<jats:title>Abstract</jats:title><jats:p>Mushroom terpenoids are biologically and chemically diverse fungal metabolites. Among them, melleolides are representative sesquiterpenoids with a characteristic protoilludane skeleton. In this study, we applied a recently established hot spot knock‐in method to elucidate the biosynthetic pathway leading to 1α‐hydroxymelleolide. The biosynthesis of the sesquiterpene core involves the cytochrome P450 catalyzing stepwise hydroxylation of the Δ<jats:sup>6</jats:sup>‐protoilludene framework and a stereochemical inversion process at the C5 position catalyzed by short‐chain dehydrogenase/reductase family proteins. The highlight of the biosynthesis is that the flavoprotein Mld7 catalyzes an oxidation‐triggered double‐bond shift accompanying dehydration and acyl‐group‐assisted substitution with two different nucleophiles at the C6 position to afford the Δ<jats:sup>7</jats:sup>‐protoilludene derivatives, such as melleolide and armillarivin. The complex reaction mechanism was proposed by DFT calculations. Of particular importance is that product distribution is regulated by interaction with the cell membrane.</jats:p>
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