Melatonin metabolism and effects (Homo sapiens)

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PInflammationAutophagyMelatonin effectsLightMelatonin synthesis and breakdownEthinhyloestradiolN-AcetylserotoninPerPKAIRAK1Cancer growthcytoskeleton rearrangement dendrite formationCaMK2 CYP1A1ASMTPinolineCYP2D6PER3ApoEhsa-mir-146aCryMAOACAM6-SulfatoxymelatoninAANATPER2ADRBSerotonin5-methoxypsoralenTRAF6MAP2 ClockFOXO1CYP2C19CSNK1ECSNK1Dcyclic 6-hydroxymelatoninNoradrenalineMelatonincAMPTryptophan metabolismEDN1ARNTLPER1MTNR1BBufoteninArntlCLOCKBiogenic Amine SynthesisSIRT1ACHEMTNR1Acircadian rhythmECE-15-Hydroxyindoleacetic acid6-HydroxymelatoninN,N-DimethyltryptamineSULT1A1GSK3BPKCCYP1B1CYP1A2Lipopolysaccharide5-MethoxytryptamineNf-kbfree radicalsedu-1-mRNA27410335662343, 91081CRY2CRY1PerCryAANATPcAMPLighthsa-mir-1262cyclic 3-hydroxymelatonin


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

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  1. Schomerus C, Korf HW; ''Mechanisms regulating melatonin synthesis in the mammalian pineal organ.''; Ann N Y Acad Sci, 2005 PubMed Europe PMC
  2. Carloni S, Favrais G, Saliba E, Albertini MC, Chalon S, Longini M, Gressens P, Buonocore G, Balduini W; ''Melatonin modulates neonatal brain inflammation through ER stress, autophagy and miR-34a/SIRT1 pathway.''; J Pineal Res, 2016 PubMed Europe PMC
  3. Ma X, Idle JR, Krausz KW, Gonzalez FJ; ''Metabolism of melatonin by human cytochromes p450.''; Drug Metab Dispos, 2005 PubMed Europe PMC
  4. Liu YJ, Meng FT, Wang LL, Zhang LF, Cheng XP, Zhou JN; ''Apolipoprotein E influences melatonin biosynthesis by regulating NAT and MAOA expression in C6 cells.''; J Pineal Res, 2012 PubMed Europe PMC
  5. 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 PubMed Europe PMC
  6. Papagiannidou E, Skene DJ, Ioannides C; ''Potential drug interactions with melatonin.''; Physiol Behav, 2014 PubMed Europe PMC
  7. Tian X, Huo X, Dong P, Wu B, Wang X, Wang C, Liu K, Ma X; ''Sulfation of melatonin: enzymatic characterization, differences of organs, species and genders, and bioactivity variation.''; Biochem Pharmacol, 2015 PubMed Europe PMC
  8. León J, Casado J, Jiménez Ruiz SM, Zurita MS, González-Puga C, Rejón JD, Gila A, Muñoz de Rueda P, Pavón EJ, Reiter RJ, Ruiz-Extremera A, Salmerón J.; ''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., 2014 PubMed Europe PMC
  9. Veatch OJ, Pendergast JS, Allen MJ, Leu RM, Johnson CH, Elsea SH, Malow BA; ''Genetic variation in melatonin pathway enzymes in children with autism spectrum disorder and comorbid sleep onset delay.''; J Autism Dev Disord, 2015 PubMed Europe PMC
  10. Yu AM, 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., 2003 PubMed Europe PMC


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107142view14:22, 17 September 2019MaintBotChEBI identifier normalization
106641view21:03, 12 September 2019KhanspersModified description
106153view12:05, 16 August 2019MaintBotHMDB identifier normalization
105644view05:09, 10 August 2019KhanspersModified description
91618view12:20, 23 March 2017Mkutmonfix references
91561view20:01, 13 March 2017Khanspersfixed literature refs
91550view13:10, 10 March 2017FehrhartID update
91549view13:03, 10 March 2017FehrhartID correction of MTNR1B and A
91533view08:14, 9 March 2017Marvin M2Reverted to version '21:59, 15 December 2016' by Marvin M2
91516view08:15, 8 March 2017JustgerrardzModified description
90887view21:59, 15 December 2016Khanspersfixed bad format lit refs
90688view15:22, 8 December 2016FehrhartUpdated IDs for cyclic hydroxymelatonins and sulfatoxymelatonin
88827view09:01, 15 August 2016Fehrhartfixed a line
88826view08:58, 15 August 2016FehrhartAdded melatonin effects on LPS induced inflammation pathways
84382view10:30, 18 February 2016FehrhartAdded AANAT breakdown
84381view10:10, 18 February 2016FehrhartUpgrade of melatonin-serotonin cycle
84145view16:04, 19 January 2016Fehrhartadded literature and details for noradrenaline pathway influencing melatonin synthesis
84143view13:41, 19 January 2016EgonwOntology Term : 'hormone signaling pathway' added !
84142view13:35, 19 January 2016EgonwOntology Term : 'cancer' added !
84141view13:35, 19 January 2016EgonwOntology Term : 'developmental disorder of mental health' added !
84140view13:33, 19 January 2016EgonwOntology Term : 'sleep disorder' added !
84139view13:27, 19 January 2016EgonwFixed the data source name.
84138view13:25, 19 January 2016EgonwAdded a extra identifiers.
83822view22:43, 11 December 2015AlexanderPicoClearing incomplete xref for PKA
82917view22:03, 12 November 2015Khanspersconnected interactions
82856view13:20, 10 November 2015FehrhartAdded dendrite formation pathway
82757view15:41, 30 October 2015Fehrhartfixed some ensembl identifiers
82738view15:35, 26 October 2015FehrhartAdded 3rd melatonin breakdown pathway via O-methylserotonin
81803view14:50, 30 August 2015EgonwFixed weird characters in a paper title.
81802view14:49, 30 August 2015EgonwFixed weird characters in autors names.
81801view13:52, 30 August 2015EgonwAdded a ChEBI ID for 'free radical'.
81796view11:19, 28 August 2015FehrhartSome more literature
81795view10:29, 28 August 2015FehrhartModified description
81794view10:26, 28 August 2015FehrhartMelatonin breakdown pathways
81784view14:24, 27 August 2015FehrhartLiver location of CYP and light dependant noradrenaline stimulation of melatonin production
81783view13:28, 27 August 2015FehrhartAdded backpage annotations
81782view10:47, 27 August 2015FehrhartAdded circadian regulation of clock genes by melatonin
81661view16:06, 22 August 2015MaintBotModified title
81212view15:47, 4 August 2015FehrhartSome more MIM stuff and addition of MAOA
81209view15:18, 4 August 2015Mkutmonfixed literature reference
81208view15:10, 4 August 2015EveloSome MIM stuff
81206view13:01, 4 August 2015FehrhartConnecting lines and added tryptophan pathway
81205view12:37, 4 August 2015FehrhartModified description
81204view12:28, 4 August 2015FehrhartConnection to biogenic amine synthesis pathway
81203view12:25, 4 August 2015FehrhartNew pathway

External references


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NameTypeDatabase referenceComment
5-Hydroxyindoleacetic acidMetaboliteCHEBI:27823 (ChEBI)
5-MethoxytryptamineMetaboliteCHEBI:2089 (ChEBI) 0-methylserotonin
5-methoxypsoralenMetabolite2355 (PubChem-compound)
6-HydroxymelatoninMetaboliteCHEBI:2198 (ChEBI)
6-SulfatoxymelatoninMetaboliteHMDB0041815 (HMDB)
AANATGeneProductENSG00000129673 (Ensembl)
AANATProteinENSP00000250615 (Ensembl)
ACHEGeneProductENSG00000087085 (Ensembl) AAA (aryl-acylamidase) is a subfunction of ACHE
ADRBGeneProductENSG00000043591 (Ensembl)
ARNTLGeneProductENSG00000133794 (Ensembl)
ASMTGeneProductENSG00000196433 (Ensembl)
ApoEGeneProductP02649 (Uniprot-TrEMBL)
ArntlProteinENSP00000374357 (Ensembl)
Biogenic Amine SynthesisPathwayWP550 (WikiPathways)
BufoteninMetaboliteCHEBI:3210 (ChEBI)
CAMGeneProductENSG00000198668 (Ensembl) calmodulin 1, CALM1
CLOCKGeneProductENSG00000134852 (Ensembl)
CRY1GeneProductENSG00000008405 (Ensembl)
CRY2GeneProductENSG00000121671 (Ensembl)
CSNK1DProteinENSG00000141551 (Ensembl)
CSNK1EProteinENSG00000213923 (Ensembl)
CYP1A1GeneProductENSG00000140465 (Ensembl)
CYP1A2GeneProductENSG00000140505 (Ensembl)
  • Synonym CP12, P3-450
  • Main melatonin hydroxylating enzyme
CYP1B1GeneProductENSG00000138061 (Ensembl) Low expression in liver, high expression in (fetal) brain and kidney
CYP2C19GeneProductENSG00000165841 (Ensembl)
CYP2D6GeneProductENSG00000100197 (Ensembl) proven only for rat
CaMK2 GeneProductENSG00000070808 (Ensembl)
Cancer growthPathway
ClockProteinENSP00000426983 (Ensembl)
CryProteinENSP00000008527 (Ensembl)
ECE-1GeneProductENSG00000117298 (Ensembl)
EDN1GeneProductENSG00000078401 (Ensembl)
EthinhyloestradiolMetabolite5991 (PubChem-compound)
FOXO1GeneProductENSG00000150907 (Ensembl)
GSK3BGeneProductENSG00000082701 (Ensembl)
IRAK1GeneProductENSG00000184216 (Ensembl)
LipopolysaccharideMetaboliteCHEBI:16412 (ChEBI)
MAOAProteinENSG00000189221 (Ensembl)
MAP2 GeneProductENSG00000078018 (Ensembl)
MTNR1AGeneProductENSG00000168412 (Ensembl)
MTNR1BGeneProductENSG00000134640 (Ensembl)
MelatoninMetaboliteCHEBI:16796 (ChEBI)
N,N-DimethyltryptamineMetaboliteCHEBI:28969 (ChEBI)
N-AcetylserotoninMetaboliteCHEBI:17697 (ChEBI)
Nf-kbGeneProductENSG00000109320 (Ensembl)
NoradrenalineMetaboliteCHEBI:33569 (ChEBI)
PER1GeneProductENSG00000179094 (Ensembl)
PER2GeneProductENSG00000132326 (Ensembl)
PER3GeneProductENSG00000049246 (Ensembl)
PKCGeneProductENSG00000154229 (Ensembl) PCK - alpha (literature does not give the exact subclass of PCK)
PerProteinENSP00000314420 (Ensembl)
PinolineMetabolite1868 (PubChem-compound)
SIRT1GeneProductENSG00000096717 (Ensembl)
SULT1A1GeneProductENSG00000196502 (Ensembl)
SerotoninMetaboliteCHEBI:28790 (ChEBI)
TRAF6GeneProductENSG00000175104 (Ensembl)
Tryptophan metabolismPathwayWP465 (WikiPathways)
cAMPMetaboliteCHEBI:17489 (ChEBI)
circadian rhythmPathwayWP1797 (WikiPathways)
cyclic 3-hydroxymelatoninMetaboliteHMDB0060069 (HMDB)
cyclic 6-hydroxymelatoninMetaboliteHMDB0060810 (HMDB)
cytoskeleton rearrangement dendrite formationPathway
free radicalsMetaboliteCHEBI:26519 (ChEBI)
hsa-mir-126RnaMI0000471 (miRBase Sequence)
hsa-mir-146aRnaMI0000477 (miRBase Sequence)

Annotated Interactions

No annotated interactions

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