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Global genome mining-driven discovery of an unusual biosynthetic logic for fungal polyketide-terpenoid hybrids.

Dexiu YanYudai Matsuda
Published in: Chemical science (2024)
Genome mining has facilitated the efficient discovery of untapped natural products. We performed global genome mining in fungi and discovered a series of biosynthetic gene clusters (BGCs) that appeared to afford polyketide-terpenoid hybrids via a distinct biosynthetic mechanism from those adopted by known pathways. Characterization of one of the BGCs revealed that it yields the drimane-phthalide hybrid 1. During the biosynthesis of 1, the farnesyl group is unusually introduced by the dimethylallyltryptophan synthase-type prenyltransferase MfmD and is then cyclized by the Pyr4-family terpene cyclase MfmH. The replacement of MfmH with its homologue OcdTC gave another hybrid molecule with a monocyclic terpenoid moiety. Moreover, PsetPT, an MfmD homologue, was found to perform dimethylallylation and was then engineered to install a geranyl group. Our study unraveled an unusual biosynthetic mechanism for fungal phthalide-terpenoid hybrids and provided insights into how their structural diversification could be achieved.
Keyphrases
  • genome wide
  • small molecule
  • high throughput
  • cell wall
  • copy number
  • single cell
  • transcription factor
  • genome wide analysis