Genome-guided discovery of clavaic acid, a decalin-containing polyketide encoded by a LovB-like polyketide synthase

Abstract

Fungal iterative type I polyketide synthases (iPKSs) generate structurally diverse natural products. A subset of these assembly line enzymes, exemplified by LovB from Aspergillus terreus, contains a C-terminal condensation domain bearing a noncanonical HRxxxDG motif. While these LovB-like iPKSs are widely distributed in fungi, the majority remain uncharacterized, leaving both their associated polyketide products and the function of their unusual condensation domains largely unexplored. Here, we report the characterization of a LovB-like iPKS from Aspergillus clavatus. Heterologous reconstitution of this PKS system in Aspergillus nidulans led to the discovery of clavaic acid, a previously undescribed polyketide featuring a trimethylated trans-decalin core and an all-E-configured carboxytriene side chain. Functional analysis of the condensation domain in vivo demonstrated that it is essential for clavaic acid biosynthesis. Surprisingly, whereas the conserved arginine residue within the HRxxxDG motif was dispensable for product formation, the conserved aspartate residue was strictly required. These findings expand our understanding of LovB-like iPKSs and establish this enzyme family as a promising source of cryptic fungal polyketides.