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Nat Chem Biol. 2017 Aug;13(8):895-901. doi: 10.1038/nchembio.2408. Epub 2017 Jun 12.

A scalable platform to identify fungal secondary metabolites and their gene clusters.

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Department of Chemistry, Northwestern University, Evanston, Illinois, USA.
Proteomics Center of Excellence, Northwestern University, Evanston, Illinois, USA.
Department of Medical Microbiology and Immunology and Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Intact Genomics, Inc., St. Louis, Missouri, USA.
Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA.
Center for Forest Mycology Research, Northern Research Station, US Forest Service, Madison, Wisconsin, USA.


The genomes of filamentous fungi contain up to 90 biosynthetic gene clusters (BGCs) encoding diverse secondary metabolites-an enormous reservoir of untapped chemical potential. However, the recalcitrant genetics, cryptic expression, and unculturability of these fungi prevent scientists from systematically exploiting these gene clusters and harvesting their products. As heterologous expression of fungal BGCs is largely limited to the expression of single or partial clusters, we established a scalable process for the expression of large numbers of full-length gene clusters, called FAC-MS. Using fungal artificial chromosomes (FACs) and metabolomic scoring (MS), we screened 56 secondary metabolite BGCs from diverse fungal species for expression in Aspergillus nidulans. We discovered 15 new metabolites and assigned them with confidence to their BGCs. Using the FAC-MS platform, we extensively characterized a new macrolactone, valactamide A, and its hybrid nonribosomal peptide synthetase-polyketide synthase (NRPS-PKS). The ability to regularize access to fungal secondary metabolites at an unprecedented scale stands to revitalize drug discovery platforms with renewable sources of natural products.

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