Biosynthesis of Fungal Resorcylic Acid Macrolactones

Resorcylic acid lactones (RALs) are macrocyclic polyketides that display diverse biological activities. This family of compounds is featured by a resorcylate core fused in a macrolactone ring. Two fungal iterative polyketide synthases (IPKSs) are required via a tandem working mode for the biosynthesis of RALs. Heterologous reconstitution of two IPKSs (Rdc1 NRPKS and Rdc5 HRPKS) from radicicol biosynthetic gene cluster in Saccharomyces cerevisiae gave rise to the production of Monocillin II at a yield of 20 mg/L. With the feeding of chemically synthesized pentaketide-S-N-acetyl cysteamine into Rdc1 expressing yeast culture, the production of monocillin II was recovered. This result suggested the chain length control of Rdc5 to be pentaketide and Rdc1 to be tetraketide. Further feeding and in vitro assays showed that the thioesterase (TE) domain of Rdc1 showed flexibility on the stereochemistry of highly reducing precursor.