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MetaCyc Pathway: dopamine degradation

Pathway diagram: dopamine degradation

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Degradation/Utilization/Assimilation Amines and Polyamines Degradation

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

Expected Taxonomic Range: Metazoa

The catecholamines dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine) function as neurotransmitters and hormones. They have important physiological regulatory roles and are involved in the development of many diseases. Their biosynthesis is shown in pathway catecholamine biosynthesis. Although the degradation of endogenous catecholamines has been well studied, many inaccuracies based on early studies still remain in the literature. For example, noradrenaline degradation has been depicted as a series of reactions, including oxidative deamination, that form 3,4-dihydroxymandelate, followed by O-methylation to form vanillylmandelate. However, different and updated pathways are shown in [Eisenhofer04] and here.

Catecholamines are biosynthesized in both neuronal and non-neuronal cells, including the central nervous system, sympathetic nerves, adrenal medulla, gastrointestinal tract, and kidneys. They have previously been considered to be metabolized after their release from cells. They are now believed to be largely metabolized in the cells in which they are biosynthesized. In addition, intracellular catecholamines stored in vesicles were believed to be released extracellularly only upon stimulation. It is now thought that vesicular catecholamines are in a dynamic equilibrium with the cytoplasm. Outward leakage from vesicles is countered by active transport back into vesicles by monoamine transporters. The small amount of catecholamines remaining in the cytoplasm are a major source of metabolites. Reviewed in [Eisenhofer04].

The metabolism of the transient (and toxic) aldehyde intermediate 3,4-dihydroxyphenylacetalcehyde by a dehydrogenase is dependent upon the presence (in noradrenaline and adrenaline) or absence (in dopamine) of the β-hydroxyl group. Its absence in dopamine and 3,4-dihydroxyphenylacetaldehyde favors oxidation by aldehyde dehydrogenase. Its presence on noradrenaline, adrenaline and 3,4-dihydroxyphenylglycolaldehyde favors reduction by aldehyde reductase or aldose reductase. Thus, dopamine is preferentially converted to an acid metabolite, and noradrenaline and adrenaline are preferentially converted to an alcohol metabolite. Reviewed in [Eisenhofer04].

Overall, approximately half of the dopamine produced in the body is not converted to noradrenaline and is degraded to inactive metabolites (in [Eisenhofer97]) (see catecholamine biosynthesis). The proportion varies as to site, with the brain being a minor source of dopamine metabolites. Dopamine and all of its metabolites are produced in mesenteric organs (gastrointestinal tract, spleen and pancreas). The major end products of dopamine metabolism, homovanillate, 3,4-dihydroxyphenylacetate, and dopamine sulfate are excreted in urine. Free dopamine is also excreted in urine in significant amounts and is thought to be formed from dihydroxyphenylalanine (DOPA) that is removed from circulation by the kidneys (in [Eisenhofer97]).

The conversion of 3,4-dihydroxyphenylacetaldehyde to 3.4-dihydroxyphenylacetate by NAD-dependent aldehyde dehydrogenase has been shown in rat liver [Tank81]. The O-methylation of 3,4-dihydroxyphenylacetate to form homovanillate is suggested by the use of this substrate by the rat enzyme [Axelrod58], and the identification of these metabolites in human plasma [Eisenhofer97]. 3-Methoxytyramine can potentially be deaminated and oxidized to homovanillate. Most homovanillate is produced in peripheral tissues, with only about 12% produced in brain. Dopamine and its metabolites 3,4-dihydroxyphenylacetate and 3-methoxytyramine can also be conjugated to their respective sulfates in the gastrointestinal tract, an important route for metabolism of dietary biogenic amines and peripherally produced dopamine. These sulfates are excreted in the urine [Eisenhofer97, Goldstein99]. Reviewed in [Eisenhofer04].


Axelrod58: Axelrod J, Tomchick R (1958). "Enzymatic O-methylation of epinephrine and other catechols." J Biol Chem 233(3);702-5. PMID: 13575440

Eisenhofer04: Eisenhofer G, Kopin IJ, Goldstein DS (2004). "Catecholamine metabolism: a contemporary view with implications for physiology and medicine." Pharmacol Rev 56(3);331-49. PMID: 15317907

Eisenhofer97: Eisenhofer G, Aneman A, Friberg P, Hooper D, Fandriks L, Lonroth H, Hunyady B, Mezey E (1997). "Substantial production of dopamine in the human gastrointestinal tract." J Clin Endocrinol Metab 82(11);3864-71. PMID: 9360553

Goldstein99: Goldstein DS, Swoboda KJ, Miles JM, Coppack SW, Aneman A, Holmes C, Lamensdorf I, Eisenhofer G (1999). "Sources and physiological significance of plasma dopamine sulfate." J Clin Endocrinol Metab 84(7);2523-31. PMID: 10404831

Tank81: Tank AW, Weiner H, Thurman JA (1981). "Enzymology and subcellular localization of aldehyde oxidation in rat liver. Oxidation of 3,4-dihydroxyphenylacetaldehyde derived from dopamine to 3,4-dihydroxyphenylacetic acid." Biochem Pharmacol 30(24);3265-75. PMID: 7034733

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

Aksoy94: Aksoy IA, Callen DF, Apostolou S, Her C, Weinshilboum RM (1994). "Thermolabile phenol sulfotransferase gene (STM): localization to human chromosome 16p11.2." Genomics 23(1);275-7. PMID: 7829089

Arcos10: Arcos M, Olivera ER, Arias S, Naharro G, Luengo JM (2010). "The 3,4-dihydroxyphenylacetic acid catabolon, a catabolic unit for degradation of biogenic amines tyramine and dopamine in Pseudomonas putida U." Environ Microbiol 12(6);1684-704. PMID: 20482587

Ashibe07: Ashibe B, Hirai T, Higashi K, Sekimizu K, Motojima K (2007). "Dual subcellular localization in the endoplasmic reticulum and peroxisomes and a vital role in protecting against oxidative stress of fatty aldehyde dehydrogenase are achieved by alternative splicing." J Biol Chem 282(28);20763-73. PMID: 17510064

Barnett04: Barnett AC, Tsvetanov S, Gamage N, Martin JL, Duggleby RG, McManus ME (2004). "Active site mutations and substrate inhibition in human sulfotransferase 1A1 and 1A3." J Biol Chem 279(18);18799-805. PMID: 14871892

Bernier94: Bernier F, Lopez Solache I, Labrie F, Luu-The V (1994). "Cloning and expression of cDNA encoding human placental estrogen sulfotransferase." Mol Cell Endocrinol 99(1);R11-5. PMID: 8187949

Bertocci91: Bertocci B, Miggiano V, Da Prada M, Dembic Z, Lahm HW, Malherbe P (1991). "Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form." Proc Natl Acad Sci U S A 88(4);1416-20. PMID: 1847521

Bidwell99: Bidwell LM, McManus ME, Gaedigk A, Kakuta Y, Negishi M, Pedersen L, Martin JL (1999). "Crystal structure of human catecholamine sulfotransferase." J Mol Biol 293(3);521-30. PMID: 10543947

Chang97: Chang C, Yoshida A (1997). "Human fatty aldehyde dehydrogenase gene (ALDH10): organization and tissue-dependent expression." Genomics 40(1);80-5. PMID: 9070922

Chen91b: Chen ZY, Hotamisligil GS, Huang JK, Wen L, Ezzeddine D, Aydin-Muderrisoglu N, Powell JF, Huang RH, Breakefield XO, Craig I (1991). "Structure of the human gene for monoamine oxidase type A." Nucleic Acids Res 19(16);4537-41. PMID: 1886775

Dajani98: Dajani R, Hood AM, Coughtrie MW (1998). "A single amino acid, glu146, governs the substrate specificity of a human dopamine sulfotransferase, SULT1A3." Mol Pharmacol 54(6);942-8. PMID: 9855620

Dajani99: Dajani R, Sharp S, Graham S, Bethell SS, Cooke RM, Jamieson DJ, Coughtrie MW (1999). "Kinetic properties of human dopamine sulfotransferase (SULT1A3) expressed in prokaryotic and eukaryotic systems: comparison with the recombinant enzyme purified from Escherichia coli." Protein Expr Purif 16(1);11-8. PMID: 10336855

De05: De Colibus L, Li M, Binda C, Lustig A, Edmondson DE, Mattevi A (2005). "Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B." Proc Natl Acad Sci U S A 102(36);12684-9. PMID: 16129825

De96a: De Laurenzi V, Rogers GR, Hamrock DJ, Marekov LN, Steinert PM, Compton JG, Markova N, Rizzo WB (1996). "Sjogren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene." Nat Genet 12(1);52-7. PMID: 8528251

Ganguly95: Ganguly TC, Krasnykh V, Falany CN (1995). "Bacterial expression and kinetic characterization of the human monoamine-sulfating form of phenol sulfotransferase." Drug Metab Dispos 23(9);945-50. PMID: 8565785

Glatt00: Glatt H, Engelke CE, Pabel U, Teubner W, Jones AL, Coughtrie MW, Andrae U, Falany CN, Meinl W (2000). "Sulfotransferases: genetics and role in toxicology." Toxicol Lett 112-113;341-8. PMID: 10720750

Glatt00a: Glatt H (2000). "Sulfotransferases in the bioactivation of xenobiotics." Chem Biol Interact 129(1-2);141-70. PMID: 11154739

Glatt01: Glatt H, Boeing H, Engelke CE, Ma L, Kuhlow A, Pabel U, Pomplun D, Teubner W, Meinl W (2001). "Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects." Mutat Res 482(1-2);27-40. PMID: 11535246

Hildebrandt04: Hildebrandt MA, Salavaggione OE, Martin YN, Flynn HC, Jalal S, Wieben ED, Weinshilboum RM (2004). "Human SULT1A3 pharmacogenetics: gene duplication and functional genomic studies." Biochem Biophys Res Commun 321(4);870-8. PMID: 15358107

Jeffery84: Jeffery DR, Roth JA (1984). "Characterization of membrane-bound and soluble catechol-O-methyltransferase from human frontal cortex." J Neurochem 42(3);826-32. PMID: 6693904

Jones95: Jones AL, Hagen M, Coughtrie MW, Roberts RC, Glatt H (1995). "Human platelet phenolsulfotransferases: cDNA cloning, stable expression in V79 cells and identification of a novel allelic variant of the phenol-sulfating form." Biochem Biophys Res Commun 208(2);855-62. PMID: 7695643

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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