Neurotransmitter clearance (Homo sapiens)

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61, 54102, 3, 117mitochondrial matrixMAOA-FAD complex[mitochondrial outermembrane]aldehydedehydrogenase,mitochondrial,tetramer[mitochondrialmatrix]cytosolSodium dependentSerotonintransporterDAMAOA [mitochondrialouter membrane]H2OHCYSNa+H2O2Na+NH35HTNa+acetate5HT-N-CH3NAd5HTAdoMetAdoMetH2O2NAdNADHNH3H+FAD [mitochondrialouter membrane]O2O2NH3H2O5HT-N-CH3DAH2OHIAAChoHIALDMAOA-FAD complexSLC22A2SLC6A3ALDH2 [mitochondrialmatrix]CDNBH2OOCT2NAD+HIALDAcChoAdoHcyaldehydedehydrogenase,mitochondrial,tetramerACHE oligomerNa+COMT8, 9


Neurotransmitter released in the synaptic cleft binds to specific receptors on the post-synaptic cell and the excess of the neurotransmitter is cleared to prevent over activation of the post-synaptic cell. The neurotransmitter is cleared by either re-uptake by the pre-synaptic neuron, diffusion in the perisynaptic area, uptake by astrocytes surrounding the synaptic cleft or enzymatic degradation of the neurotransmitter.
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  1. Kryger G, Harel M, Giles K, Toker L, Velan B, Lazar A, Kronman C, Barak D, Ariel N, Shafferman A, Silman I, Sussman JL.; ''Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II.''; PubMed Europe PMC Scholia
  2. Velan B, Grosfeld H, Kronman C, Leitner M, Gozes Y, Lazar A, Flashner Y, Marcus D, Cohen S, Shafferman A.; ''The effect of elimination of intersubunit disulfide bonds on the activity, assembly, and secretion of recombinant human acetylcholinesterase. Expression of acetylcholinesterase Cys-580----Ala mutant.''; PubMed Europe PMC Scholia
  3. DEEDS F, BOOTH AN, JONES FT.; ''Methylation and dehydroxylation of phenolic compounds by rats and rabbits.''; PubMed Europe PMC Scholia
  4. Weyler W.; ''Monoamine oxidase A from human placenta and monoamine oxidase B from bovine liver both have one FAD per subunit.''; PubMed Europe PMC Scholia
  5. Weinstock M, Groner E.; ''Rational design of a drug for Alzheimer's disease with cholinesterase inhibitory and neuroprotective activity.''; PubMed Europe PMC Scholia
  6. Greenfield NJ, Pietruszko R.; ''Two aldehyde dehydrogenases from human liver. Isolation via affinity chromatography and characterization of the isozymes.''; PubMed Europe PMC Scholia
  7. Fernandez E, Koek W, Ran Q, Gerhardt GA, France CP, Strong R.; ''Monoamine metabolism and behavioral responses to ethanol in mitochondrial aldehyde dehydrogenase knockout mice.''; PubMed Europe PMC Scholia
  8. Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, Baumann C, Lang F, Busch AE, Koepsell H.; ''Cloning and characterization of two human polyspecific organic cation transporters.''; PubMed Europe PMC Scholia
  9. Vandenbergh DJ, Thompson MD, Cook EH, Bendahhou E, Nguyen T, Krasowski MD, Zarrabian D, Comings D, Sellers EM, Tyndale RF, George SR, O'Dowd BF, Uhl GR.; ''Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations.''; PubMed Europe PMC Scholia
  10. O'Carroll AM, Fowler CJ, Phillips JP, Tobbia I, Tipton KF.; ''The deamination of dopamine by human brain monoamine oxidase. Specificity for the two enzyme forms in seven brain regions.''; PubMed Europe PMC Scholia
  11. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD.; ''Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization.''; PubMed Europe PMC Scholia
  12. Brenner B, Harney JT, Ahmed BA, Jeffus BC, Unal R, Mehta JL, Kilic F.; ''Plasma serotonin levels and the platelet serotonin transporter.''; PubMed Europe PMC Scholia
  13. Beck O, Helander A, Carlsson S, Borg S.; ''Changes in serotonin metabolism during treatment with the aldehyde dehydrogenase inhibitors disulfiram and cyanamide.''; PubMed Europe PMC Scholia
  14. Guldberg HC, Sharman DF, Tegerdine PR.; ''Some observations on the estimation of 3-methoxytyramine in brain tissue.''; PubMed Europe PMC Scholia
  15. Hempel J, Kaiser R, Jörnvall H.; ''Mitochondrial aldehyde dehydrogenase from human liver. Primary structure, differences in relation to the cytosolic enzyme, and functional correlations.''; PubMed Europe PMC Scholia
  16. Du X, Schwander M, Moresco EM, Viviani P, Haller C, Hildebrand MS, Pak K, Tarantino L, Roberts A, Richardson H, Koob G, Najmabadi H, Ryan AF, Smith RJ, Müller U, Beutler B.; ''A catechol-O-methyltransferase that is essential for auditory function in mice and humans.''; PubMed Europe PMC Scholia
  17. Ahmed ZM, Masmoudi S, Kalay E, Belyantseva IA, Mosrati MA, Collin RW, Riazuddin S, Hmani-Aifa M, Venselaar H, Kawar MN, Tlili A, van der Zwaag B, Khan SY, Ayadi L, Riazuddin SA, Morell RJ, Griffith AJ, Charfedine I, Caylan R, Oostrik J, Karaguzel A, Ghorbel A, Riazuddin S, Friedman TB, Ayadi H, Kremer H.; ''Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans.''; PubMed Europe PMC Scholia
  18. Sotnikova TD, Beaulieu JM, Espinoza S, Masri B, Zhang X, Salahpour A, Barak LS, Caron MG, Gainetdinov RR.; ''The dopamine metabolite 3-methoxytyramine is a neuromodulator.''; PubMed Europe PMC Scholia
  19. Canli T, Lesch KP.; ''Long story short: the serotonin transporter in emotion regulation and social cognition.''; PubMed Europe PMC Scholia


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101216view11:11, 1 November 2018ReactomeTeamreactome version 66
100754view20:36, 31 October 2018ReactomeTeamreactome version 65
100298view19:13, 31 October 2018ReactomeTeamreactome version 64
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99401view14:34, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99092view12:39, 31 October 2018ReactomeTeamreactome version 62
94498view09:04, 14 September 2017Mkutmonreactome version 61
87768view10:01, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
87767view10:00, 25 July 2016RyanmillerOntology Term : 'signaling pathway pertinent to the brain and nervous system' added !
86397view09:17, 11 July 2016ReactomeTeamreactome version 56
83079view09:53, 18 November 2015ReactomeTeamVersion54
81400view12:55, 21 August 2015ReactomeTeamVersion53
76869view08:14, 17 July 2014ReactomeTeamFixed remaining interactions
76574view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75907view09:56, 11 June 2014ReactomeTeamRe-fixing comment source
75607view10:46, 10 June 2014ReactomeTeamReactome 48 Update
74962view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74606view08:39, 30 April 2014ReactomeTeamReactome46
58006view22:02, 5 February 2013AriuttaPeriodical save, work in progress
42088view21:56, 4 March 2011MaintBotAutomatic update
39896view05:55, 21 January 2011MaintBotNew pathway

External references


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NameTypeDatabase referenceComment
5HT-N-CH3MetaboliteCHEBI:3210 (ChEBI)
5HTMetaboliteCHEBI:28790 (ChEBI)
ACHE oligomerComplexREACT_117773 (Reactome)
ALDH2 [mitochondrial matrix]ProteinP05091 (Uniprot-TrEMBL)
AcChoMetaboliteCHEBI:15355 (ChEBI)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
CDNBMetaboliteCHEBI:34718 (ChEBI)
COMTProteinP21964 (Uniprot-TrEMBL)
ChoMetaboliteCHEBI:15354 (ChEBI)
DAMetaboliteCHEBI:18243 (ChEBI)
FAD [mitochondrial outer membrane]MetaboliteCHEBI:16238 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCYSMetaboliteCHEBI:17230 (ChEBI)
HIAAMetaboliteCHEBI:27823 (ChEBI)
HIALDMetaboliteCHEBI:50157 (ChEBI)
MAOA [mitochondrial outer membrane]ProteinP21397 (Uniprot-TrEMBL)
MAOA-FAD complexComplexREACT_5113 (Reactome)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NAdMetaboliteCHEBI:18357 (ChEBI)
NH3MetaboliteCHEBI:16134 (ChEBI)
Na+MetaboliteCHEBI:29101 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
OCT2ProteinREACT_160574 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
SLC22A2ProteinO15244 (Uniprot-TrEMBL)
SLC6A3ProteinQ01959 (Uniprot-TrEMBL)
Sodium dependent


REACT_15766 (Reactome)
acetateMetaboliteCHEBI:30089 (ChEBI)

dehydrogenase, mitochondrial,

ComplexREACT_2466 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
5HT-N-CH3ArrowREACT_15434 (Reactome)
5HT-N-CH3ArrowREACT_15485 (Reactome)
5HT-N-CH3ArrowREACT_15553 (Reactome)
5HT-N-CH3REACT_15553 (Reactome)
5HTArrowREACT_15458 (Reactome)
5HTREACT_15458 (Reactome)
5HTREACT_1795 (Reactome)
ACHE oligomermim-catalysisREACT_14816 (Reactome)
AcChoREACT_14816 (Reactome)
AdoHcyArrowREACT_15531 (Reactome)
AdoMetREACT_15531 (Reactome)
AdoMetREACT_15553 (Reactome)
CDNBArrowREACT_15434 (Reactome)
CDNBArrowREACT_15531 (Reactome)
CDNBREACT_15434 (Reactome)
COMTmim-catalysisREACT_15531 (Reactome)
COMTmim-catalysisREACT_15553 (Reactome)
ChoArrowREACT_14816 (Reactome)
DAArrowREACT_15468 (Reactome)
DAREACT_15468 (Reactome)
DAREACT_15485 (Reactome)
DAREACT_15531 (Reactome)
H+ArrowREACT_15407 (Reactome)
H2O2ArrowREACT_15434 (Reactome)
H2O2ArrowREACT_1795 (Reactome)
H2OREACT_14816 (Reactome)
H2OREACT_15434 (Reactome)
H2OREACT_15485 (Reactome)
H2OREACT_1795 (Reactome)
HCYSArrowREACT_15553 (Reactome)
HIAAArrowREACT_15407 (Reactome)
HIALDArrowREACT_1795 (Reactome)
HIALDREACT_15407 (Reactome)
MAOA-FAD complexmim-catalysisREACT_15434 (Reactome)
MAOA-FAD complexmim-catalysisREACT_15485 (Reactome)
MAOA-FAD complexmim-catalysisREACT_1795 (Reactome)
NAD+REACT_15407 (Reactome)
NADHArrowREACT_15407 (Reactome)
NAdArrowREACT_15341 (Reactome)
NAdREACT_15341 (Reactome)
NH3ArrowREACT_15434 (Reactome)
NH3ArrowREACT_15485 (Reactome)
NH3ArrowREACT_1795 (Reactome)
Na+ArrowREACT_15458 (Reactome)
Na+ArrowREACT_15468 (Reactome)
Na+REACT_15458 (Reactome)
Na+REACT_15468 (Reactome)
O2REACT_15434 (Reactome)
O2REACT_15485 (Reactome)
O2REACT_1795 (Reactome)
OCT2mim-catalysisREACT_15341 (Reactome)
REACT_14816 (Reactome) Acetylcholinesterase (ACHE) oligomers (comprising monomers, dimers and tetramers), anchored to the extracellular side of the plasma membrane, hydrolyze acetylcholine (AcCho) to form choline (Cho) and acetate (Weinstock & Groner 2008, Velan et al. 1991, Kryger et al. 2000).

Acetylcholine from the synaptic cleft is degraded into inactive molecules, Cho and acetate by ACHE, which is located in the synaptic cleft (Weinstock & Groner 2008).
REACT_15341 (Reactome) Noradrenaline is cleared from the synaptic cleft by Noaradrenaline uptake transporter. This reaction is carried out by neurons as well as astrocytes.
REACT_15407 (Reactome) 5-hydroxyindole acetaldehyde is then catalyzed by aldehyde dehydrogenase to form 5-hydroxyindole acetic acid
REACT_15434 (Reactome) 3-methoxytyramine generated by COMT after methylation of dopamine is oxidized into homovanillic acid by monoamine oxidase A
REACT_15458 (Reactome) The human gene SLC6A4 encodes the sodium-dependent serotonin transporter 5HTT which mediates the re-uptake of serotonin from the synaptic cleft thus terminating the action of serotonin (Canli T and Lesch KP, 2007). The serotonin taken up in the cytosol from the synaptic cleft may be recycled into synaptic vesicles or metabolized.
REACT_15468 (Reactome) The human gene SLC6A3 encodes the sodium-dependent dopamine transporter, DAT which mediates the re-uptake of dopamine from the synaptic cleft (Vandenbergh DJ et al, 2000). Dopamine can then be degraded by either COMT or monoamine oxidase.
REACT_15485 (Reactome) Dopamine is oxidized to 3,4-dihydroxyphenylacetic acid by monoamine oxidase.
REACT_15531 (Reactome) Dopamine in the cytosol is metabolized to 3-methoxytyramine by catecholamine o-methyltransferase (COMT), which uses s-adenosylmethionine as a methyl group donor.
REACT_15553 (Reactome) 3,4-dihydroxyphenylacetic acid, generated after oxidation of dopamine by monoamineoxidase, is methylated by catecholamine o-methyltransferase to homovanillic acid.
REACT_1795 (Reactome) At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of 'H2O', and 1 molecule of '5-Hydroxytryptamine' are present. At the end of this reaction, 1 molecule of 'NH3', 1 molecule of '5-Hydroxyindoleacetaldehyde', and 1 molecule of 'H2O2' are present.

This reaction takes place in the 'mitochondrial outer membrane' and is mediated by the 'amine oxidase activity' of 'MAOA-FAD complex'.

SLC6A3mim-catalysisREACT_15468 (Reactome)
Sodium dependent


mim-catalysisREACT_15458 (Reactome)
acetateArrowREACT_14816 (Reactome)

dehydrogenase, mitochondrial,

mim-catalysisREACT_15407 (Reactome)
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