Salutaridinol is a modified benzyl
tetrahydroisoquinoline alkaloid with the formula C
19H
23NO
4. 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
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
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 ...
.
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
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 ...
. 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
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 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
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 ...
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
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 ...
. 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