Alcohol Dehydrogenase-Mediated Generation of Cytotoxic Thiophene-Containing Eremophilane Sesquiterpenes

Sulfur-containing heterocyclic natural products are valued for their bioactivity and unique biosynthesis. By reconstituting the <i>jan</i> cluster derived from the marine fungus <i>Penicillium janthinellum</i> H7-4, we discovered two thiophene-bearing cytotoxic eremophilanes, janthiophenes A and B (<b>1</b> and <b>2</b>), together with ten unreported congeners. Biosynthetic studies demonstrated that JanH, a key alcohol dehydrogenase, is responsible for the formation of the janthiophene structures. These findings enrich the oxidoreductase toolbox for the biosynthesis of sulfur-containing architectures.