Reticuline

This article is about an alkaloid chemical. For the connective-tissue fiber, see reticular fiber.

Reticuline

(S)-(+)-reticuline
Names
IUPAC name 3,10-Dimethoxy-8,8a-secoberbine-2,9-diol
Systematic IUPAC name (1S)-1-[(3-Hydroxy-4-methoxyphenyl)methyl]-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol
Identifiers
CAS Number	(S): 485-19-8  Y (R): 3968-19-2
3D model (JSmol)	(S): Interactive image
Beilstein Reference	95671
ChEBI	(S): CHEBI:16718
ChEMBL	(S): ChEMBL235212  Y
ChemSpider	(S): 388724  Y
ECHA InfoCard	100.006.920
EC Number	(S):207-611-3
KEGG	(S): C02105  Y
PubChem CID	(S): 439653 (R): 440586
UNII	(S): X35Z551WT4  Y
CompTox Dashboard (EPA)	(S): DTXSID001317199
InChI InChI=1S/C19H23NO4/c1-20-7-6-13-10-19(24-3)17(22)11-14(13)15(20)8-12-4-5-18(23-2)16(21)9-12/h4-5,9-11,15,21-22H,6-8H2,1-3H3/t15-/m0/s1 Y Key: BHLYRWXGMIUIHG-HNNXBMFYSA-N Y
SMILES (S):CN1CCC2=CC(=C(C=C2[C@@H]1CC3=CC(=C(C=C3)OC)O)O)OC
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

Reticuline is a tetrahydroisoquinoline alkaloid. It is also classified as a benzylisoquinoline alkaloid. ^[1] It is produced in the opium poppy from the amino acid tyrosine, initially as (S)-reticuline, which is a precursor to alkaloids including papaverine and stylopine. Another large group of alkaloids including morphine are made after (S)-reticuline has been converted in the poppy to its enantiomer, (R)-reticuline. ^[2]

Occurrence

Reticuline is found in opium and a variety of plants including Lindera aggregata , ^[3] Annona squamosa , ^[4] and Ocotea fasciculata . ^[5]

Physiological effects

In rodents reticuline possesses potent central nervous system depressing effects. ^[5] It is the precursor of morphine and many other alkaloids. It is also toxic to dopaminergic neurons causing a form of atypical parkinsonism known as Guadeloupean Parkinsonism. ^[6]

Biosynthesis

Benzylisoquinoline alkaloids produced in the opium poppy are derived from the amino acid tyrosine. A sequence of enzyme-catalysed reactions produces (S)-norcoclaurine which goes through three further transformations to give (S)-3'-hydroxy-N-methylcoclaurine. (S)-reticuline is made when the enzyme 3'-hydroxy-N-methyl-(S)-coclaurine 4'-O-methyltransferase adds a methyl group using S-adenosyl methionine as its cofactor. ^{[2] [7]}

(S)-3'-hydroxy-N-methylcoclaurine

+ SAM

 

 

 

 

 

 

 

(S)-reticuline

+ SAH

 

Although (S)-reticuline can be metabolised into a diverse range of alkaloids including papaverine and stylopine, the route to morphinan alkaloids proceeds solely via its enantiomer, (R)-reticuline. ^[2] This is formed by oxidation from the (S) isomer, giving the reticulinylium cation, followed by reduction back to reticuline but of opposite stereochemistry. In the opium poppy, this is accomplished by a fusion protein which combines the function of the enzymes 1,2-dehydroreticuline synthase and 1,2-dehydroreticulinium reductase (NADPH). ^{[8] [9] [10]}

(S)-reticuline

+ NADPH

 

Synthase

O₂

2 H₂O

 

 

 

reticulinylium cation

+ NADP⁺

 

reticulinylium cation

+ NADPH

 

Reductase

H⁺

 

 

 

 

(R)-reticuline

+ NADP⁺

 

This is an irreversible step in the biosynthesis of morphinan alkaloids. ^[2]

Metabolism

Reticuline oxidase uses (S)-reticuline and oxygen to produce the benzylisoquinoline scoulerine, with hydrogen peroxide as a by-product. ^[11]

(S)-reticuline

 

O₂

2 H₂O

 

 

 

scoulerine

Salutaridine synthase uses (R)-reticuline, NADPH, and oxygen to produce salutaridine. ^[12]

(R)-reticuline

+ NADPH

 

 

O₂

2 H₂O

 

 

 

salutaridine

+ NADP⁺

 

Salutaridine can then be transformed progressively to thebaine, oripavine, and morphine. ^[2]

References

1. Hawkins, Kristy M.; Smolke, Christina D. (2008). "Production of Benzylisoquinoline Alkaloids in Saccharomyces cerevisiae". Nature Chemical Biology. 4 (9): 564–573. Bibcode:2008NatCB...4..564H. doi:10.1038/nchembio.105. PMC   2830865 . PMID   18690217.
2. Tian Y, Kong L, Li Q, Wang Y, Wang Y, An Z, Ma Y, Tian L, Duan B, Sun W, Gao R, Chen S, Xu Z (November 2024). "Structural diversity, evolutionary origin, and metabolic engineering of plant specialized benzylisoquinoline alkaloids". Natural Product Reports. 41 (11): 1787–1810. doi:10.1039/d4np00029c. PMID   39360417.
3. Han, Zheng; Zheng, Yunliang; Chen, Na; Luan, Lianjun; Zhou, Changxin; Gan, Lishe; Wu, Yongjiang (2008). "Simultaneous determination of four alkaloids in Lindera aggregata by ultra-high-pressure liquid chromatography–tandem mass spectrometry". Journal of Chromatography A. 1212 (1–2): 76–81. doi:10.1016/j.chroma.2008.10.017. PMID   18951552.
4. Dholvitayakhun, Achara; Trachoo, Nathanon; Sakee, Uthai; et al. (2013). "Potential applications for Annona squamosa leaf extract in the treatment and prevention of foodborne bacterial disease". Natural Product Communications. 8 (3): 385–388. doi: 10.1177/1934578X1300800327 . PMID   23678817.
5. de Morais, Liana Clébia Soares Lima; Barbosa-Filho, José Maria; de Almeida, Reinaldo Nóbrega (1998). "Central depressant effects of reticuline extracted from Ocotea duckei in rats and mice". Journal of Ethnopharmacology. 62 (1): 57–61. doi:10.1016/S0378-8741(98)00044-0. PMID   9720612.
6. Daroff, Robert B.; Jankovic, Joseph; Mazziotta, John C.; Pomeroy, Scott Loren; Bradley, W. G. (25 October 2015). Bradley's neurology in clinical practice (Seventh ed.). London: Elsevier. ISBN   9780323339162. OCLC   932031625.
7. Frenzel T, Zenk MH (1990). "S-Adenosyl-L-methionine: 3'-hydroxy-N-methyl-(S)-coclaurine 4'-O-methyltransferase, a regio- and stereoselective enzyme of the (S)-reticuline pathway". Phytochemistry . 29 (11): 3505–3511. doi:10.1016/0031-9422(90)85265-H.
8. De-Eknamkul W, Zenk MH (1992). "Purification and properties of 1,2-dehydroreticulinium reductase from Papaver somniferum seedlings". Phytochemistry . 31 (3): 813–821. Bibcode:1992PChem..31..813D. doi:10.1016/0031-9422(92)80020-F.
9. Winzer, Thilo; Kern, Marcelo; King, Andrew J.; Larson, Tony R.; Teodor, Roxana I.; Donninger, Samantha L.; Li, Yi; Dowle, Adam A.; Cartwright, Jared; Bates, Rachel; Ashford, David; Thomas, Jerry; Walker, Carol; Bowser, Tim A.; Graham, Ian A. (2015). "Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein". Science. 349 (6245): 309–312. doi:10.1126/science.aab1852. PMID   26113639.
10. Carr, Samuel C.; Rehman, Fasih; Hagel, Jillian M.; Chen, Xue; Ng, Kenneth K. S.; Facchini, Peter J. (2024). "Two ubiquitous aldo-keto reductases in the genus Papaver support a patchwork model for morphine pathway evolution". Communications Biology. 7 (1) 1410. doi: 10.1038/s42003-024-07100-w . PMC   11522673 . PMID   39472466.
11. Kutchan TM, Dittrich H (1995). "Characterization and mechanism of the berberine bridge enzyme, a covalently flavinylated oxidase of benzophenanthridine alkaloid biosynthesis in plants". J. Biol. Chem. 270 (41): 24475–81. doi: 10.1074/jbc.270.41.24475 . PMID   7592663.
12. Gerady R, Zenk MH (1993). "Formation of salutaridine from (R)-reticuline by a membrane-bound cytochrome P-450 enzyme from Papaver somniferum". Phytochemistry . 32: 79–86. doi:10.1016/0031-9422(92)80111-Q.

External links

The dictionary definition of reticuline at Wiktionary