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MetaCyc Pathway: morphine biosynthesis

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

Some taxa known to possess this pathway include ? : Homo sapiens , Papaver somniferum

Expected Taxonomic Range: Mammalia , Papaveraceae

Summary:
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. (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 last two enzymes of the pathway to be discovered were thebaine 6-O-demethylase and codeine O-demethylase, both members of the Fe(II)/2-oxoglutarate-dependent dioxygenase family [Hagel10].

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).

Credits:
Created 14-Jul-2006 by Zhang P , TAIR
Revised 26-Mar-2010 by Caspi R , SRI International


References

Boettcher05: Boettcher C, Fellermeier M, Boettcher C, Drager B, Zenk MH (2005). "How human neuroblastoma cells make morphine." Proc Natl Acad Sci U S A 102(24);8495-500. PMID: 15937106

Facchini05: Facchini, Peter (2005). "Regulation of alkaloid biosynthesis in plants." The alkaloids, vol 62: 1-50.

Fisinger07: Fisinger, U., Grobe, N., Zenk, M.H. (2007). "Thebaine synthase: a new enzyme in the morphine pathway in Papaver somniferum." Nat. Prod. Commun. 2:249-253.

Hagel10: Hagel JM, Facchini PJ (2010). "Dioxygenases catalyze the O-demethylation steps of morphine biosynthesis in opium poppy." Nat Chem Biol 6(4);273-5. PMID: 20228795

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

Morimoto03: Morimoto S, Suemori K, Taura F, Shoyama Y (2003). "New dimeric morphine from opium poppy (Papaver somuniferum) and its physiological function." J Nat Prod 66(7);987-9. PMID: 12880320

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

DeEknamkul92: De-Eknamkul, Wanchai, Zenk, Meinhart (1992). "Purification and properties of 1,2-dehydroreticuline reductase from Papaver somniferum seedlings." Phytochemistry, 31(3):813-821.

Gerardy93: Gerardy, Roswitha, Zenk, Meinhart (1993). "Formation of salutaridine from (R)reticuline by a membrane-bound cytochrome P-450 enzyme from Papaver somniferum." Phytochemistry, 32(1): 79-86.

Gerardy93a: Gerardy, Roswitha, Zenk, Meinhart (1993). "Purification and characterization of salutaridine:NADPH 7-oxidoreductase from Papaver somniferum." Phytochemistry, 34(1):125-132.

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

Hirata04: Hirata K, Poeaknapo C, Schmidt J, Zenk MH (2004). "1,2-Dehydroreticuline synthase, the branch point enzyme opening the morphinan biosynthetic pathway." Phytochemistry 65(8);1039-46. PMID: 15110683

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Lenz95: 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

Lenz95a: 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

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


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Sun Nov 23, 2014, BIOCYC13B.