Genome mining for fungal secondary metabolites

Axel A. Brakhage1, Julia Schuemann2, Sebastian Bergmann1, Kirstin Scherlach2, Volker Schroeckh1, Christian Hertweck2

Author address: 

1Molecular and Applied Microbiology, Leibniz-Institute for Natural Product Research and Infection Biology (HKI), and Friedrich Schiller University, Jena, Germany, 2Biomolecular Chemistry, Leibniz-Institute for Natural Product Research and Infection B

Abstract: 

Mixing both genomic data and analytical techniques can be a powerful approach to the discovery of novel and potentially bioactive natural products. Today, if the genome sequence is at hand, it will be possible to estimate the biosynthesis potential for a given organism by mining the whole genome for typical secondary metabolite biosynthesis genes. This approach is particularly promising in microorganisms because most of the natural product biosynthesis genes are organized in clusters. The formation of many important fungal secondary metabolites, polyketides and non-ribosomal peptides involves multifunctional enzymes: polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). Sequence alignments between genomes of different Aspergilli suggest that Aspergillus nidulans has the potential to generate up to 32 polyketides, 14 nonribosomal peptides, and 2 indole alkaloids. This high number of putative metabolites is greater than the known metabolites ascribed to these species, and it may be a reflection of incomplete natural product analysis in these species or failure of many clusters to be expressed, at least under the culture conditions commonly used in laboratories. We reported a new strategy for the successful induction of a silent metabolic pathway in A. nidulans, which led to the discovery of novel PKS-NRPS hybrid metabolites, named aspyridones A and B. In a broad bioactivity screening they exhibited moderate cytotoxic activities. The function of the aspyridones in the natural context and possible triggers for the onset of their biosynthesis remain the subject of ongoing investigations. However, the results shown here provide the proof of principle for a strategy that may be generally applicable to the activation of silent biosynthesis gene clusters, in particular in eukaryotes, which will lead to the discovery of many so far unknown products and therefore represents a novel avenue to drug discovery. Furthermore, using novel tools we try to identify natural triggers of secondary metabolism gene clusters. Bergmann, S., J. Schuemann, K. Scherlach, C. Lange, A. A. Brakhage and C. Hertweck (2007) Nature Chemical Biology 3: 213-217
2008

abstract No: 

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Full conference title: 

9th EUROPEAN CONFERENCE ON FUNGAL GENETICS
    • ECFG 9th (2008)