Cryptic Isomerization in Diterpene Biosynthesis and the Restoration of an Evolutionarily Defunct P450

Biosynthetic modifications of the 6/10-bicyclic hydrocarbon skeletons of the eunicellane family of diterpenoids are unknown. We explored the biosynthesis of a bacterial trans-eunicellane natural product, albireticulone A (3), and identified a novel isomerase that catalyzes cryptic isomerization in the biosynthetic pathway. We also assigned functions of two cytochromes P450 that oxidize the eunicellane skeleton, one of which was a naturally evolved non-functional P450 that, when genetically repaired, catalyzes allylic oxidation. Finally, we described the chemical susceptibility of the trans-eunicellane skeleton to undergo Cope rearrangement to yield inseparable atropisomers.