Discovery and characterization of a cytochalasan biosynthetic cluster from the marine-derived fungus Aspergillus flavipes CNL-338


Cytochalasans are a large family of well-studied cytotoxic molecules isolated from fungi. Investigation into the organic extract of the marine-derived fungal strain Aspergillus flavipes CNL-338 led to the isolation of seven leucine-containing cytochalasans. Genome mining allowed for the identification of the ffs biosynthetic gene cluster, and genetic inactivation studies verified its involvement in cytochalasan biosynthesis. In addition, comparative analysis of key residues in the binding pocket of core cytochalasan biosynthetic enzymes revealed significant similarities among fungal adenylation domains despite differences in substrate preference. We report the identification of leucine-containing cytochalasans from the marine-derived A. flavipes CNL-338 and the characterization of the ffs biosynthetic cluster as verified by genetic inactivation studies.

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S.C.H. thanks ARUP Laboratories for a graduate research fellowship, and this work was supported by the ALSAM Foundation (no. 10046217) and Moore Foundation (GBMF7621, to J.M.W. We thank Professor William Fenical and his laboratory from Scripps Institution of Oceanography for providing A. flavipes CNL-338. We would also like to thank Dr. Jack Skalicky (U of Utah) for his assistance with NMR methods.

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Correspondence to Guangwei Wu or Jaclyn M. Winter.

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Dedication: We would like to dedicate this work to Professor William Fenical and the contributions and impact he has had to the field of natural products. We thank him for his mentorship, generosity, and friendship over the years.

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Heard, S.C., Wu, G. & Winter, J.M. Discovery and characterization of a cytochalasan biosynthetic cluster from the marine-derived fungus Aspergillus flavipes CNL-338. J Antibiot 73, 803–807 (2020).

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