Chemistry:Reticuline
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]
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]
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]
Salutaridine synthase uses (R)-reticuline, NADPH, and oxygen to produce salutaridine.[12]
Salutaridine can then be transformed progressively to thebaine, oripavine, and morphine.[2]
References
- ↑ Hawkins, Kristy M.; Smolke, Christina D. (2008). "Production of Benzylisoquinoline Alkaloids in Saccharomyces cerevisiae". Nature Chemical Biology 4 (9): 564–573. doi:10.1038/nchembio.105. PMID 18690217. Bibcode: 2008NatCB...4..564H.
- ↑ 2.0 2.1 2.2 2.3 2.4 "Structural diversity, evolutionary origin, and metabolic engineering of plant specialized benzylisoquinoline alkaloids". Natural Product Reports 41 (11): 1787–1810. November 2024. doi:10.1039/d4np00029c. PMID 39360417.
- ↑ 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.
- ↑ Dholvitayakhun, Achara 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.
- ↑ 5.0 5.1 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.
- ↑ 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.
- ↑ "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. 1990. doi:10.1016/0031-9422(90)85265-H.
- ↑ "Purification and properties of 1,2-dehydroreticulinium reductase from Papaver somniferum seedlings". Phytochemistry 31 (3): 813–821. 1992. doi:10.1016/0031-9422(92)80020-F. Bibcode: 1992PChem..31..813D.
- ↑ Winzer, Thilo; Kern, Marcelo; King, Andrew J.; Larson, Tony R.; Teodor, Roxana I.; Donninger, Samantha L.; Li, Yi; Dowle, Adam A. et al. (2015). "Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein". Science 349 (6245): 309–312. doi:10.1126/science.aab1852. PMID 26113639.
- ↑ 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). doi:10.1038/s42003-024-07100-w. PMID 39472466.
- ↑ "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. 1995. doi:10.1074/jbc.270.41.24475. PMID 7592663.
- ↑ "Formation of salutaridine from (R)-reticuline by a membrane-bound cytochrome P-450 enzyme from Papaver somniferum". Phytochemistry 32: 79–86. 1993. doi:10.1016/0031-9422(92)80111-Q.
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