Genome mining of multi-substituted alkylresorcinols from a hybrid highly reducing- and type III- polyketide pathway

Fungal alkylresorcinols are a class of polyketides, which are commonly synthesized by the hybridization of highly reducing polyketide synthase (hrPKS) with non-reducing polyketide synthase (nrPKS). In this study, we identified and demonstrated a new assembly model for synthesizing alkylresorcinol (1), which was accomplished by collaboration of a hrPKS (FscA) and a type III PKS (FscB). Furthermore, three post-tailoring enzymes (FscC, FscD, and FscE) act iteratively on 1 skeleton, including successive 14e− oxidation of inert carbons, di-halogenation, and di-methylation, to form highly oxidized and multi-substituted alkylresorcinols. Our work presents an unusual synthesis manner of alkylresorcinols, sheds light on the collaborative mechanism between hrPKS and type III PKS and provides three valuable enzymatic catalysts for the tailoring of alkylresorcinol family natural products in future.