If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Secondary Metabolites Biosynthesis → Nitrogen-Containing Secondary Compounds Biosynthesis → Alkaloids Biosynthesis → Isoquinoline and Benzylisoquinoline Alkaloids Biosynthesis|
Morphine is an alkaloid found only in opium poppy ( Papaver somniferum) and related species (e.g., Papaver somniferum setigerum). Opium alkaloids, including morphine, are known to act as chemical defense compounds to protect opium poppy against various herbivores.
In response to stress, the capsules of opium poppies immediately metabolize morphine to dimeric morphine species, called bismorphine A and bismorphine B. These compounds bind to the cell wall polysaccharide pectins, resulting in cross-linking pectins to each other through bismorphine bridges and leading to resistance against hydrolysis by pectinase [Morimoto01, Morimoto03].
Morphine is an extremely potent opiate analgesic psychoactive drug in mammals, due to its strong binding to the opioid receptors, a group of G-protein coupled receptors. Morphine and its precursor codeine are used extensively in medicine to relieve severe or agonizing pain and suffering. Although pharmaceutical synthesis of these compounds has been successful for many years, a commercially feasible total chemical synthesis of morphine has not been achieved, and these compounds are still extracted from the plants. That fact has stimulated recent interests in dissecting the biosynthetic pathway, and the possible development of a combined chemical and enzymatic synthesis alternative.
The pathway was best studied in Papaver somniferum. The accumulation of morphine in the poppy occurs in laticifer cells, but many of the pathway enzymes and their corresponding gene transcripts are localized in several cell types. The biosynthesis of morphine and related alkaloids in opium poppy occurs via a multistep pathway beginning with the amino acid L-tyrosine. L-tyrosine is converted to (S)-reticuline in 7 steps (see (S)-reticuline biosynthesis I). (S)-reticuline is then converted to its stereomer (R)-reticuline, a unique case among the many benzylisoquinone pathways that are known. The conversion occurs via a 1,2-dehydroreticulinium intermediate, and is catalyzed by reticuline epimerase, a fusion protein between a cytochrome P450 (CYP) and an aldo-keto reductase (AKR) [Winzer15, Farrow15].
(R)-reticuline is converted to 7-O-acetylsalutaridinol in three steps. Although an enzyme for the conversion from 7-O-acetylsalutaridinol to thebaine has been reported [Fisinger07], thebaine can also be formed spontaneously. At this point there is a potential split in the pathway - depending on the order in which enzymes act, the pathway can proceed either via codeinone and codeine, or via oripavine and morphinone. Kinetic analysis of the enzymes suggests that the codeinone route is active in vivo [Hagel10]. All enzymes characterized for this pathway show high substrate specificities and stereo-selectivities. In addition, all four oxidoreductases of this pathway are strictly NADPH-dependent, and NADH cannot take its place.
The biosynthetic morphine pathway, that was believed to be restricted to certain members of poppies [Facchini05], was recently demonstrated in human neuroblastoma cells [Boettcher05]. However, the earlier part of the pathway, leading to production of (S)-reticuline, appears to be different in humans (see (S)-reticuline biosynthesis II).
Morimoto01: Morimoto S, Suemori K, Moriwaki J, Taura F, Tanaka H, Aso M, Tanaka M, Suemune H, Shimohigashi Y, Shoyama Y (2001). "Morphine metabolism in the opium poppy and its possible physiological function. Biochemical characterization of the morphine metabolite, bismorphine." J Biol Chem 276(41);38179-84. PMID: 11498543
Winzer15: Winzer T, Kern M, King AJ, Larson TR, Teodor RI, Donninger SL, Li Y, Dowle AA, Cartwright J, Bates R, Ashford D, Thomas J, Walker C, Bowser TA, Graham IA (2015). "Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein." Science 349(6245);309-12. PMID: 26113639
Gesell09: Gesell A, Rolf M, Ziegler J, Diaz Chavez ML, Huang FC, Kutchan TM (2009). "CYP719B1 is salutaridine synthase, the C-C phenol-coupling enzyme of morphine biosynthesis in opium poppy." J Biol Chem 284(36);24432-42. PMID: 19567876
Grothe01: Grothe T, Lenz R, Kutchan TM (2001). "Molecular characterization of the salutaridinol 7-O-acetyltransferase involved in morphine biosynthesis in opium poppy Papaver somniferum." J Biol Chem 276(33);30717-23. PMID: 11404355
Lenz95: Lenz R, Zenk MH (1995). "Acetyl coenzyme A:salutaridinol-7-O-acetyltransferase from papaver somniferum plant cell cultures. The enzyme catalyzing the formation of thebaine in morphine biosynthesis." J Biol Chem 270(52);31091-6. PMID: 8537369
Lenz95a: Lenz R, Zenk MH (1995). "Purification and properties of codeinone reductase (NADPH) from Papaver somniferum cell cultures and differentiated plants." Eur J Biochem 233(1);132-9. PMID: 7588736
Luo06: Luo L, Pappalardi MB, Tummino PJ, Copeland RA, Fraser ME, Grzyska PK, Hausinger RP (2006). "An assay for Fe(II)/2-oxoglutarate-dependent dioxygenases by enzyme-coupled detection of succinate formation." Anal Biochem 353(1);69-74. PMID: 16643838
Rubio06: Rubio S, Larson TR, Gonzalez-Guzman M, Alejandro S, Graham IA, Serrano R, Rodriguez PL (2006). "An Arabidopsis mutant impaired in coenzyme A biosynthesis is sugar dependent for seedling establishment." Plant Physiol 140(3);830-43. PMID: 16415216
Unterlinner99: Unterlinner B, Lenz R, Kutchan TM (1999). "Molecular cloning and functional expression of codeinone reductase: the penultimate enzyme in morphine biosynthesis in the opium poppy Papaver somniferum." Plant J 18(5);465-75. PMID: 10417697
Ziegler06: Ziegler J, Voigtlander S, Schmidt J, Kramell R, Miersch O, Ammer C, Gesell A, Kutchan TM (2006). "Comparative transcript and alkaloid profiling in Papaver species identifies a short chain dehydrogenase/reductase involved in morphine biosynthesis." Plant J 48(2);177-92. PMID: 16968522
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