Three cytochrome P450 enzymes consecutively catalyze the biosynthesis of furanoclerodane precursors in Salvia species.
Ruoxi Lin, Haixiu Li, Yiren Xiao, Zhuo Wang, Licheng Liu, Gerhard Saalbach, Carlo Martins, Matthew Furry, Christopher D Vanderwal, Cathie Martin, Evangelos C Tatsis
Plant communications May 12, 2025 DOI: 10.1016/j.xplc.2025.101286 via PubMed
Summary
AI-generated from the abstractThree cytochrome P450 enzymes in the ornamental sage Salvia splendens convert kolavenol into salviarin precursors: annonene, hardwickiic acid, and hautriwaic acid. Orthologous genes in Salvia divinorum encode enzymes with kolavenol synthase, annonene synthase, and hardwickiic acid synthase activity, supporting these as intermediate steps in the biosynthesis of the psychoactive furanoclerodane salvinorin A, which is used in treating opioid addiction. S. splendens can serve as a model for studying furanoclerodane biosynthesis, and the findings provide tools for producing salvinorin A in biotechnological systems.
Study at a glance
| Characteristics | Experimental study with RNA-seq co-expression analysis and functional characterization Peer reviewed |
|---|---|
| Topics | Salvia divinorum |
| Keywords | Salvia splendens Cytochrome p450 Diterpenoid metabolism Furanoclerodanes |
| Key finding | Three cytochrome P450 enzymes in Salvia splendens catalyze consecutive steps in salviarin biosynthesis, and orthologous genes in Salvia divinorum support these as intermediate steps in salvinorin A biosynthesis. |
Abstract
Salvia species native to the Americas are rich in valuable bioactive furanoclerodanes like the psychoactive salvinorin A found in Salvia divinorum, which is used in the treatment of opioid addiction. However, relatively little is known about their biosynthesis. To address this, we investigated the biosynthesis of salviarin, the most abundant furanoclerodane structure in the ornamental sage Salvia splendens. Using a self-organizing map and mutual rank analysis of RNA-seq co-expression data, we identified three cytochrome P450 enzymes responsible for the consecutive conversion of kolavenol into the salviarin precursors: annonene, hardwickiic acid, and hautriwaic acid. Annonene and hardwickiic acid have been proposed as intermediates in the biosynthesis of salvinorin A, and we therefore tested for a common evolutionary origin of the furanoclerodane pathway in these Salvia species by searching for homologous genes in available data for S. divinorum. The enzymes encoded by orthologous genes from S. divinorum displayed kolavenol synthase, annonene synthase, and hardwickiic acid synthase activity, respectively, supporting the view that these are intermediate steps in the biosynthesis of salvinorin A. We further investigated the origin of annonene synthase and the role of gene duplication in the evolution of this specific activity. Our work shows how S. splendens can serve as a model species for the study of furanoclerodane biosynthesis in Salvia species, contributes to understanding the evolution of specialized metabolism in plants, and provides new tools for the production of salvinorin A in biotechnological chassis.