Neurotransmitter clearance (Homo sapiens)

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63, 188, 191124, 141911, 207, 135, 12, 162210, 15, 23cytosolmitochondrial matrixCl-NH3HIAAAdoHcySLC6A3ChoH2O2HVASLC22A1,SLC22A2NADHH2OCOMT:COMT inhibitorsNa+AcChoCOMT inhibitorsBCHE H2O2NH3LRTOMTMAOA:FADCl-H+acetateH2ONAD+MAOA ALDH2 COMTNa+5HT5HTDADAACHE SLC6A4DOPACAdoMet3MTNAdAdoMetH2O2COMT H2OSLC22A1 O2ACHENAdALDH2 tetramerH2OO2ACHEIsFAD ACHE 5HIALDACHE:ACHEIsNH3CholinesteraseSLC22A2 Na+HCYSO2HIALDNa+17, 21


Description

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. View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 112311
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Mahajan, SS

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Ontology Terms

 

Bibliography

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  1. Stahl SM.; ''The new cholinesterase inhibitors for Alzheimer's disease, Part 2: illustrating their mechanisms of action.''; PubMed Europe PMC Scholia
  2. DEEDS F, BOOTH AN, JONES FT.; ''Methylation and dehydroxylation of phenolic compounds by rats and rabbits.''; PubMed Europe PMC Scholia
  3. 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
  4. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melén K, Julkunen I, Taskinen J.; ''Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme.''; PubMed Europe PMC Scholia
  5. Canli T, Lesch KP.; ''Long story short: the serotonin transporter in emotion regulation and social cognition.''; PubMed Europe PMC Scholia
  6. 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
  7. 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
  8. Lambert GW, Eisenhofer G, Jennings GL, Esler MD.; ''Regional homovanillic acid production in humans.''; PubMed Europe PMC Scholia
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. Lanier M, Ambrus G, Cole DC, Davenport R, Ellery J, Fosbeary R, Jennings AJ, Kadotani A, Kamada Y, Kamran R, Matsumoto S, Mizukami A, Okubo S, Okada K, Saikatendu K, Walsh L, Wu H, Hixon MS.; ''A fragment-based approach to identifying S-adenosyl-l-methionine -competitive inhibitors of catechol O-methyl transferase (COMT).''; PubMed Europe PMC Scholia
  15. 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
  16. 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
  17. 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
  18. 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
  19. Guldberg HC, Sharman DF, Tegerdine PR.; ''Some observations on the estimation of 3-methoxytyramine in brain tissue.''; PubMed Europe PMC Scholia
  20. 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
  21. Greenfield NJ, Pietruszko R.; ''Two aldehyde dehydrogenases from human liver. Isolation via affinity chromatography and characterization of the isozymes.''; PubMed Europe PMC Scholia
  22. 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
  23. Weinstock M, Groner E.; ''Rational design of a drug for Alzheimer's disease with cholinesterase inhibitory and neuroprotective activity.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114635view16:09, 25 January 2021ReactomeTeamReactome version 75
113083view11:14, 2 November 2020ReactomeTeamReactome version 74
112317view15:23, 9 October 2020ReactomeTeamReactome version 73
101216view11:11, 1 November 2018ReactomeTeamreactome version 66
100754view20:36, 31 October 2018ReactomeTeamreactome version 65
100298view19:13, 31 October 2018ReactomeTeamreactome version 64
99844view15:57, 31 October 2018ReactomeTeamreactome version 63
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

DataNodes

View all...
NameTypeDatabase referenceComment
3MTMetaboliteCHEBI:1582 (ChEBI)
5HIALDMetaboliteCHEBI:50157 (ChEBI)
5HTMetaboliteCHEBI:28790 (ChEBI)
ACHE ProteinP22303 (Uniprot-TrEMBL)
ACHE:ACHEIsComplexR-HSA-9634839 (Reactome)
ACHEIsComplexR-ALL-9634838 (Reactome)
ACHEProteinP22303 (Uniprot-TrEMBL)
ALDH2 ProteinP05091 (Uniprot-TrEMBL)
ALDH2 tetramerComplexR-HSA-71721 (Reactome)
AcChoMetaboliteCHEBI:15355 (ChEBI)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
BCHE ProteinP06276 (Uniprot-TrEMBL)
COMT ProteinP21964 (Uniprot-TrEMBL)
COMT inhibitorsComplexR-ALL-9679778 (Reactome)
COMT:COMT inhibitorsComplexR-HSA-9679812 (Reactome)
COMTProteinP21964 (Uniprot-TrEMBL)
ChoMetaboliteCHEBI:15354 (ChEBI)
CholinesteraseComplexR-HSA-3640837 (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.
Cl-MetaboliteCHEBI:17996 (ChEBI)
DAMetaboliteCHEBI:18243 (ChEBI)
DOPACMetaboliteCHEBI:41941 (ChEBI)
FAD MetaboliteCHEBI:16238 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCYSMetaboliteCHEBI:17230 (ChEBI)
HIAAMetaboliteCHEBI:27823 (ChEBI)
HIALDMetaboliteCHEBI:50157 (ChEBI)
HVAMetaboliteCHEBI:545959 (ChEBI)
LRTOMTProteinQ8WZ04 (Uniprot-TrEMBL)
MAOA ProteinP21397 (Uniprot-TrEMBL)
MAOA:FADComplexR-HSA-141332 (Reactome)
NAD+MetaboliteCHEBI:57540 (ChEBI)
NADHMetaboliteCHEBI:57945 (ChEBI)
NAdMetaboliteCHEBI:18357 (ChEBI)
NH3MetaboliteCHEBI:16134 (ChEBI)
Na+MetaboliteCHEBI:29101 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
SLC22A1 ProteinO15245 (Uniprot-TrEMBL)
SLC22A1,SLC22A2ComplexR-HSA-2901780 (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.
SLC22A2 ProteinO15244 (Uniprot-TrEMBL)
SLC6A3ProteinQ01959 (Uniprot-TrEMBL)
SLC6A4ProteinP31645 (Uniprot-TrEMBL)
acetateMetaboliteCHEBI:30089 (ChEBI)
donepezil
entacapone

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
3MTArrowR-HSA-379387 (Reactome)
3MTArrowR-HSA-8955010 (Reactome)
3MTR-HSA-379395 (Reactome)
5HIALDArrowR-HSA-141186 (Reactome)
5HTArrowR-HSA-444008 (Reactome)
5HTR-HSA-141186 (Reactome)
5HTR-HSA-444008 (Reactome)
ACHE:ACHEIsArrowR-HSA-9634834 (Reactome)
ACHE:ACHEIsTBarR-HSA-372519 (Reactome)
ACHEIsR-HSA-9634834 (Reactome)
ACHER-HSA-9634834 (Reactome)
ALDH2 tetramermim-catalysisR-HSA-380608 (Reactome)
AcChoR-HSA-372519 (Reactome)
AdoHcyArrowR-HSA-379387 (Reactome)
AdoHcyArrowR-HSA-8955010 (Reactome)
AdoMetR-HSA-379387 (Reactome)
AdoMetR-HSA-379464 (Reactome)
AdoMetR-HSA-8955010 (Reactome)
COMT inhibitorsR-HSA-9679775 (Reactome)
COMT:COMT inhibitorsArrowR-HSA-9679775 (Reactome)
COMT:COMT inhibitorsTBarR-HSA-379387 (Reactome)
COMTR-HSA-9679775 (Reactome)
COMTmim-catalysisR-HSA-379387 (Reactome)
COMTmim-catalysisR-HSA-379464 (Reactome)
ChoArrowR-HSA-372519 (Reactome)
Cholinesterasemim-catalysisR-HSA-372519 (Reactome)
Cl-ArrowR-HSA-444008 (Reactome)
Cl-R-HSA-444008 (Reactome)
DAArrowR-HSA-379393 (Reactome)
DAR-HSA-379382 (Reactome)
DAR-HSA-379387 (Reactome)
DAR-HSA-379393 (Reactome)
DAR-HSA-8955010 (Reactome)
DOPACArrowR-HSA-379382 (Reactome)
DOPACR-HSA-379464 (Reactome)
H+ArrowR-HSA-380608 (Reactome)
H2O2ArrowR-HSA-141186 (Reactome)
H2O2ArrowR-HSA-379382 (Reactome)
H2O2ArrowR-HSA-379395 (Reactome)
H2OR-HSA-141186 (Reactome)
H2OR-HSA-372519 (Reactome)
H2OR-HSA-379382 (Reactome)
H2OR-HSA-379395 (Reactome)
HCYSArrowR-HSA-379464 (Reactome)
HIAAArrowR-HSA-380608 (Reactome)
HIALDR-HSA-380608 (Reactome)
HVAArrowR-HSA-379395 (Reactome)
HVAArrowR-HSA-379464 (Reactome)
LRTOMTmim-catalysisR-HSA-8955010 (Reactome)
MAOA:FADmim-catalysisR-HSA-141186 (Reactome)
MAOA:FADmim-catalysisR-HSA-379382 (Reactome)
MAOA:FADmim-catalysisR-HSA-379395 (Reactome)
NAD+R-HSA-380608 (Reactome)
NADHArrowR-HSA-380608 (Reactome)
NAdArrowR-HSA-374919 (Reactome)
NAdR-HSA-374919 (Reactome)
NH3ArrowR-HSA-141186 (Reactome)
NH3ArrowR-HSA-379382 (Reactome)
NH3ArrowR-HSA-379395 (Reactome)
Na+ArrowR-HSA-379393 (Reactome)
Na+ArrowR-HSA-444008 (Reactome)
Na+R-HSA-379393 (Reactome)
Na+R-HSA-444008 (Reactome)
O2R-HSA-141186 (Reactome)
O2R-HSA-379382 (Reactome)
O2R-HSA-379395 (Reactome)
R-HSA-141186 (Reactome) Amine oxidase (flavin-containing) A (MAOA) catalyses the oxidative deamination of biogenic and dietary amines, the regulation of which is critical for mental state homeostasis. MAOA, located on the mitochondrial outer membrane and requiring FAD as cofactor (Weyler 1989), preferentially oxidises biogenic amines such as 5-hydroxytryptamine (5HT), dopamine, noradrenaline and adrenaline (latter three not shown here). 5HT is deaminated to 5-hydroxyindolacetaldehyde (5HIALD).
R-HSA-372519 (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).
R-HSA-374919 (Reactome) Noradrenaline is cleared from the synaptic cleft by Noaradrenaline uptake transporter. This reaction is carried out by neurons as well as astrocytes.
R-HSA-379382 (Reactome) Dopamine (DA) is oxidatively deaminated to 3,4-dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase A (MAOA), bound to its cofactor FAD (O'Caroll et al.1983).
R-HSA-379387 (Reactome) Dopamine (DA) in the cytosol is methylated to 3-methoxytyramine (3MT) by catecholamine O-methyltransferase (COMT), which uses s-adenosylmethionine (AdoMet) as a methyl group donor (Männistö & Kaakkola 1991, Westerink & Spaan 1989).
R-HSA-379393 (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.
R-HSA-379395 (Reactome) 3-methoxytyramine (3MT) generated by COMT after methylation of dopamine is oxidized into homovanillic acid (HVA) by monoamine oxidase A (MAOA), bound to its cofactor FAD (Guldberg et al. 1997).
R-HSA-379464 (Reactome) 3,4-dihydroxyphenylacetic acid (DOPAC), generated after oxidative deamination of dopamine by monoamine oxidase A (MAOA), is methylated by catecholamine O-methyltransferase (COMT) to homovanillic acid (HVA) (Deeds et al.1957).
R-HSA-380608 (Reactome) 5-hydroxyindole acetaldehyde is then catalyzed by aldehyde dehydrogenase to form 5-hydroxyindole acetic acid
R-HSA-444008 (Reactome) Serotonin (5HT) is a monoamine neurotransmitter. It's clearance (and therefore termination) from the synaptic cleft is mediated by the sodium- and chloride-dependent serotonin transporter SERT (SLC6A4, aka 5HTT). SERT is encoded by the human gene SLC6A4 and is expressed in the CNS, PNS and platelets (Ramamoorthy et al. 1993, Brenner et al. 2007, Canli & Lesch 2007).
R-HSA-8955010 (Reactome) Transmembrane O-methyltransferase (LRTOMT aka COMT2) catalyses the O-methylation of catecholamine neurotransmitters, thereby inactivating them (Du et al. 2008). LRTOMT is highly expressed in sensory hair cells of the inner ear. Defects in LRTOMT can cause autosomal recessive deafness 63 (DFNB63), a form of non-syndromic sensorineural hearing loss (Ahmed et al. 2008, Du et al. 2008). In this example, dopamine (DA) is O-methylated using S-adenosyl-L-methionine (AdoMet) as the methyl donor to form 3-methyltyramine (3MT) and S-adenosyl-L-homocysteine (AdoHcy).
R-HSA-9634834 (Reactome) Acetylcholinesterase (ACHE) is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors (Stahl 2000), leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission (Pohanka 2011, Colović et al. 2013). ACHE inhibitors (ACHEIs) are classified as reversible, irreversible, or quasi-irreversible.
Compounds which function as reversible competitive or noncompetitive inhibitors of cholinesterase are those most likely to have therapeutic uses. Compounds which function as quasi-irreversible inhibitors of cholinesterase are those most likely to have use as chemical weapons or pesticides. Acetylcholinesterase inhibitors are also found naturally in venoms and poisons. When used medicinally, ACHEIs are used to treat neurodegenerative conditions such as Alzheimer's, Parkinson’s and schizophrenia. They are also used for myasthenia gravis, autism and glaucoma. The following reversible ACHEIs are used as therapeutic drugs.

Rivastigmine (trade name Exelon) is a reversible carbamate ACHEI used in the treatment of mild to moderate Alzheimer's disease (Rosler et al. 1999, Birks et al. 2015) and Parkinson's (Emre et al. 2004, Barone et al. 2008). The drug is taken orally or applied as a transdermal patch (the latter method of delivery can reduce nausea and vomiting) (Inglis 2002). Galantamine (trade name Razadyne) is a reversible phenanthrene ACHEI used in the treatment of cognitive decline in mild to moderate Alzheimer's disease and in other memory impairment disorders (Lilienfeld 2002, Mohammad et al. 2017). Galantamine has a unique, dual mode of action; as a reversible inhibitor of AChE and as an allosteric modulator of nicotinic acetylcholine receptors (nAChRs) (Albuquerque et al. 2001). Physostigmine (trade names Antilirium and Isopto Eserine) is a reversible carbamate ACHEI used to treat glaucoma (Lindén & Alm 1997), anticholinergic poisoning (Watkins et al. 2015) and recently, sepsis and septic shock (Zimmermann et al. 2017). It was discovered to be the active ingredient in the Calabar bean found in Nigeria and was used as a poison test for individuals accused of witchcraft. If they survived, they were set free (Proudfoot 2006, Scheindlin 2010).

Neostigmin (brand name Prostigmin), is a is a reversible carbamate ACHEI (Calvey et al. 1979) with a slightly shorter duration of action than physostigmine. It is primarily used to treat myasthenia gravis (Grob & Namba 1976, Aquilonius et al. 1983) and to reverse the effects of muscle relaxants such as gallamine and tubocurarine. Neostigmine, unlike physostigmine, does not cross the blood-brain barrier. By inhibiting ACHE, neostigmine indirectly stimulates both nicotinic and muscarinic receptors which are involved in muscle contraction. Pyridostigmine (trade name Mestinon) is a peripherally acting, orally active reversible ACHEI used to treat MG (Aquilonius et al. 1983, Maggi & Mantegazza 2011) and to combat the effects of curariform drug toxicity. During the first Gulf War, pyridostigmine bromide was given prior to exposure to the nerve agent Soman in order to increase survival. Pyridostigmine bromide has been implicated as a causal factor in Gulf War syndrome (Golomb 2008). Pyridostigmine is also used for postural orthostatic tachycardia (Gales & Gales 2007, Kanjwal et al. 2011). Donepezil (trade name Aricept) is a reversible piperidine ACHEI used in the palliative treatment of mild to moderate Alzheimer's disease (Sabbagh et al. 2013, Lee et al. 2015). It is generally accepted that the symptoms of Alzheimer’s disease are related to a substantial loss of cholinergic neurons in the CNS that correlates with the severity of cognitive impairment. The precise mechanism of action of donepezil in patients with Alzheimer's disease is not fully understood but by inhibiting ACHE breakdown, acetylcholine levels at cholinergic synapses is prolonged.

Tacrine (trade name Cognex) is a dual inhibitor of butyrylcholineesterase and acetylcholinesterase (ACHE) being the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease in 1993. Tacrine appears to have little beneficial effect on congnition in AD patients (Qizilbash et al. 1998) and currently, it is no longer used as a treatment for AD due to serious hepatotoxicity which limited its clinical use (Qizilbash et al. 2007, Patocka et al. 2008). Edrophonium (trade name Tensilon) is a reversible ACHEI In the treatment of myasthenia gravis, edrophonium reduces muscle weakness by prolonging the presence of acetylcholine in the synaptic cleft. The Tensilon test uses edrophonium to differentiate myasthenia gravis from cholinergic crisis and Lambert-Eaton (Pascuzzi 2003). In practice, the edroophonium test has been replaced by testing for autoantibodies (Benatar 2006, Meriggioli & Sanders 2012). The Tensilon test may also be used to predict if neurotoxic paralysis caused by snake envenomation is presynaptic or postsynaptic. If it is a postsynaptic then paralysis will be temporally reversed, indicating that can be reversed by adequate antivenom therapy. If the neurotoxic is presynaptic then the Tensilon test will show no response and antivenom will not reverse such paralysis.

Pralidoxime is an antidote to organophosphate poisoning in conjunction with atropine and diazepam. Organophosphates such as sarin bind to the hydroxy component (the esteric site) of the active site of the acetylcholinesterase enzyme, thereby blocking its activity. Pralidoxime binds to the other half (the unblocked, anionic site) of the active site and then displaces the phosphate from the serine residue. The conjoined poison/antidote then unbinds from the site, and thus regenerates the fully functional enzyme (Jokanović & Prostran 2009, Jokanović 2009). Echothiophate (Trade name Phospholine) is an irreversible ACHEI used as an ocular antihypertensive in the treatment of chronic glaucoma (Schmidt et al. 2010, Kraus et al. 2015). Echothiophate covalently binds its phosphate group to a serine in the active site of acetylcholinesterase, rendering the enzyme permanently inactive.
R-HSA-9679775 (Reactome) Catechol-O-methyltransferase (COMT) is one of several enzymes that degrade catecholamines (such as dopamine, epinephrine, and norepinephrine) and various substances having a catechol structure. COMT inhibitors such as entacapone, tolcapone and opicapone are used in the treatment of Parkinson's disease.
SLC22A1,SLC22A2mim-catalysisR-HSA-374919 (Reactome)
SLC6A3mim-catalysisR-HSA-379393 (Reactome)
SLC6A4mim-catalysisR-HSA-444008 (Reactome)
acetateArrowR-HSA-372519 (Reactome)
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