Early Steps of the Biosynthesis of the Anticancer Antibiotic Pleurotin

Pleurotin is a meroterpenoid specialized metabolite made
by the
fungus Hohenbuehelia grisea, and it is a lead anticancer
molecule due to its irreversible inhibition of the thioredoxin-thioredoxin
reductase system. Total synthesis of pleurotin has been achieved,
including through a stereoselective route; however, its biosynthesis
has not been characterized. In this study, we used isotope-labeled
precursor feeding to show that the nonterpenoid quinone ring of pleurotin
and its congeners is derived from phenylalanine. We sequenced the
genome of H. grisea and used comparative transcriptomics
to identify putative genes involved in pleurotin biosynthesis. We
heterologously expressed a UbiA-like prenyltransferase from H. grisea that led to the accumulation of the first predicted
pleurotin biosynthetic intermediate, 3-farnesyl-4-hydroxybenzoic acid.
This work sets the foundation to fully elucidate the biosynthesis
of pleurotin and its congeners, with long-term potential to optimize
their production for therapeutic use and engineer the pathway toward
the biosynthesis of valuable analogues.