Genome Mining-Guided Discovery of Polyketide-Tropolone Hybrids Reveals Their Biosynthetic Logic and Antitumor Activity
- 1Guangzhou Key Laboratory of Formula-Pattern Research Centre School of Traditional Chinese Medicine
- 2Jinan University Guangzhou
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.
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BibTeX
@misc{wu2026genome,
title = {{Genome Mining-Guided Discovery of Polyketide-Tropolone Hybrids Reveals Their Biosynthetic Logic and Antitumor Activity}},
author = {Changzheng Wu and Yanfu Wang and Daixi Liu and Leyuan Yu and Zhanghao Wang and Lijuan Deng and Runping Fang and Jianhua Ju and Haiyan Tian and Zhuo Shang},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010572/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010572/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Genome Mining-Guided Discovery of Polyketide-Tropolone Hybrids Reveals Their Biosynthetic Logic and Antitumor Activity
AU - Changzheng Wu
AU - Yanfu Wang
AU - Daixi Liu
AU - Leyuan Yu
AU - Zhanghao Wang
AU - Lijuan Deng
AU - Runping Fang
AU - Jianhua Ju
AU - Haiyan Tian
AU - Zhuo Shang
PY - 2026
DA - 2026/10/16
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010572/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010572/v1
AB - 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.
ER -