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MetaCyc Pathway: serotonin and melatonin biosynthesis
Inferred from experiment

Enzyme View:

Pathway diagram: serotonin and melatonin biosynthesis

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: BiosynthesisHormones Biosynthesis

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

Expected Taxonomic Range: Metazoa, Viridiplantae


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 ]

Created 09-Sep-2008 by Evsikov A, The Jackson Laboratory
Revised 22-May-2013 by Weerasinghe D, SRI International


Barnard08: Barnard AR, Nolan PM (2008). "When clocks go bad: neurobehavioural consequences of disrupted circadian timing." PLoS Genet 4(5);e1000040. PMID: 18516223

Berger09: Berger M, Gray JA, Roth BL (2009). "The expanded biology of serotonin." Annu Rev Med 60;355-66. PMID: 19630576

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

Cho99: Cho SH, Na JU, Youn H, Hwang CS, Lee CH, Kang SO (1999). "Sepiapterin reductase producing L-threo-dihydrobiopterin from Chlorobium tepidum." Biochem J 340 ( Pt 2);497-503. PMID: 10333495

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

Ebihara86: Ebihara S, Marks T, Hudson DJ, Menaker M (1986). "Genetic control of melatonin synthesis in the pineal gland of the mouse." Science 231(4737);491-3. PMID: 3941912

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

Popova06: Popova NK (2006). "From genes to aggressive behavior: the role of serotonergic system." Bioessays 28(5);495-503. PMID: 16615082

Reiter10: Reiter RJ, Tan DX, Fuentes-Broto L (2010). "Melatonin: a multitasking molecule." Prog Brain Res 181;127-51. PMID: 20478436

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

Thony00: Thony B, Auerbach G, Blau N (2000). "Tetrahydrobiopterin biosynthesis, regeneration and functions." Biochem J 347 Pt 1;1-16. PMID: 10727395

Vanecek98: Vanecek J (1998). "Cellular mechanisms of melatonin action." Physiol Rev 78(3);687-721. PMID: 9674691

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

Wang11b: 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

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

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

Chang96: Chang YT, Mues G, Hyland K (1996). "Alternative splicing in the coding region of human aromatic L-amino acid decarboxylase mRNA." Neurosci Lett 202(3);157-60. PMID: 8848255

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 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

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

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

Lindstrom86: Lindstrom P (1986). "Aromatic-L-amino-acid decarboxylase activity in mouse pancreatic islets." Biochim Biophys Acta 884(2);276-81. PMID: 3533158

Lovenberg62: Lovenberg, W, Weissbach, H, Udenfriend, S (1962). "Aromatic L-amino acid decarboxylase." J Biol Chem 237;89-93. PMID: 14466899

Maneckjee83: Maneckjee R, Baylin SB (1983). "Use of radiolabeled monofluoromethyl-Dopa to define the subunit structure of human L-Dopa decarboxylase." Biochemistry 22(26);6058-63. PMID: 6661425

Mappouras90: Mappouras DG, Stiakakis J, Fragoulis EG (1990). "Purification and characterization of L-dopa decarboxylase from human kidney." Mol Cell Biochem 94(2);147-56. PMID: 2374548

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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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 Pathway Tools version 19.5 (software by SRI International) on Tue Jan 1, 2002, biocyc12.