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Title: Biosynthesis of Salvinorin A Proceeds via the Deoxyxylulose Phosphate Pathway

Author
item KUTRZEBA, LUKASZ - UNIVERSITY OF MISSISSIPPI
item Dayan, Franck
item Howell, J Lynn
item FENG, JU - STATE UNIV. OF NEW YORK
item GINER, JOSE'-LUIZ - STATE UNIV. OF NEW YORK
item ZJAWIONY, JORDAN - UNIVERSITY OF MISSISSIPPI

Submitted to: Phytochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/20/2007
Publication Date: 6/3/2007
Citation: Kutrzeba, L., Dayan, F.E., Howell, J., Feng, J., Giner, J., Zjawiony, J.K. 2007. Biosynthesis of Salvinorin A Proceeds via the Deoxyxylulose Phosphate Pathway. Phytochemistry. 68:1872-1881.

Interpretive Summary: Salvinorin A is a compound isolated from the Mexican hallucinogenic plant, Salvia divinorum. Its biosynthesis was studied by feeding plants with labeled substrates and determining where the labeled carbons were incorporated in the molecule, using NMR and MS analysis. This work was made possible by developing a tissue culture method. Our data indicate that salvinorin A is derived from the DOXP pathway, instead of the classic mevalonic acid pathway. This indicates that salvinorin is made primarily in glands and it will guide future research on the individual steps involved in the synthesis of this compound.

Technical Abstract: Salvinorin A, a neoclerodane diterpenoid, isolated from the Mexican hallucinogenic plant, Salvia divinorum is a potent kappa opioid receptor agonist. Its biosynthetic route was studied by NMR and HR-ESI-MS analysis of the products of the incorporation of [1-13C]-glucose, [Me-13C]-methionine, and [1-13C; 3,4-2H2]-1-deoxy-D-xylulose into its structure. The use of cuttings and direct stem injection were unsuccessful, however, incorporation of 13C into salvinorin A was achieved using in vitro sterile culture of microshoots. NMR analysis of salvinorin A (2.7 mg) isolated from 200 microshoots grown in the presence of [1-13C]-glucose established that this pharmacologically important diterpene is biosynthesized via the 1-deoxy-D-xylulose-5-phosphate pathway, instead of the classic mevalonic acid pathway. This was confirmed in plants grown in the presence of [1-13C; 3,4-2H2]-1-deoxy-D-xylulose. In addition, analysis of salvinorin A produced by plants grown in the presence of [Me-13C]-methionine indicates that the methylation of the C-4 carboxyl group is catalyzed by a type III S-adenosyl-L-methionine-dependent O-methyltransferase.