Alkyl salicylaldehyde derivatives are polyketide natural products, which are widely distributed in fungi and exhibit great structural diversity. Their biosynthetic mechanisms have recently been intensively studied; however, how the polyketide synthases (PKSs) involved in the fungal alkyl salicylaldehyde biosyntheses release their products remained elusive. In this study, we discovered an orphan biosynthetic gene cluster of salicylaldehyde derivatives in the fungus Stachybotrys sp. g12. Intriguingly, the highly reducing PKS StrA, encoded by the gene cluster, performs a reductive polyketide chain release, although it lacks a C-terminal reductase domain, which is typically required for such a reductive release. Our study revealed that the chain release is achieved by the ketoreductase (KR) domain of StrA, which also conducts cannonical β-keto reductions during polyketide chain elongation. Furthermore, we found that the cupin domain-containing protein StrC plays a critical role in the aromatization reaction. Collectively, we have provided an unprecedented example of a KR domain-catalyzed polyketide chain release and a clearer image of how the salicylaldehyde scaffold is generated in fungi.
Two undescribed eudesmane‐type sesquiterpenoids together with four known compounds were isolated from Clonostachys sp. Y6‐1 associated. Their chemical structures were unambiguously determined by NMR, mass spectrometry, and 13C NMR calculation as well as DP4+ probability analyses. The absolute configurations of compounds 1 and 2 were determined by ECD calculation and X‐ray single‐crystal diffraction methods. Furthermore, all isolates were evaluated for in vitrocytotoxic activities against MCF‐7, HCT‐116, MDA‐MB‐231, and SW620 cancer cells. Among them, bioactivity evaluation of compound 5 revealed that weak activity (IC50 = 66.55 ± 0.82 µM) against SW620.
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