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

Abstract

Abstract 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.