Salutaridinol

Salutaridinol is a modified benzyltetrahydroisoquinoline alkaloid with the formula C19H23NO4. It is produced in the secondary metabolism of the opium poppy Papaver somniferum (Papaveraceae) as an intermediate in the biosynthetic pathway that generates morphine.[1] As an isoquinoline alkaloid, it is fundamentally derived from tyrosine as part of the shikimate pathway of secondary metabolism.[2] Salutaridinol is a product of the enzyme salutaridine: NADPH 7-oxidoreductase and the substrate for the enzyme salutaridinol 7-O-acetyltransferase, which are two of the four enzymes in the morphine biosynthesis pathway that generates morphine from (R)-reticuline.[3][4] Salutaridinol's unique position adjacent to two of the four enzymes in the morphine biosynthesis pathway gives it an important role in enzymatic, genetic, and synthetic biology studies of morphine biosynthesis. Salutaridinol levels are indicative of the flux through the morphine biosynthesis pathway and the efficacy of both salutaridine: NADPH 7-oxidoreductase and salutaridinol 7-O-acetyltransferase.[5][6]

Salutaridinol
Names
IUPAC name
3,6-Dimethoxy-17-methyl-5,6,8,14-tetradehydromorphinan-4,7α-diol
Other names
5,6,8,14-Tetradehydro-3,6-dimethoxy-17-methyl-morphinan-4,7-diol
Identifiers
CAS Number
ChEBI
ChEMBL
ChemSpider
KEGG
PubChem CID
InChI
  • InChI=1S/C19H23NO4/c1-20-7-6-19-10-16(24-3)14(21)9-12(19)13(20)8-11-4-5-15(23-2)18(22)17(11)19/h4-5,9-10,13-14,21-22H,6-8H2,1-3H3/t13-,14+,19+/m1/s1 Y
    Key: LLSADFZHWMEBHH-TYILLQQXSA-N Y
Properties
Chemical formula
 C19H23NO4
Molar mass 329.396 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

History

Salutaridinol was first identified as an intermediate in the morphine biosynthesis pathway in the mid 1960s.[7][8]

Biosynthesis

In the morphine biosynthetic pathway, salutaridinol is derived in three steps from (R)-reticuline. First, (R)-reticuline undergoes an oxidation at each of its phenol rings mediated by the cytochrome P-450-dependent monooxygenase salutaridine synthase. These phenol group oxidations yield a diradical species that undergoes ortho coupling to the phenol group of the tetrahydroisoquinoline and para coupling to the benzyl group to create the salutaridinol precursor salutaridine. A stereospecific reduction of the salutaridine carbonyl group by salutaridine: NADPH 7-oxidoreductase then generates salutaridinol.[9]

Downstream transformation to morphine
Morphine biosynthesis pathway with salutaridinol highlighted in the box

Salutaridinol can be converted in two reaction steps to the morphine precursor thebaine. The first step is an esterification of the hydroxyl group previously reduced in the conversion of salutaridine to salutaridinol with acetyl-CoA. This step is mediated by the enzyme salutaridinol 7-O-acetyltransferase. The second step is a ring closure achieved by a nucleophilic attack of the phenol group on the dienol system to generate an oxide bridge and kick out an acetate leaving group, giving thebaine.[10][11] This second step does not require an enzyme. Thebaine can then be converted to morphine through two slightly different biosynthetic routes, one of which makes use of the fourth enzyme codeinone reductase.[12][13]

References
  1. Grothe, Torsten, Rainer Lenz, and Toni M. Kutchan. "Molecular characterization of the salutaridinol 7-O-acetyltransferase involved in morphine biosynthesis in opium poppy Papaver somniferum." Journal of Biological Chemistry 276.33 (2001): 30717-30723.
  2. Mann, John. Secondary metabolism. Vol. 2. Oxford: Clarendon press, 1987.
  3. Lenz, Rainer, and Meinhart H. Zenk. "Acetyl coenzyme A: salutaridinol-7-O-acetyltransferase from Papaver somniferum plant cell cultures: The enzyme catalyzing the formation of thebaine in morphine biosynthesis." Journal of Biological Chemistry 270.52 (1995): 31091-31096.
  4. Kutchan, Toni M. "Molecular genetics of plant alkaloid biosynthesis." The alkaloids 50 (1998): 257-316.
  5. Fossati, Elena, et al. "Synthesis of morphinan alkaloids in Saccharomyces cerevisiae." PLoS ONE 10.4 (2015): e0124459.
  6. Galanie, Stephanie, et al. "Complete biosynthesis of opioids in yeast." Science 349.6252 (2015): 1095-1100.
  7. Barton, D. H. R., et al. "444. Investigations on the biosynthesis of morphine alkaloids." Journal of the Chemical Society (Resumed) (1965): 2423-2438.
  8. Battersby, A. R., D. M. Foulkes, and R. Binks. "603. Alkaloid biosynthesis. Part VIII. Use of optically active precursors for investigation on the biosynthesis of morphine alkaloids." Journal of the Chemical Society (Resumed) (1965): 3323-3332.
  9. Dewick, Paul M. Medicinal natural products: a biosynthetic approach. John Wiley & Sons, 2002.
  10. Sharafi, Ali, et al. "Enhanced morphinan alkaloid production in hairy root cultures of Papaver bracteatum by over-expression of salutaridinol 7-o-acetyltransferase gene via Agrobacterium rhizogenes mediated transformation." World Journal of Microbiology and Biotechnology 29.11 (2013): 2125-2131.
  11. Lenz, Rainer, and Meinhart H. Zenk. "Closure of the oxide bridge in morphine biosynthesis." Tetrahedron letters 35.23 (1994): 3897-3900.
  12. Hosztafi, Sandor. "Recent Advances in the Chemistry of Oripavine and Its Derivatives." Advances in Bioscience and Biotechnology 5.8 (2014): 704.
  13. Kramlinger, Valerie M., et al. "Cytochrome P450 3A enzymes catalyze the O6-demethylation of thebaine, a key step in endogenous mammalian morphine biosynthesis." Journal of Biological Chemistry 290.33 (2015): 20200-20210.
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