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Collaborative Biosynthesis of a Class of Bioactive Azaphilones by Two Separate Gene Clusters Containing Four PKS/NRPSs with Transcriptional Crosstalk in Fungi
Author(s) -
Huang Xuenian,
Zhang Wei,
Tang Shen,
Wei Suhui,
Lu Xuefeng
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201915514
Subject(s) - polyketide synthase , biosynthesis , aspergillus terreus , polyketide , crosstalk , secondary metabolism , gene , gene cluster , nonribosomal peptide , natural product , biology , enzyme , chemistry , biochemistry , stereochemistry , physics , optics
Azaphilones are a family of fungal polyketide metabolites with diverse chemical structures and biological activities with a highly oxygenated pyranoquinone bicyclic core. Here, a class of azaphilones possessing a 6/6/6/6 tetracyclic ring system was identified in Aspergillus terreus , and exhibited potential anticancer activities. The gene deletions and biochemical investigations demonstrated that these azaphilones were collaboratively synthesized by two separate clusters containing four core‐enzymes, two nonreducing PKSs, one highly reducing PKS, and one NRPS‐like. More interestingly, we found that the biosynthesis is coordinately regulated by a crosstalk mechanism between these two gene clusters based on three transcriptional factors. This is a meaningful mechanism of fungal secondary metabolism, which allows fungi to synthesize more complex compounds and gain new physiological functions. The results provide a new insight into fungal natural product biosynthesis.