • Andreas Kulik - , University of Tübingen (Author)
  • Liane Flor - , Chair of Biochemistry (Author)
  • Alexander Lang - , Chair of Biochemistry (Author)
  • Thibault Caradec - , Université de Lille (Author)
  • David P Fewer - , University of Helsinki (Author)
  • Kaarina Sivonen - , University of Helsinki (Author)
  • Willem J H van Berkel - , Wageningen University & Research (Author)
  • Philippe Jacques - , Université de Lille (Author)
  • Tilmann Weber - , University of Tübingen, Technical University of Denmark (Author)
  • Harald Gross - , University of Tübingen (Author)
  • Karl-Heinz van Pée - , Chair of Biochemistry (Author)
  • Wolfgang Wohlleben - , University of Tübingen (Author)
  • Jutta Ludwig-Müller - , Chair of Plant Physiology (Author)

Abstract

Medicinal plants are a prolific source of natural products with remarkable chemical and biological properties, many of which have considerable remedial benefits. Numerous medicinal plants are suffering from wildcrafting, and thus biotechnological production processes of their natural products are urgently needed. The plant Aster tataricus is widely used in traditional Chinese medicine and contains unique active ingredients named astins. These are macrocyclic peptides showing promising antitumor activities and usually containing the highly unusual moiety 3,4-dichloroproline. The biosynthetic origins of astins are unknown despite being studied for decades. Here we show that astins are produced by the recently discovered fungal endophyte Cyanodermella asteris. We were able to produce astins in reasonable and reproducible amounts using axenic cultures of the endophyte. We identified the biosynthetic gene cluster responsible for astin biosynthesis in the genome of C. asteris and propose a production pathway that is based on a nonribosomal peptide synthetase. Striking differences in the production profiles of endophyte and host plant imply a symbiotic cross-species biosynthesis pathway for astin C derivatives, in which plant enzymes or plant signals are required to trigger the synthesis of plant-exclusive variants such as astin A. Our findings lay the foundation for the sustainable biotechnological production of astins independent from aster plants.

Details

Original languageEnglish
Pages (from-to)26909-26917
JournalProceedings of the National Academy of Sciences of the United States of America
Volume2019
Issue number116
Publication statusE-pub ahead of print - 6 Dec 2019
Peer-reviewedYes

External IDs

PubMedCentral PMC6936678
Scopus 85077321413

Keywords