Aspertetranones are a unique class of marine fungal meroditerpenoids characterized by a highly oxygenated, linear 6/6/6/6 tetracyclic core fused to an α-pyrone scaffold. Although the pathway of aspertetranone biosynthesis in Aspergillus ochraceopetaliformis has been partially elucidated, the full potential of these compounds remains untapped. The structural diversity and enzyme promiscuity of tailoring reactions offer unexplored opportunities for the generation of bioactive derivatives through combinatorial biosynthesis. In this study, we identified the atn biosynthetic gene cluster responsible for aspertetranone production in deep-sea-derived Aspergillus versicolor ADS-F20. Through the systematic heterologous expression of 12 key genes in Aspergillus oryzae, the full pathway reconstitution and targeted biosynthesis of 17 metabolites were achieved, thus expanding the known chemical space of meroterpenoids. Notably, bioactivity screening identified compound 6 as having potent antibacterial and antifungal activities against Vibrio vulnificus ATCC 27562 (MIC = 4.50 μg/mL) and Phytophthora nicotianae (MIC = 9.01 μg/mL). Compound 11 demonstrated broad-spectrum anticancer and cytotoxic effects against the K-562, MCF7, and PATU8988T cell lines. This study underscores the power of pathway reprogramming and catalytic network engineering as versatile strategies for expanding the structural and functional diversity of biosynthetic pathway components.
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