Cytochrome P450-Catalyzed Biosynthesis of a Dihydrofuran Neoclerodane in Magic Mint (<i>Salvia divinorum</i>)
Moonhyuk Kwon, Joseph Christian Utomo, Keunwan Park, Cameron A. Pascoe, Sorina Chiorean, Iris Ngo, Kyle A. Pelot, Cheol‐Ho Pan, Seon-Won Kim, Philipp Zerbe, John C. Vederas, Dae‐Kyun Ro
Abstract
The hallucinogenic plant, Salvia divinorum, synthesizes neoclerodane diterpenes, such as salvinorins, salvidivins, and salvinicins, which are agonistic or antagonistic to μ- or κ-opioid receptors. From S. divinorum trichomes, crotonolide G synthase (SdCS; CYP76AH39) was identified. It catalyzes the conversion of kolavenol to a dihydrofuran neoclerodane, crotonolide G. 18O2-feeding studies confirmed that SdCS incorporates an aerobic oxygen into crotonolide G, rather than forming a cation at C16 that is trapped by the alcohol at C15. Structural modeling of SdCS accompanied by site-directed mutagenesis established the importance of V367 and F479 residues in substrate-binding. The dihydrofuran neoclerodane can serve as a unique lead structure for drug development.