Biosynthesis of Annullatin D in Penicillium roqueforti Implies Oxidative Lactonization between Two Hydroxyl Groups Catalyzed by a BBE-like Enzyme.

Annullatins from Cordyceps annullata are alkylated aromatic polyketides including annullatin D with a fused dihydrobenzofuran lactone ring system. Here, we report the identification of a silent biosynthetic gene cluster for annullatins from Penicillium roqueforti by heterologous expression in Aspergillus nidulans , gene deletion, and feeding experiments as well as by biochemical characterization. The polyketide core structure is consecutively modified by hydroxylation and prenylation. A berberine bridge enzyme-like protein catalyzes the final step, an oxidative lactonization between two hydroxyl groups, to form (2 S , 9 S )-annullatin D.