Cytochrome P450 Catalyzes Benzene Ring Formation in the Biosynthesis of Trialkyl‐Substituted Aromatic Polyketides

Lorneic acid and related natural products are characterized by a trialkyl‐substituted benzene ring. The formation of the aromatic core in the middle of the polyketide chain is unusual. We characterized a cytochrome P450 enzyme that can catalyze the hallmark benzene ring formation from an acyclic polyene substrate through genetic and biochemical analysis. Using this P450 as a beacon for genome mining, we obtained 12 homologous type I polyketide synthase (PKS) gene clusters, among which two gene clusters are activated and able to produce trialkyl‐substituted aromatic polyketides. Quantum chemical calculations were performed to elucidate the plausible mechanism for P450‐catalyzed benzene ring formation. Our work expands our knowledge of the catalytic diversity of cytochrome P450. A small group of P450 enzymes were identified to form a benzene ring from an acyclic polyene substrate in the biosynthesis of lorneic acid and other trialkyl‐substituted aromatic polyketides. Quantum chemical calculations were performed to elucidate the mechanism of this unique P450‐catalyzed benzene ring formation.