Insights into the Natural Occurrence of Monomeric and Dimeric Chromanone Lactones

Chromanone lactones (CLs) are a group of fungal metabolites biologically linked to tetrahydroxanthones (THXs); however, their formation in nature, particularly the occurrence of dimeric CLs, remains largely unknown. Herein, we report the discovery and identification of a biosynthetic gene cluster (ble) for the production of dimeric CLs in Dothideomycetes sp. BMC-101 through genome mining. Investigations into the biosynthetic pathway reveal that the CL moiety is derived from a THX derivative via a nonenzymatic retro-Dieckmann fragmentation. Furthermore, we demonstrate that the P450 monooxygenase BleJ accepts only THXs, rather than CLs, as substrates for dimerization. Subsequently, the THX dimers can convert into CL dimers spontaneously. Our work not only explores the spontaneous conversion of THXs to CLs, which supports the natural occurrence of CLs, but also demonstrates that CL dimers do not arise from the dimerization of CL monomers.