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 → Hormones Degradation → Melatonin Degradation|
Expected Taxonomic Range:
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
Relationship Links: KEGG:PART-OF:map00380
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
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
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
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
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
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
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
Kobayashi00b: 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
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
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
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