Biosynthesis of prenylated fused-ring aromatic polyketides in fungi: From viridicatumtoxin to the immunosuppressive neosartoricin

The prenyltransferase (PTase) gene vrtC was proposed to be involved in viridicatumtoxin biosynthesis in Penicillium aethiopicum. Targeted gene deletion and reconstitution of recombinant VrtC activity in vitro established that VrtC catalyzes a regiospecific Friedel-Crafts alkylation of the naphthacenedione carboxamide intermediate with geranyl diphosphate (GPP). Genome mining using the VrtC protein sequence leads to the identification of a homologous group of polycyclic aromatic PTase (pcPTase) genes in the genomes of human and animal-associated fungi. Three enzymes from this new subgroup of pcPTases were shown to be able to catalyze transfer of dimethylallyl to several tetracyclic substrates in vitro. In total, seven C₅- or C₁₀-prenylated naphthacedione compounds were generated. Furthermore, activation of the silent gene cluster containing the pcPTase gene in N. fischeri led to the isolation of a tricyclic prenylated polyketide – neosartoricin. Neosartoricin exhibits T-cell antiproliferative activity with an IC₅₀ of 3µM. The discovery of this new subgroup of PTases extends our enzymatic tools for modifying polycyclic compounds and enables genome mining of new prenylated polyketides.