10.1021/jacs.9b09669.s001 Ling Liu Ling Liu Man-Cheng Tang Man-Cheng Tang Yi Tang Yi Tang Fungal Highly Reducing Polyketide Synthases Biosynthesize Salicylaldehydes That Are Precursors to Epoxycyclohexenol Natural Products American Chemical Society 2019 HRPKS biosynthetic gene clusters Polyketide Synthases Biosynthesize Salicylaldehydes HRPKS pathways β- hydroxyl groups Trichoderma virens HRPKS gene cluster enzyme Epoxycyclohexenol Natural Products Fungal intramolecular aldol condensation product trichoxide 1 2019-12-05 19:58:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Fungal_Highly_Reducing_Polyketide_Synthases_Biosynthesize_Salicylaldehydes_That_Are_Precursors_to_Epoxycyclohexenol_Natural_Products/11328083 Fungal highly reducing polyketide synthases (HRPKSs) are highly programmed multidomain enzymes that synthesize reduced polyketide structures. Recent reports indicated salicylaldehydes are synthesized by HRPKS biosynthetic gene clusters, which are unexpected based on known enzymology of HRPKSs. Using genome mining of a <i>Trichoderma virens</i> HRPKS gene cluster that encodes a number of redox enzymes, we uncover the strategy used by HRPKS pathways in the biosynthesis of aromatic products such as salicylaldehyde <b>4</b>, which can be oxidatively modified to the epoxycyclohexanol natural product trichoxide <b>1</b>. We show selective β-hydroxyl groups in the linear HRPKS product are individually reoxidized to β-ketones by short-chain dehydrogenase/reductase enzymes, which enabled intramolecular aldol condensation and aromatization. Our work expands the chemical space of natural products accessible through HRPKS pathways.