Genome Mining-Guided Discovery of Polyketide-Tropolone Hybrids Reveals Their Biosynthetic Logic and Antitumor Activity
Year: 2026
Type: preprint
Abstract: 2 ABSTRACT: Tropolone-containing natural products display diverse biological activities, yet characterized fungal tropolone hybrids are dominated by sesquiterpene-derived systems, leaving polyketide-tropolone hybridization largely unexplored. Here, genome mining guided by conserved tropolone biosynthetic enzymes and an unusual dual-polyketide synthase architecture led to the discovery of fusariolones A–E and semifusariolone A from Fusarium sp. WA57, defining a distinct family of fungal polyketide-tropolone hybrids. Heterologous pathway reconstitution supported fusABCDEF as the minimal gene set for scaffold assembly and revealed a biosynthetic logic in which a canonical tropolone pathway converges with a highly reducing polyketide synthase. The resulting linear pentaene hydrocarbon represents, to the best of our knowledge, the first such intermediate identified in fungal natural product biosynthesis and supports a proposed FusF-mediated dehydration/hetero-Diels-Alder cascade in scaffold construction. Fusariolone A displayed low-nanomolar antiproliferative activity with pronounced selectivity toward K562 and HT-29 cells. In HT-29 cells, it suppressed DNA synthesis, altered cell cycle progression, and increased apoptosis, while also reducing xenograftassociated fluorescence in zebrafish. Together, these findings establish a distinct biosynthetic strategy for polyketide-tropolone hybrid assembly and expand the chemical and functional space of fungal tropolone natural products.
Source: ChemRxiv
Institutions: Shandong University, Jinan University
Language: English
Subfield: Applied Microbiology and Biotechnology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Award: G905810312
OpenAlex ID: W7222425232