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:||Biosynthesis → Hormones Biosynthesis|
Serotonin and melatonin are both derived from the amino acid L-tryptophan. Serotonin is a monoamine neurotransmitter found in the CNS and gut. In the CNS, it is causally involved in the regulation of mood, sleep, appetite, memory and learning [Popova06]. Modulation of serotonin at synapses is the modus operandi of several classes of antidepressants. Serotonin in the periphery is expressed in the enterochromaffin cells of the gastrointestinal tract and regulates gut motility. Released from the enterochromaffin cells, it is taken up by platelets and plays a role in primary homeostasis and cell mediated immune responses [Berger09]. Circulating serotonin derived from peripheral tissues is primarily metabolized in the liver to 5-hydroxyindole acetate, which is excreted in the urine, see serotonin degradation.
Melatonin is a hormone regulating a number of different physiological functions including sleep induction, circadian rhythm, oxidative stress and immune response [Vanecek98]. It is synthesized nocturnally in the pineal gland [Reiter10].
About this Pathway
The biosynthesis of serotonin and melatonin utilize some common reactions starting from L-tryptophan. Tryptophan hydroxylase catalyzes the rate-limiting step of serotonin biosynthesis, the oxidation of L-tryptophan to 5-hydroxy-L-tryptophan [Wang02]. The reaction, which occurs in the presence of molecular oxygen, requires tetrahydrobiopterin as a cofactor. Aromatic L-amino-acid decarboxylase is a pyridoxal 5-phosphate (PLP)-dependent enzyme that catalyzes the decarboxylation of 5-hydroxy-L-tryptophan to the indoleamine serotonin [SumiIchinose92].
Serotonin N-acetyltransferase catalyzes the N-acetylation of serotonin to N-acetylserotonin, the rate-limiting step in melatonin synthesis. It is this enzyme which controls the circadian rhythm of melatonin production by the pineal gland. In all vertebrates, enzyme activity is highest at night time and activity decreases very rapidly upon exposure to light [Klein97]. Rhythms in the mammalian pineal gland are set by afferent information derived from the endogenous clock in the hypothalamic suprachiasmatic nucleus (SCN).
Acetylserotonin O-methyltransferase is the last enzyme of the melatonin biosynthesis pathway, catalyzing the transfer of a methyl group from S-adenosyl-L-methionine onto N-acetyl-serotonin, to produce melatonin.
Melatonin levels are under strong genetic influence and have heterogeneous expression among individuals [Stehle11]. Abnormal melatonin synthesis has been reported as a risk factor for a variety of medical conditions, such as diabetes and psychiatric disorders [Barnard08].
Citations: [Kang10 ]
Blau: Blau N, Bonafe L, Thony B "Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency." Mol Genet Metab 74(1-2);172-85. PMID: 11592814
Cho98: Cho SH, Na JU, Youn H, Hwang CS, Lee CH, Kang SO (1998). "Tepidopterin, 1-O-(L-threo-biopterin-2'-yl)-beta-N-acetylglucosamine from Chlorobium tepidum." Biochim Biophys Acta 1379(1);53-60. PMID: 9468332
Chung00: Chung HJ, Kim YA, Kim YJ, Choi YK, Hwang YK, Park YS (2000). "Purification and characterization of UDP-glucose:tetrahydrobiopterin glucosyltransferase from Synechococcus sp. PCC 7942." Biochim Biophys Acta 1524(2-3);183-8. PMID: 11113566
Kang10: Kang K, Lee K, Park S, Kim YS, Back K (2010). "Enhanced production of melatonin by ectopic overexpression of human serotonin N-acetyltransferase plays a role in cold resistance in transgenic rice seedlings." J Pineal Res 49(2);176-82. PMID: 20586889
Klein97: Klein DC, Coon SL, Roseboom PH, Weller JL, Bernard M, Gastel JA, Zatz M, Iuvone PM, Rodriguez IR, Begay V, Falcon J, Cahill GM, Cassone VM, Baler R (1997). "The melatonin rhythm-generating enzyme: molecular regulation of serotonin N-acetyltransferase in the pineal gland." Recent Prog Horm Res 52;307-57; discussion 357-8. PMID: 9238858
Maier95: Maier J, Ninnemann H (1995). "Biosynthesis of pteridines in Neurospora crassa, Phycomyces blakesleeanus and Euglena gracilis: detection and characterization of biosynthetic enzymes." Photochem Photobiol 61(1);43-53. PMID: 7899493
Mataga91: Mataga N, Imamura K, Watanabe Y (1991). "6R-tetrahydrobiopterin perfusion enhances dopamine, serotonin, and glutamate outputs in dialysate from rat striatum and frontal cortex." Brain Res 551(1-2);64-71. PMID: 1680529
Schallreuter94: Schallreuter KU, Wood JM, Pittelkow MR, Gutlich M, Lemke KR, Rodl W, Swanson NN, Hitzemann K, Ziegler I (1994). "Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin." Science 263(5152);1444-6. PMID: 8128228
Slominski02: Slominski A, Semak I, Pisarchik A, Sweatman T, Szczesniewski A, Wortsman J (2002). "Conversion of L-tryptophan to serotonin and melatonin in human melanoma cells." FEBS Lett 511(1-3);102-6. PMID: 11821057
Stehle11: Stehle JH, Saade A, Rawashdeh O, Ackermann K, Jilg A, Sebesteny T, Maronde E (2011). "A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases." J Pineal Res 51(1);17-43. PMID: 21517957
SumiIchinose92: Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T (1992). "Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis." Biochemistry 31(8);2229-38. PMID: 1540578
Tanaka89: Tanaka K, Kaufman S, Milstien S (1989). "Tetrahydrobiopterin, the cofactor for aromatic amino acid hydroxylases, is synthesized by and regulates proliferation of erythroid cells." Proc Natl Acad Sci U S A 86(15);5864-7. PMID: 2762302
Wang02: Wang L, Erlandsen H, Haavik J, Knappskog PM, Stevens RC (2002). "Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin." Biochemistry 41(42);12569-74. PMID: 12379098
Wang11: Wang H, Yang B, Hao G, Feng Y, Chen H, Feng L, Zhao J, Zhang H, Chen YQ, Wang L, Chen W (2011). "Biochemical characterization of the tetrahydrobiopterin synthesis pathway in the oleaginous fungus Mortierella alpina." Microbiology 157(Pt 11);3059-70. PMID: 21852350
BenAbdallah11: Ben-Abdallah M, Bondet V, Fauchereau F, Beguin P, Goubran-Botros H, Pagan C, Bourgeron T, Bellalou J (2011). "Production of soluble, active acetyl serotonin methyl transferase in Leishmania tarentolae." Protein Expr Purif 75(1);114-8. PMID: 20688166
Botros12: Botros HG, Legrand P, Pagan C, Bondet V, Weber P, Ben-Abdallah M, Lemiere N, Huguet G, Bellalou J, Maronde E, Beguin P, Haouz A, Shepard W, Bourgeron T (2012). "Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway." J Pineal Res. PMID: 22775292
Cichon08: Cichon S, Winge I, Mattheisen M, Georgi A, Karpushova A, Freudenberg J, Freudenberg-Hua Y, Babadjanova G, Van Den Bogaert A, Abramova LI, Kapiletti S, Knappskog PM, McKinney J, Maier W, Jamra RA, Schulze TG, Schumacher J, Propping P, Rietschel M, Haavik J, Nothen MM (2008). "Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder." Hum Mol Genet 17(1);87-97. PMID: 17905754
Coon96: Coon SL, Mazuruk K, Bernard M, Roseboom PH, Klein DC, Rodriguez IR (1996). "The human serotonin N-acetyltransferase (EC 184.108.40.206) gene (AANAT): structure, chromosomal localization, and tissue expression." Genomics 34(1);76-84. PMID: 8661026
Donohue93: Donohue SJ, Roseboom PH, Illnerova H, Weller JL, Klein DC (1993). "Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA." DNA Cell Biol 12(8);715-27. PMID: 8397829
Duchemin00: Duchemin AM, Berry MD, Neff NH, Hadjiconstantinou M (2000). "Phosphorylation and activation of brain aromatic L-amino acid decarboxylase by cyclic AMP-dependent protein kinase." J Neurochem 75(2);725-31. PMID: 10899948
Ferry00: Ferry G, Loynel A, Kucharczyk N, Bertin S, Rodriguez M, Delagrange P, Galizzi JP, Jacoby E, Volland JP, Lesieur D, Renard P, Canet E, Fauchere JL, Boutin JA (2000). "Substrate specificity and inhibition studies of human serotonin N-acetyltransferase." J Biol Chem 275(12);8794-805. PMID: 10722724
Hohjoh03: Hohjoh H, Takasu M, Shishikura K, Takahashi Y, Honda Y, Tokunaga K (2003). "Significant association of the arylalkylamine N-acetyltransferase ( AA-NAT) gene with delayed sleep phase syndrome." Neurogenetics 4(3);151-3. PMID: 12736803
Ichinose85: Ichinose H, Kojima K, Togari A, Kato Y, Parvez S, Parvez H, Nagatsu T (1985). "Simple purification of aromatic L-amino acid decarboxylase from human pheochromocytoma using high-performance liquid chromatography." Anal Biochem 150(2);408-14. PMID: 4091266
Ledley87: Ledley FD, Grenett HE, Bartos DP, van Tuinen P, Ledbetter DH, Woo SL (1987). "Assignment of human tryptophan hydroxylase locus to chromosome 11: gene duplication and translocation in evolution of aromatic amino acid hydroxylases." Somat Cell Mol Genet 13(5);575-80. PMID: 2889273
McKinney08: McKinney J, Johansson S, Halmoy A, Dramsdahl M, Winge I, Knappskog PM, Haavik J (2008). "A loss-of-function mutation in tryptophan hydroxylase 2 segregating with attention-deficit/hyperactivity disorder." Mol Psychiatry 13(4);365-7. PMID: 18347598
OMalley95: O'Malley KL, Harmon S, Moffat M, Uhland-Smith A, Wong S (1995). "The human aromatic L-amino acid decarboxylase gene can be alternatively spliced to generate unique protein isoforms." J Neurochem 65(6);2409-16. PMID: 7595534
Ota90: Ota M, Naoi M, Hamanaka T, Nagatsu T (1990). "Inhibition of human brain aromatic L-amino acid decarboxylase by cooked food-derived 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and other heterocyclic amines." Neurosci Lett 116(3);372-8. PMID: 2243617
Rodriguez94: Rodriguez IR, Mazuruk K, Schoen TJ, Chader GJ (1994). "Structural analysis of the human hydroxyindole-O-methyltransferase gene. Presence of two distinct promoters." J Biol Chem 269(50);31969-77. PMID: 7989373
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