Editing Salvinorin A (section)

=== Biosynthesis ===

The biogenic origin of salvinorin&nbsp;A synthesis has been elucidated using [[nuclear magnetic resonance]] and [[Electrospray ionization|ESI]]-[[mass spectrometry|MS]] analysis of incorporated precursors [[Isotopic labeling|labeled]] with stable [[isotopes]] of [[carbon]] ([[carbon-13]] <sup>13</sup>C) and [[hydrogen]] ([[deuterium]] <sup>2</sup>H). It "is biosynthesized via the [[Non-mevalonate pathway|1-deoxy-d-xylulose-5-phosphate pathway]]", rather than the classic [[mevalonate pathway]], consistent with the common plastidial localization of diterpenoid metabolism.<ref name=Kutrzeba2007/>

[[Terpenoid]]s are biosynthesized from two 5-carbon precursors, [[isopentenyl diphosphate]] (IPP) and [[dimethylallyl diphosphate]] (DMAPP). The NMR and MS study by Zjawiony suggested that the biosynthesis of salvinorin A proceeds via the 1-deoxy-d-xylulose-5-phosphate pathway. In the deoxyxylulose phosphate pathway, D-glyceraldehyde 3-phosphate and pyruvate, the intermediates of the glycolysis, are converted into 1-deoxy-D-xylulose 5-phosphate via decarboxylation. Subsequent reduction with NADPH generates 2C-methyl-D-erythritol 2,4-cyclodiphosphate, via the intermediates 4-diphosphocytidyl-2-C-methyl-D-erythritol and 4-diphosphocytidyl-2c-methyl-d-erythritol-2-phosphate, which then lead to IPP and DMAPP.

[[File:Synthesis of IPP and DMAPP via 1-deoxy-d-xylulose-5-phosphate Pathway.png|class=skin-invert-image|thumb|Synthesis of IPP and DMAPP via 1-deoxy-d-xylulose-5-phosphate pathway]]

Subsequent addition of three 5-carbon IPP units to a single 5-carbon DMAPP unit generates the 20-carbon central precursor, [[geranylgeranyl diphosphate]] (GGPP). Bicyclization of GGPP by the class II diterpene synthase, ''ent''-clerodienyl diphosphate synthase (SdCPS2<ref name=SdCPS2>{{cite web |url=http://www.ncbi.nlm.nih.gov/nuccore/KX424877.1|title=Salvia divinorum kolavenyl diphosphate synthase (CPS2) mRNA, complete cds|date=December 11, 2016|via=NCBI Nucleotide}}</ref>), produces a labdanyl diphosphate carbocation, which is subsequently rearranged through a sequence of 1,2-hydride and methyl shifts to form the [[Clerodane diterpene|''ent''-clerodienyl diphosphate intermediate]].<ref>{{cite journal | vauthors = Pelot KA, Mitchell R, Kwon M, Hagelthorn LM, Wardman JF, Chiang A, Bohlmann J, Ro DK, Zerbe P | display-authors = 6 | title = Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase | journal = The Plant Journal | volume = 89 | issue = 5 | pages = 885–897 | date = March 2017 | pmid = 27865008 | doi = 10.1111/tpj.13427 | doi-access = free }}</ref> SdCPS2 catalyzes the first committed reaction in the biosynthesis of salvinorin A by producing its characteristic clerodane scaffold. A series of oxygenation, acylation and methylation reactions is then required to complete the biosynthesis of salvinorin A.<ref name=SdCPS2/>

[[File:Biosynthesis of Salvinorin A.png|class=skin-invert-image|thumb|Biosynthesis of salvinorin A]]

Similar to many plant-derived psychoactive compounds, salvinorin&nbsp;A is excreted via [[peltate]] glandular [[trichome]]s, which reside external to the [[Epidermis (botany)|epidermis]].<ref name=Siebert2004/><ref name="urlKunkel2007"/>