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MetaCyc Pathway: melatonin degradation I
Inferred from experimentTraceable author statement to experimental support

Enzyme View:

Pathway diagram: melatonin degradation I

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/AssimilationHormones DegradationMelatonin Degradation

Some taxa known to possess this pathway include : Homo sapiens, Mus musculus, Oryctolagus cuniculus, Rattus norvegicus

Expected Taxonomic Range: Vertebrata

General Background

The indoleamine melatonin is a vertebrate hormone secreted by the pineal gland. It is involved in regulation of circadian and seasonal rhythms. melatonin also has immunomodulatory, anti-inflammatory and antioxidant properties. In addition to the pineal gland it is synthesized in many vertebrate cells and tissues (see pathway serotonin and melatonin biosynthesis). It is ubiquitously present in cells and body fluids due to its amphiphilic properties that allow it to cross membranes. Mitochondria have the highest intracellular concentration of melatonin [Semak05]. Its functional groups allow both specific receptor binding and a role in oxidation chemistry. melatonin is also found in invertebrates [Hardeland03], protozoa [Kohidai03], plants [Van01], fungi [Hardeland03] and bacteria [Tilden97] although its function in many cases remains incompletely defined. melatonin is also used as a human dietary supplement. In vertebrates, endogenous or ingested melatonin is catabolized several ways in different tissues (see below and pathways melatonin degradation II and melatonin degradation III). Reviewed in [Hardeland06, Hardeland08].

The enzymatic pathways of melatonin degradation are shown in this pathway and pathways melatonin degradation II and melatonin degradation III. Melatonin can also be degraded by nonenzymatic pathways involving melatonin radical species, reactive oxygen species, reactive nitrogen species, or ultraviolet B radiation. It can also be degraded by nonenzymatic reactions involving oxoferryl hemoglobin, or hemin. These nonenzymatic reactions are not shown here, but are shown in [Hardeland08, Slominski08, Tan07, Fischer06].

About This Pathway

The main pathway for degradation of circulating, pineal-derived melatonin in humans is via 6-hydroxylation, catalyzed by some isoforms of cytochrome P450 enzymes in the liver, or in extrahepatic tissues [Ma05]. This compound is then sulfated and excreted in urine (in [Fischer06]). Some cytochrome P450 enzymes can also catalyze the O-demethylation of melatonin to N-acetyl-serotonin (N-acetyl-5-hydroxytryptamine) which is either sulfated, or glucuronidated, and excreted in urine [Ma05]. However this latter pathway is quantitatively more minor than the 6-hydroxylation route. 6-hydroxymelatonin can also be generated by nonenzymatic means, via reactive oxygen species or reactive nitrogen species (see above, not shown). Both microsomal and mitochondrial cytochrome P450 enzymes metabolize melatonin by these two routes [Semak08]. Reviewed in [Hardeland08, Tan07].

Superpathways: superpathway of melatonin degradation

Variants: melatonin degradation II, melatonin degradation III

Relationship Links: KEGG:PART-OF:map00380

Created 07-Dec-2009 by Fulcher CA, SRI International


Fischer06: Fischer TW, Sweatman TW, Semak I, Sayre RM, Wortsman J, Slominski A (2006). "Constitutive and UV-induced metabolism of melatonin in keratinocytes and cell-free systems." FASEB J 20(9);1564-6. PMID: 16793870

Hardeland03: Hardeland R, Poeggeler B (2003). "Non-vertebrate melatonin." J Pineal Res 34(4);233-41. PMID: 12662344

Hardeland06: Hardeland R, Pandi-Perumal SR, Cardinali DP (2006). "Melatonin." Int J Biochem Cell Biol 38(3);313-6. PMID: 16219483

Hardeland08: Hardeland R (2008). "Melatonin, hormone of darkness and more: occurrence, control mechanisms, actions and bioactive metabolites." Cell Mol Life Sci 65(13);2001-18. PMID: 18344019

Kohidai03: Kohidai L, Vakkuri O, Keresztesi M, Leppaluoto J, Csaba G (2003). "Induction of melatonin synthesis in Tetrahymena pyriformis by hormonal imprinting--a unicellular "factory" of the indoleamine." Cell Mol Biol (Noisy-le-grand) 49(4);521-4. PMID: 12899443

Ma05: Ma X, Idle JR, Krausz KW, Gonzalez FJ (2005). "Metabolism of melatonin by human cytochromes p450." Drug Metab Dispos 33(4);489-94. PMID: 15616152

Semak05: Semak I, Naumova M, Korik E, Terekhovich V, Wortsman J, Slominski A (2005). "A novel metabolic pathway of melatonin: oxidation by cytochrome C." Biochemistry 44(26);9300-7. PMID: 15981996

Semak08: Semak I, Korik E, Antonova M, Wortsman J, Slominski A (2008). "Metabolism of melatonin by cytochrome P450s in rat liver mitochondria and microsomes." J Pineal Res 45(4);515-23. PMID: 18717775

Slominski08: Slominski A, Tobin DJ, Zmijewski MA, Wortsman J, Paus R (2008). "Melatonin in the skin: synthesis, metabolism and functions." Trends Endocrinol Metab 19(1);17-24. PMID: 18155917

Tan07: Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ (2007). "One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?." J Pineal Res 42(1);28-42. PMID: 17198536

Tilden97: Tilden AR, Becker MA, Amma LL, Arciniega J, McGaw AK (1997). "Melatonin production in an aerobic photosynthetic bacterium: an evolutionarily early association with darkness." J Pineal Res 22(2);102-6. PMID: 9181522

Van01: Van Tassel DL, Roberts N, Lewy A, O'Neill SD (2001). "Melatonin in plant organs." J Pineal Res 31(1);8-15. PMID: 11485009

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

Fukami05: Fukami M, Horikawa R, Nagai T, Tanaka T, Naiki Y, Sato N, Okuyama T, Nakai H, Soneda S, Tachibana K, Matsuo N, Sato S, Homma K, Nishimura G, Hasegawa T, Ogata T (2005). "Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients." J Clin Endocrinol Metab 90(1);414-26. PMID: 15483095

Glatt00: Glatt H (2000). "Sulfotransferases in the bioactivation of xenobiotics." Chem Biol Interact 129(1-2);141-70. PMID: 11154739

Glatt00a: 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

Gonzalez92: Gonzalez FJ (1992). "Human cytochromes P450: problems and prospects." Trends Pharmacol Sci 13(9);346-52. PMID: 1529480

Ikeya89: Ikeya K, Jaiswal AK, Owens RA, Jones JE, Nebert DW, Kimura S (1989). "Human CYP1A2: sequence, gene structure, comparison with the mouse and rat orthologous gene, and differences in liver 1A2 mRNA expression." Mol Endocrinol 3(9);1399-408. PMID: 2575218

Jaiswal87: Jaiswal AK, Nebert DW, McBride OW, Gonzalez FJ (1987). "Human P(3)450: cDNA and complete protein sequence, repetitive Alu sequences in the 3' nontranslated region, and localization of gene to chromosome 15." J Exp Pathol 3(1);1-17. PMID: 3681487

Kobayashi00: Kobayashi K, Yamamoto T, Taguchi M, Chiba K (2000). "High-performance liquid chromatography determination of N- and O-demethylase activities of chemicals in human liver microsomes: application of postcolumn fluorescence derivatization using Nash reagent." Anal Biochem 284(2);342-7. PMID: 10964418

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

Romkes91: Romkes M, Faletto MB, Blaisdell JA, Raucy JL, Goldstein JA (1991). "Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily." Biochemistry 30(13);3247-55. PMID: 2009263

Sekura79: Sekura RD, Jakoby WB (1979). "Phenol sulfotransferases." J Biol Chem 254(13);5658-63. PMID: 447677

Tang96: Tang YM, Wo YY, Stewart J, Hawkins AL, Griffin CA, Sutter TR, Greenlee WF (1996). "Isolation and characterization of the human cytochrome P450 CYP1B1 gene." J Biol Chem 271(45);28324-30. PMID: 8910454

Wu03: Wu MT, Wang YT, Ho CK, Wu DC, Lee YC, Hsu HK, Kao EL, Lee JM (2003). "SULT1A1 polymorphism and esophageal cancer in males." Int J Cancer 103(1);101-4. PMID: 12455060

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
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