Comparative genome analysis provides a foundation for defining salvinorin A biosynthesis in Salvia divinorum

The synthesis of salvinorin A by Salvia divinorum is of considerable interest for developing pain relief, anti-opioid addiction and antidepressant medications, but progress has been compromised by limited access to plant material and the complexity of the biosynthetic pathway. Initially using S. splendens, a closely related species, the first steps in the biosynthetic pathway have been elucidated. Here, by preparing a genome sequence for S. divinorum, we are able to undertake comparative genomic analyses with closely related species that do not produce salvinorin A. We establish the genetic basis for additional activities in salvinorin A biosynthesis involving cytochrome P450 and methyl-transferase enzymes. Our genome-based, microevolutionary approach provides insight into how specialized furanoclerodanes of immense pharmacological importance evolved. These results lay a clear path for identification of the remaining steps in the biosynthetic pathway which would allow synthetic production for the development of new therapeutics.