The Plant Journal
November 19, 2016
Kyle A. Pelot, Rod Mitchell, Moonhyuk Kwon et al.
76 citations
Salvia divinorum (diviner's sage) produces clerodane-type diterpenoids, including the bioactive salvinorin A, the first non-nitrogenous natural compound that acts as an opioid-receptor agonist. Two diterpene synthases were discovered and characterized: SdCPS1, an ent-copalyl diphosphate synthase, and SdCPS2, a clerodienyl diphosphate synthase. SdCPS2 catalyzes the committed step in salvinorin A biosynthesis, supported by its trichome-specific expression and the absence of other class II diTPSs. Structure-guided mutagenesis identified four catalytic residues that allowed reprogramming SdCPS2 to produce four distinct products, advancing understanding of neo-functionalization in plant diterpene synthases and offering potential for synthetic biology platforms.
BMC plant biology
October 1, 2024
Scott A Ford, Rob W Ness, Moonhyuk Kwon et al.
9 citations
Diviner's sage (Salvia divinorum) produces salvinorin A (SalA), a hallucinogen that activates the human κ-opioid receptor and may help treat chronic pain, addiction, and PTSD. Only two of the roughly twelve steps in SalA's biosynthesis were known. A high-quality chromosome-level genome assembly was produced, with an N50 of 41.4 Mb and 98.4% BUSCO completeness. The diploid genome is about 541 Mb. Two diterpene biosynthetic gene clusters were found, rich in new cytochrome P450s and crotonolide G synthase, which forms an early dihydrofuran ring. Other enzyme classes for later steps were scattered across the genome. Most candidate genes were not induced by methyl jasmonate. This genome enables discovery of the remaining SalA pathway steps.
Physiologia plantarum
January 1, 2024
Iris Ngo, Rahul Kumar, Liang Li et al.
6 citations
A newly identified enzyme, CYP728D26, catalyzes a specific oxygenation step in the biosynthesis of salvinorin A, a potent κ-opioid receptor agonist from the hallucinogenic plant Salvia divinorum. This enzyme acts on crotonolide G, a compound with a clerodane backbone, and has a Michaelis constant (Km) of 13.9 μM. A close relative, CYP728D25, shows activity only in yeast overexpression systems but not in purified assays, highlighting the need for cautious interpretation of such results. Understanding this pathway could enable biomanufacturing of semi-synthetic derivatives for developing alternative, non-opioid pain relievers targeting the κ-opioid receptor.
bioRxiv (Cold Spring Harbor Laboratory)
Scott A. Ford, Rob W. Ness, Moonhyuk Kwon et al.
preprint
A chromosome-level genome assembly of the diviners sage plant, which produces the hallucinogen salvinorin A, has been produced. The genome is about 541 million base pairs, diploid, and comparable to other sage species. Two gene clusters involved in diterpene biosynthesis were identified, including a gene that forms the dihydrofuran ring early in the salvinorin A pathway. Other enzyme classes likely involved in later steps are scattered across the genome. Most of these genes are not activated by methyl jasmonate treatment. This high-quality genome sequence will help uncover the remaining steps in salvinorin A biosynthesis and support exploration of its medical potential for chronic pain, addiction, and post-traumatic stress disorder.