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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with RNA-seq co-expression analysis and functional characterization Peer reviewed |
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| Topics | Salvia divinorum |
| Keywords | Salvia splendens Cytochrome p450 Diterpenoid metabolism Furanoclerodanes Gene discovery |
| Key findings | 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.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Identified three cytochrome P450 enzymes catalyzing consecutive steps in furanoclerodane biosynthesis, with orthologous S. divinorum genes supporting intermediate steps in salvinorin A biosynthesis.
Synthesized
Comparable studies
Other experimental studies on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. | 2002 | Experimental study | |
| Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. Cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells and... | 2004 | Experimental study | |
| Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues. Animal model | 2014 | Experimental study | |
| Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to kappa-opioid receptors. | 2005 | Experimental study | |
| Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil. Rat brain striatum homogenates | 2009 | Laboratory experiment |
Citations in the library
Cites 9
- Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase The Plant Journal November 19, 2016
- Antinociceptive effects of Salvia divinorum and bioactive salvinorins in experimental pain models in mice. Journal of Ethnopharmacology February 10, 2020
- A chromosome level reference genome of Diviner's sage (Salvia divinorum) provides insight into salvinorin A biosynthesis. BMC plant biology October 1, 2024
- Identification of clerodane diterpene modifying cytochrome P450 (CYP728D26) in Salvia divinorum - en route to psychotropic salvinorin A biosynthesis. Physiologia plantarum 2024
- A Review of Salvinorin Analogs and their Kappa-Opioid Receptor Activity Bioorganic & Medicinal Chemistry Letters March 12, 2018
and 4 more in the library