Melatonin metabolism and effects (WP3298)

Melatonin is an important regulator of circadian rythmus and influences also insulin secretion, immune function, retinal function and neuroprotection. The synthesis starts with the amino acid tryptophan which is catalyzed to serotonin. AANAT and ASMT catalyze the reaction to N-acetylserotonin and melatonin, respectively. Melatonin is mainly discarded by the liver enzyme CYP1A2 but other enzymes from the cytochrome family are also known to metabolize melatonin. Recent investigation show e.g. that melatonin plays an important role in colon cancer growth. Proteins on this pathway have targeted assays available via the [ CPTAC Assay Portal]
last edited


Fehrhart, Evelo, Mkutmon, MaintBot, Egonw, Khanspers, AlexanderPico, Justgerrardz, Marvin M2, and Eweitz

Cited In


Homo sapiens



Disease Ontology: sleep disorder cancer developmental disorder of mental health

Pathway Ontology: hormone signaling pathway


Label Type Compact Identifier
MAP2 GeneProduct ensembl:ENSG00000078018
Clock Protein ensembl:ENSP00000426983
MTNR1B GeneProduct ensembl:ENSG00000134640
N-Acetylserotonin Metabolite chebi:17697
Serotonin Metabolite chebi:28790
Cry Protein ensembl:ENSP00000008527
SULT1A1 GeneProduct ensembl:ENSG00000196502
CSNK1D Protein ensembl:ENSG00000141551
edu-1-mRNA GeneProduct None
Lipopolysaccharide Metabolite chebi:16412
Cytoskeleton rearrangement Dendrite formation Pathway None
EDN1 GeneProduct ensembl:ENSG00000078401
Biogenic amine synthesis Pathway wikipathways:WP550
CAM GeneProduct ensembl:ENSG00000198668
5-Hydroxyindoleacetic acid Metabolite chebi:27823
CYP1B1 GeneProduct ensembl:ENSG00000138061
free radicals Metabolite chebi:26519
ACHE GeneProduct ensembl:ENSG00000087085
CaMK2 GeneProduct ensembl:ENSG00000070808
MAOA Protein ensembl:ENSG00000189221
Arntl Protein ensembl:ENSP00000374357
ARNTL GeneProduct ensembl:ENSG00000133794
Tryptophan metabolism Pathway wikipathways:WP465
Circadian rhythm Pathway wikipathways:WP1797
Pinoline Metabolite pubchem.compound:1868
CYP2D6 GeneProduct ensembl:ENSG00000100197
5-Methoxytryptamine Metabolite chebi:2089
TRAF6 GeneProduct ensembl:ENSG00000175104
IRAK1 GeneProduct ensembl:ENSG00000184216
PER2 GeneProduct ensembl:ENSG00000132326
hsa-mir-146a Rna mirbase:MI0000477
MTNR1A GeneProduct ensembl:ENSG00000168412
Melatonin Metabolite chebi:16796
CLOCK GeneProduct ensembl:ENSG00000134852
cyclic 6-hydroxymelatonin Metabolite hmdb:HMDB0060810
Per Protein ensembl:ENSP00000314420
PKC GeneProduct ensembl:ENSG00000154229
Ethinhyloestradiol Metabolite pubchem.compound:5991
6-Sulfatoxymelatonin Metabolite hmdb:HMDB0041815
AANAT GeneProduct ensembl:ENSG00000129673
cAMP Metabolite chebi:17489
GSK3B GeneProduct ensembl:ENSG00000082701
N,N-Dimethyltryptamine Metabolite chebi:28969
CSNK1E Protein ensembl:ENSG00000213923
SIRT1 GeneProduct ensembl:ENSG00000096717
5-methoxypsoralen Metabolite pubchem.compound:2355
ADRB GeneProduct ensembl:ENSG00000043591
NFKB1 GeneProduct ensembl:ENSG00000109320
FOXO1 GeneProduct ensembl:ENSG00000150907
CYP1A1 GeneProduct ensembl:ENSG00000140465
PKA Protein None
PER3 GeneProduct ensembl:ENSG00000049246
Cancer growth Pathway None
ECE-1 GeneProduct ensembl:ENSG00000117298
Noradrenaline Metabolite chebi:33569
6-Hydroxymelatonin Metabolite chebi:2198
APOE GeneProduct uniprot:P02649
PER1 GeneProduct ensembl:ENSG00000179094
CYP1A2 GeneProduct ensembl:ENSG00000140505
Bufotenin Metabolite chebi:3210
ASMT GeneProduct ensembl:ENSG00000196433
CYP2C19 GeneProduct ensembl:ENSG00000165841
CRY2 GeneProduct ensembl:ENSG00000121671
CRY1 GeneProduct ensembl:ENSG00000008405
Per Protein ensembl:ENSP00000314420
Cry Protein ensembl:ENSP00000008527
AANAT Protein ensembl:ENSP00000250615
cAMP Metabolite chebi:17489
hsa-mir-126 Rna mirbase:MI0000471
cyclic 3-hydroxymelatonin Metabolite hmdb:HMDB0060069


  1. Yu A-M, Idle JR, Byrd LG, Krausz KW, Küpfer A, Gonzalez FJ. Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6. Pharmacogenetics. 2003 Mar;13(3):173–81. PubMed Europe PMC Scholia
  2. Ma X, Idle JR, Krausz KW, Gonzalez FJ. Metabolism of melatonin by human cytochromes p450. Drug Metab Dispos. 2005 Apr;33(4):489–94. PubMed Europe PMC Scholia
  3. Schomerus C, Korf H-W. Mechanisms regulating melatonin synthesis in the mammalian pineal organ. Ann N Y Acad Sci. 2005 Dec;1057:372–83. PubMed Europe PMC Scholia
  4. Liu Y-J, Meng F-T, Wang L-L, Zhang L-F, Cheng X-P, Zhou J-N. Apolipoprotein E influences melatonin biosynthesis by regulating NAT and MAOA expression in C6 cells. J Pineal Res. 2012 May;52(4):397–402. PubMed Europe PMC Scholia
  5. León J, Casado J, Jiménez Ruiz SM, Zurita MS, González-Puga C, Rejón JD, et al. Melatonin reduces endothelin-1 expression and secretion in colon cancer cells through the inactivation of FoxO-1 and NF-κβ. J Pineal Res. 2014 May;56(4):415–26. PubMed Europe PMC Scholia
  6. Papagiannidou E, Skene DJ, Ioannides C. Potential drug interactions with melatonin. Physiol Behav. 2014 May 28;131:17–24. PubMed Europe PMC Scholia
  7. Veatch OJ, Pendergast JS, Allen MJ, Leu RM, Johnson CH, Elsea SH, et al. Genetic variation in melatonin pathway enzymes in children with autism spectrum disorder and comorbid sleep onset delay. J Autism Dev Disord. 2015 Jan;45(1):100–10. PubMed Europe PMC Scholia
  8. Domínguez-Alonso A, Valdés-Tovar M, Solís-Chagoyán H, Benítez-King G. Melatonin stimulates dendrite formation and complexity in the hilar zone of the rat hippocampus: participation of the Ca++/Calmodulin complex. Int J Mol Sci. 2015 Jan 16;16(1):1907–27. PubMed Europe PMC Scholia
  9. Tian X, Huo X, Dong P, Wu B, Wang X, Wang C, et al. Sulfation of melatonin: enzymatic characterization, differences of organs, species and genders, and bioactivity variation. Biochem Pharmacol. 2015 Apr 15;94(4):282–96. PubMed Europe PMC Scholia
  10. Carloni S, Favrais G, Saliba E, Albertini MC, Chalon S, Longini M, et al. Melatonin modulates neonatal brain inflammation through endoplasmic reticulum stress, autophagy, and miR-34a/silent information regulator 1 pathway. J Pineal Res. 2016 Oct;61(3):370–80. PubMed Europe PMC Scholia