Salutaridinol is a modified benzyl tetrahydroisoquinoline 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. As an isoquinoline alkaloid, it is fundamentally derived from tyrosine as part of the

shikimate Shikimic acid, more commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a cyclohexanecarboxylic acid. It is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower ''sh ...

pathway of secondary metabolism. Salutaridinol is a product of the enzyme

salutaridine Salutaridine, also known as floripavine, is an alkaloid that is present in the morphinian alkaloid pathway of opium poppy. Its biosynthetic precursor is the alkaloid reticuline, (''R'')-reticuline. (''R'')-Reticuline is converted to salutaridine b ...

NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...

7- oxidoreductase and the substrate for the enzyme

salutaridinol 7-O-acetyltransferase In enzymology, a salutaridinol 7-O-acetyltransferase () is an enzyme that catalysis, catalyzes the chemical reaction :acetyl-CoA + salutaridinol \rightleftharpoons CoA + 7-O-acetylsalutaridinol Thus, the two substrate (biochemistry), substrates o ...

, which are two of the four enzymes in the morphine biosynthesis pathway that generates morphine from

(R)-reticuline Reticuline is a chemical compound found in a variety of plants including ''Lindera aggregata'', '' Annona squamosa'', and '' Ocotea fasciculata'' (also known as ''Ocotea duckei''). It is based on the benzylisoquinoline structure. Reticuline is o ...

. 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

7- oxidoreductase and

History

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

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 In enzymology, a salutaridine synthase () is an enzyme that catalyzes the chemical reaction :(R)-reticuline + NADPH + H+ + O2 \rightleftharpoons salutaridine + NADP+ + 2 H2O The 4 substrates of this enzyme are (R)-reticuline, NADPH, H+, an ...

. These phenol group

oxidations Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...

yield a diradical species that undergoes ortho coupling to the phenol group of the tetrahydroisoquinoline and

para Para, or PARA, may refer to: Businesses and organizations * Paramount Global, traded as PARA on the Nasdaq stock exchange * Para Group, the former name of CT Corp * Para Rubber, now Skellerup, a New Zealand manufacturer * Para USA, formerly ...

coupling to the benzyl group to create the salutaridinol precursor

. A

stereospecific In chemistry, stereospecificity is the property of a reaction mechanism that leads to different stereoisomeric reaction products from different stereoisomeric reactants, or which operates on only one (or a subset) of the stereoisomers."Overlap Con ...

reduction of the salutaridine carbonyl group by

7- oxidoreductase then generates salutaridinol.

Downstream transformation to morphine

Salutaridinol can be converted in two reaction steps to the morphine precursor thebaine. The first step is an esterification of the

hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy g ...

previously reduced in the conversion of

to salutaridinol with

acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...

. This step is mediated by the enzyme

. The second step is a

ring closure A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where al ...

achieved by a nucleophilic attack of the phenol group on the dienol system to generate an

oxide An oxide () is a chemical compound that contains at least one oxygen atom and one other element in its chemical formula. "Oxide" itself is the dianion of oxygen, an O2– (molecular) ion. with oxygen in the oxidation state of −2. Most of the E ...

bridge and kick out an

acetate An acetate is a salt (chemistry), salt formed by the combination of acetic acid with a base (e.g. Alkali metal, alkaline, Alkaline earth metal, earthy, Transition metal, metallic, nonmetallic or radical Radical (chemistry), base). "Acetate" als ...

leaving group, giving thebaine. 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 A reductase is an enzyme that catalyzes a reduction reaction. Examples * 5α-Reductase * 5β-Reductase * Dihydrofolate reductase * HMG-CoA reductase * Methemoglobin reductase * Ribonucleotide reductase * Thioredoxin reductase * ''E. coli'' ...

.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.

References

External links

{{Opioids Benzylisoquinoline alkaloids Morphinans