Editing Monoamine oxidase

{{Short description|Family of enzymes}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{enzyme
| Name = Monoamine oxidase
| EC_number = 1.4.3.4
| CAS_number = 9001-66-5
| GO_code = 0008131
| image =
| width =
| caption =
}}
{{Infobox protein family
| Symbol = MAO
| Name = Monoamine oxidase
| image =
| width =
| caption =
| Pfam= PF01593
| Pfam_clan =
| InterPro= IPR001613
| SMART=
| PROSITE =
| SCOP =
| TCDB =
| OPM family= 119
| OPM protein= 2z5x
| PDB=
| Membranome family = 418
}}
{{infobox protein
| Name = [[MAOA|monoamine oxidase A]]
| caption = [[Ribbon diagram]] of a [[monomer]] of human MAO-A, with [[Flavin adenine dinucleotide|FAD]] and [[clorgiline]] bound, oriented as if attached to the [[Outer mitochondrial membrane|outer membrane]] of a [[mitochondrion]]. From {{PDB|2BXS}}.
| image = Monoamine oxidase A 2BXS.png
| width =
| HGNCid = 6833
| Symbol = [[MAOA]]
| AltSymbols =
| EntrezGene = 4128
| OMIM = 309850
| RefSeq = NM_000240
| UniProt = P21397
| PDB =
| ECnumber =
| Chromosome = X
| Arm = p
| Band = 11
| LocusSupplementaryData = .4-p11.3
}}
{{infobox protein
| Name = [[monoamine oxidase B]]
| caption = Ribbon diagram of human MAO-B. From {{PDB|1GOS}}.
| image = MonoamineOxidase-1GOS.png
| width =
| HGNCid = 6834
| Symbol = [[Monoamine oxidase B|MAOB]]
| AltSymbols =
| EntrezGene = 4129
| OMIM = 309860
| RefSeq = NM_000898
| UniProt = P27338
| PDB =
| ECnumber =
| Chromosome = X
| Arm = p
| Band = 11
| LocusSupplementaryData = .4-p11.3
}}
'''Monoamine oxidases''' ('''MAO''') ({{EC number|1.4.3.4}}) are a family of [[enzyme]]s that [[catalysis|catalyze]] the [[oxidation]] of [[monoamine]]s, employing oxygen to clip off their amine group.<ref name="pmid15279561">{{cite journal |vauthors=Tipton KF, Boyce S, O'Sullivan J, Davey GP, Healy J |title=Monoamine oxidases: certainties and uncertainties |journal=Current Medicinal Chemistry |volume=11 |issue=15 |pages=1965–82 |date=August 2004 |pmid=15279561 |doi=10.2174/0929867043364810|doi-broken-date=2024-11-02 }}</ref><ref name="pmid15279562">{{cite journal |vauthors=Edmondson DE, Mattevi A, Binda C, Li M, Hubálek F |title=Structure and mechanism of monoamine oxidase |journal=Current Medicinal Chemistry |volume=11 |issue=15 |pages=1983–93 |date=August 2004 |pmid=15279562 |doi=10.2174/0929867043364784|doi-broken-date=2024-11-02 }}</ref> They are found bound to the outer membrane of [[mitochondria]] in most cell types of the body. The first such enzyme was discovered in 1928 by [[Mary Bernheim]] in the liver and was named tyramine oxidase.<ref name="pmid16744124">{{cite journal |vauthors=Hare ML |title=Tyramine oxidase: A new enzyme system in liver |journal=The Biochemical Journal |volume=22 |issue=4 |pages= 968–79 |year=1928 |pmid=16744124 |pmc=1252213 |doi=10.1042/bj0220968}}</ref><ref name="pmid10643441">{{cite journal |vauthors=Slotkin TA |title=Mary Bernheim and the discovery of monoamine oxidase |journal=Brain Research Bulletin |volume=50 |issue=5–6 |pages=373 |year=1999 |pmid=10643441 |doi=10.1016/S0361-9230(99)00110-0 |s2cid=35565156}}</ref> The MAOs belong to the [[protein family]] of [[flavin-containing amine oxidoreductase]]s.<ref>{{cite web | url=https://www.ncbi.nlm.nih.gov/Structure/cdd/cl38049 | title=CDD Conserved Protein Domain Family: Amino_oxidase }}</ref>

MAOs are important in the breakdown of monoamines ingested in food, and also serve to inactivate  [[monoamine neurotransmitter]]s. Because of the latter, they are involved in a number of psychiatric and neurological diseases, some of which can be treated with [[monoamine oxidase inhibitors]] (MAOIs) which block the action of MAOs.<ref name="pmid31191248">{{Cite journal |vauthors=Yeung AW, Georgieva MG, Atanasov AG, Tzvetkov NT |date=2019 |title=Monoamine Oxidases (MAOs) as Privileged Molecular Targets in Neuroscience: Research Literature Analysis |journal=Frontiers in Molecular Neuroscience |volume=12 |pages=143 |doi=10.3389/fnmol.2019.00143 |pmc=6549493 |pmid=31191248 |doi-access=free}}</ref>

== Subtypes and tissue distribution ==
In humans there are two types of MAO: [[Monoamine oxidase A|MAO-A]] and [[Monoamine oxidase B|MAO-B]].<ref name="pmid15279563">{{Cite journal |author-link=Jean Chen Shih |vauthors=Shih JC, Chen K |date=August 2004 |title=Regulation of MAO-A and MAO-B gene expression |journal=Current Medicinal Chemistry |volume=11 |issue=15 |pages=1995–2005 |doi=10.2174/0929867043364757 |pmid=15279563}}</ref>
* Both are found in [[neuron]]s and [[astroglia]].
* Outside the [[central nervous system]]:
** MAO-A is also found in the [[liver]], [[pulmonary vascular system|pulmonary vascular]] [[endothelium]], [[Human gastrointestinal tract|gastrointestinal tract]], and [[placenta]].
** MAO-B is mostly found in [[blood]] [[platelet]]s.

MAO-A appears at roughly 80% of adulthood levels at birth, increasing very slightly after the first 4 years of life, while MAO-B is almost non-detectable in the infant brain. Regional distribution of the monoamine oxidases is characterized by extremely high levels of both MAOs in the [[hypothalamus]] and hippocampal uncus, as well as a large amount of MAO-B with very little MAO-A in the [[striatum]] and [[globus pallidus]]. The cortex has relatively high levels of only MAO-A, with the exception of areas of the [[cingulate cortex]], which contains a balance of both. Autopsied brains demonstrated the predicted increased concentration of MAO-A in regions dense in serotonergic neurotransmission, however MAO-B only correlated with norepinephrine.<ref name="pmid23403377">{{Cite journal |vauthors=Tong J, Meyer JH, Furukawa Y, Boileau I, Chang LJ, Wilson AA, Houle S, Kish SJ |date=June 2013 |title=Distribution of monoamine oxidase proteins in human brain: implications for brain imaging studies |journal=Journal of Cerebral Blood Flow and Metabolism |volume=33 |issue=6 |pages=863–71 |doi=10.1038/jcbfm.2013.19 |pmc=3677103 |pmid=23403377}}</ref>

Other studies, in which the activities of MAO (not protein amounts) were examined in rat brain, revealed the highest MAO-B activity in the median eminence of hypothalamus. Dorsal raphe nucleus and medial preoptic area have relatively high MAO-B activity, but much lower than MAO-B activity in the median eminence.<ref name=":0">{{cite journal| vauthors = Razygraev AV, Arutjunyan AV |date=2007-09-01|title=Monoamine oxidase activity in several structures of rat brain |journal=Neurochemical Journal |volume=1|issue=3|pages=204–207|doi=10.1134/S1819712407030051 |s2cid=9550341}}</ref><ref name=":1">{{cite journal| vauthors = Razygraev AV, Taborskaya KI, Volovik KY, Bunina AA, Petrosyan MA |date=2016-04-01|title=Monoamine oxidase activity in the rat pineal gland: Comparison with brain areas and alteration during aging |journal=Advances in Gerontology |volume=6 |issue=2 |pages=111–116 |doi= 10.1134/S2079057016020120 |s2cid=88975594}}</ref> Among cerebral endocrine glands, pineal gland has high MAO-B activity (its median value is lower than that for median eminence and higher than that for medial preoptic area).<ref name=":1" /> Pituitary has the lowest level of MAO-B activity when compared with brain areas studied.<ref name=":0" />

== Function ==
[[File:Noradrenaline breakdown.svg|thumb|350px|Norepinephrine degradation. Monoamine oxidase is shown left in the blue box.<ref name=Rang&Dale6th-11-4>Figure 11-4 in: {{cite book | vauthors = Flower R, Rang HP, Dale MM, Ritter JM | title = Rang & Dale's pharmacology | publisher = Churchill Livingstone | location = Edinburgh | year = 2007 | isbn = 978-0-443-06911-6 }}</ref>]]

Monoamine oxidases catalyze the [[oxidative deamination]] of monoamines. In the first part of the reaction, [[Cofactor (biochemistry)|cofactor]] [[Flavin adenine dinucleotide|FAD]] oxidizes the substrate yielding the corresponding [[imine]] which converts the cofactor into its reduced form [[FADH2]]. The imine is then non-enzymatically hydrolyzed to the corresponding [[ketone]] (or [[aldehyde]]) and [[ammonia]]. [[Oxygen]] is used to restore the reduced [[Flavin adenine dinucleotide|FADH2]] cofactor back to the active [[FAD]] form. Monoamine [[oxidase]]s contain the covalently bound [[cofactor (biochemistry)|cofactor]] [[Flavin adenine dinucleotide|FAD]] and are, thus, classified as [[flavoprotein]]s.  Monoamine oxidase A and B share roughly 70% of their structure and both have substrate binding sites that are predominantly [[hydrophobic]]. Two [[tyrosine]] residues (398, 435 within [[Monoamine oxidase B|MAO-B]],  407 and 444 within [[MAO-A]]) in the binding pocket that are commonly involved in inhibitor activity have been hypothesized to be relevant to orienting substrates, and mutations of these residues are relevant to mental health.  Four main models have been proposed for the mechanism of [[electron transfer]] (single electron transfer, hydrogen atom transfer, nucleophilic model, and hydride transfer<ref>{{cite journal| vauthors = Vianello R, Repič M, Mavri J |date=2012-10-25|title=How are Biogenic Amines Metabolized by Monoamine Oxidases? |journal=European Journal of Organic Chemistry |volume=2012 |issue=36 |pages=7057–7065 |doi=10.1002/ejoc.201201122}}</ref>) although there is insufficient evidence to support any of them.<ref name="pmid22022344">{{cite journal | vauthors = Gaweska H, Fitzpatrick PF | title = Structures and Mechanism of the Monoamine Oxidase Family | journal = Biomolecular Concepts | volume = 2 | issue = 5 | pages = 365–377 | date = October 2011 | pmid = 22022344 | pmc = 3197729 | doi = 10.1515/BMC.2011.030 }}</ref>

In 2021, it was discovered that MAO-B does not mediate dopamine [[catabolism]] in the rodent [[striatum]] but instead participates in striatal [[γ-aminobutyric acid]] (GABA) synthesis from [[putrescine]] and that synthesized GABA in turn inhibits [[dopaminergic]] [[neuron]]s in this brain area.<ref name="NamSaJu2022">{{cite journal | vauthors = Nam MH, Sa M, Ju YH, Park MG, Lee CJ | title = Revisiting the Role of Astrocytic MAOB in Parkinson's Disease | journal = Int J Mol Sci | volume = 23 | issue = 8 | date = April 2022 | page = 4453 | pmid = 35457272 | pmc = 9028367 | doi = 10.3390/ijms23084453 | doi-access = free | url = }}</ref><ref name="ChoKimSim2021" /> It has been found that MAO-B, via the putrescine pathway, importantly mediates GABA synthesis in [[astrocyte]]s in various brain areas, including in the [[hippocampus]], [[cerebellum]], striatum, [[cerebral cortex]], and [[substantia nigra pars compacta]] (SNpc).<ref name="NamSaJu2022" /><ref name="ChoKimSim2021" /> These findings may warrant a rethinking of the actions of [[MAO-B inhibitor]]s in the treatment of [[Parkinson's disease]].<ref name="NamSaJu2022" /><ref name="ChoKimSim2021" />

== Substrates and specificities ==
Monoamine oxidases are well known [[enzymes]] in [[pharmacology]], since they are the target for the action of a number of [[monoamine oxidase inhibitor]] [[drugs]].  MAO-A is particularly important in the [[catabolism]] of monoamines ingested in food. Both MAOs are also vital to the inactivation of [[monoamine neurotransmitter]]s, for which they display different [[Enzyme#Specificity|specificities]].{{medical citation needed|date=May 2024}}
* [[Serotonin]], [[norepinephrine]], and [[epinephrine]] are mainly broken down by MAO-A.{{medical citation needed|date=May 2024}}
* [[Phenethylamine]] and [[benzylamine]] are mainly broken down by MAO-B.{{medical citation needed|date=May 2024}}
* Both forms metabolize [[dopamine]], [[tyramine]], and [[tryptamine]];<ref name="pmid11559028">{{cite journal | vauthors = Kalgutkar AS, Dalvie DK, Castagnoli N, Taylor TJ | title = Interactions of nitrogen-containing xenobiotics with monoamine oxidase (MAO) isozymes A and B: SAR studies on MAO substrates and inhibitors | journal = Chemical Research in Toxicology | volume = 14 | issue = 9 | pages = 1139–62 | date = September 2001 | pmid = 11559028 | doi = 10.1021/tx010073b }}</ref> however, some evidence suggests MAO-B may not be responsible for a significant amount of dopamine degradation.<ref name="pmid34244591">{{cite journal | vauthors = Cho HU, Kim S, Sim J, Yang S, An H, Nam MH, Jang DP, Lee CJ | title = Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis | journal = Exp Mol Med | volume = 53 | issue = 7 | pages = 1148–1158 | date = July 2021 | pmid = 34244591 | pmc = 8333267 | doi = 10.1038/s12276-021-00646-3 }}</ref>

Specific reactions catalyzed by MAO include:<ref name="Tipton2018">{{cite journal | vauthors = Tipton KF | title = 90 years of monoamine oxidase: some progress and some confusion | journal = J Neural Transm (Vienna) | volume = 125 | issue = 11 | pages = 1519–1551 | date = November 2018 | pmid = 29637260 | doi = 10.1007/s00702-018-1881-5 | url = }}</ref><ref name="BortolatoShih2011">{{cite journal | vauthors = Bortolato M, Shih JC | title = Behavioral outcomes of monoamine oxidase deficiency: preclinical and clinical evidence | journal = Int Rev Neurobiol | series = International Review of Neurobiology | volume = 100 | issue = | pages = 13–42 | date = 2011 | pmid = 21971001 | pmc = 3371272 | doi = 10.1016/B978-0-12-386467-3.00002-9 | isbn = 978-0-12-386467-3 | url = }}</ref>
* [[Serotonin]] to [[5-Hydroxyindoleacetaldehyde|5-hydroxyindoleacetaldehyde]] (5-HIAL; 5-HIAAL; serotonin aldehyde)<ref name="BortolatoChenShih2010">{{cite book | last1=Bortolato | first1=Marco | last2=Chen | first2=Kevin | last3=Shih | first3=Jean C. | title=Handbook of Behavioral Neuroscience | chapter=The Degradation of Serotonin: Role of MAO | publisher=Elsevier | volume=21 | date=2010 | isbn=978-0-12-374634-4 | doi=10.1016/s1569-7339(10)70079-5 | pages=203–218}}</ref><ref name="MatthesMosienkoBashammakh2010">{{cite journal | vauthors = Matthes S, Mosienko V, Bashammakh S, Alenina N, Bader M | title = Tryptophan hydroxylase as novel target for the treatment of depressive disorders | journal = Pharmacology | volume = 85 | issue = 2 | pages = 95–109 | date = 2010 | pmid = 20130443 | doi = 10.1159/000279322 | url = }}</ref>
* [[5-Methoxytryptamine]] ([[melatonin]] metabolite) to [[5-methoxyindoleacetaldehyde]] (5-MIAL; 5-MIAAL)<ref name="SlominskiTobinZmijewski2008">{{cite journal | vauthors = Slominski A, Tobin DJ, Zmijewski MA, Wortsman J, Paus R | title = Melatonin in the skin: synthesis, metabolism and functions | journal = Trends Endocrinol Metab | volume = 19 | issue = 1 | pages = 17–24 | date = January 2008 | pmid = 18155917 | doi = 10.1016/j.tem.2007.10.007 | url = }}</ref>
* [[Tryptamine]] to [[indole-3-acetaldehyde|indoleacetaldehyde]] (IAAL; tryptamine aldehyde)<ref name="BortolatoShih2011" />
* [[Dopamine]] to [[3,4-dihydroxyphenylacetaldehyde]] (DOPAL; dopamine aldehyde)<ref name="MeiserWeindlHiller2013">{{cite journal | vauthors = Meiser J, Weindl D, Hiller K | title = Complexity of dopamine metabolism | journal = Cell Commun Signal | volume = 11 | issue = 1 | pages = 34 | date = May 2013 | pmid = 23683503 | pmc = 3693914 | doi = 10.1186/1478-811X-11-34 | doi-access = free | url = }}</ref>
* [[Norepinephrine]] to [[3,4-dihydroxymandelaldehyde]] (DHMAL; norepinephrine/epinephrine aldehyde)<ref name="KawamuraEisenhoferKopin2002">{{cite journal | vauthors = Kawamura M, Eisenhofer G, Kopin IJ, Kador PF, Lee YS, Fujisawa S, Sato S | title = Aldose reductase: an aldehyde scavenging enzyme in the intraneuronal metabolism of norepinephrine in human sympathetic ganglia | journal = Auton Neurosci | volume = 96 | issue = 2 | pages = 131–139 | date = March 2002 | pmid = 11958479 | doi = 10.1016/s1566-0702(01)00385-x | url = }}</ref>
* [[Epinephrine]] to [[3,4-dihydroxymandelaldehyde]] (DHMAL; norepinephrine/epinephrine aldehyde)<ref name="KawamuraEisenhoferKopin2002" />
* [[Normetanephrine]] to [[3-methoxy-4-hydroxymandelaldehyde]] (MHMAL; normetanephrine/metanephrine aldehyde)<ref name="KawamuraEisenhoferKopin2002" />
* [[Metanephrine]] to [[3-methoxy-4-hydroxymandelaldehyde]] (MHMAL; normetanephrine/metanephrine aldehyde)<ref name="KawamuraEisenhoferKopin2002" />
* [[3-Methoxytyramine]] to [[3-methoxy-4-hydroxyphenylacetaldehyde]] (HMPAL)<ref name="BandalaCárdenas-RodríguezMendoza-Torreblanca2023">{{cite journal | vauthors = Bandala C, Cárdenas-Rodríguez N, Mendoza-Torreblanca JG, Contreras-García IJ, Martínez-López V, Cruz-Hernández TR, Carro-Rodríguez J, Vargas-Hernández MA, Ignacio-Mejía I, Alfaro-Rodriguez A, Lara-Padilla E | title = Therapeutic Potential of Dopamine and Related Drugs as Anti-Inflammatories and Antioxidants in Neuronal and Non-Neuronal Pathologies | journal = Pharmaceutics | volume = 15 | issue = 2 | date = February 2023 | page = 693 | pmid = 36840015 | pmc = 9966027 | doi = 10.3390/pharmaceutics15020693 | doi-access = free | url = }}</ref>
* [[Phenethylamine]] to [[phenylacetaldehyde]] (PAAL)<ref name="DalvieDi2019">{{cite journal | vauthors = Dalvie D, Di L | title = Aldehyde oxidase and its role as a drug metabolizing enzyme | journal = Pharmacol Ther | volume = 201 | issue = | pages = 137–180 | date = September 2019 | pmid = 31128989 | doi = 10.1016/j.pharmthera.2019.05.011 | url = }}</ref>
* [[Tyramine]] to [[4-hydroxyphenylacetaldehyde]] (HPAL)<ref name="BortolatoShih2011" />
* [[Benzylamine]] to [[benzaldehyde]]<ref name="Holt2018">{{cite journal | vauthors = Holt A | title = On the practical aspects of characterising monoamine oxidase inhibition in vitro | journal = J Neural Transm (Vienna) | volume = 125 | issue = 11 | pages = 1685–1705 | date = November 2018 | pmid = 30374594 | doi = 10.1007/s00702-018-1943-8 | url = }}</ref>

Other endogenous substrates of MAO include [[telemethylhistamine]], a metabolite of [[histamine]], and [[N-acetylputrescine|''N''-acetylputrescine]], a metabolite of [[putrescine]] and a [[precursor (biochemistry)|precursor]] and [[metabolic intermediate]] in a minor [[metabolic pathway]] resulting in the synthesis of [[γ-aminobutyric acid]] (GABA).<ref name="BenedettiDostert1994" /><ref name="AmbroziakMaśliński1988">{{cite journal | vauthors = Ambroziak W, Maśliński C | title = Participation of aldehyde dehydrogenase in the oxidative deamination pathway of histamine and putrescine | journal = Agents Actions | volume = 23 | issue = 3–4 | pages = 311–313 | date = April 1988 | pmid = 3394581 | doi = 10.1007/BF02142573 | url = }}</ref><ref name="WatanabeMaemuraKanbara2002">{{cite book | vauthors = Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H | chapter = GABA and GABA Receptors in the Central Nervous System and Other Organs | title = A Survey of Cell Biology | journal = Int Rev Cytol | series = International Review of Cytology | volume = 213 | issue = | pages = 1–47 | date = 2002 | pmid = 11837891 | doi = 10.1016/s0074-7696(02)13011-7 | isbn = 978-0-12-364617-0 | chapter-url = }}</ref><ref name="Seiler2004">{{cite journal | vauthors = Seiler N | title = Catabolism of polyamines | journal = Amino Acids | volume = 26 | issue = 3 | pages = 217–233 | date = June 2004 | pmid = | doi = 10.1007/s00726-004-0070-z | url = }}</ref><ref name="ChoKimSim2021">{{cite journal | vauthors = Cho HU, Kim S, Sim J, Yang S, An H, Nam MH, Jang DP, Lee CJ | title = Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis | journal = Exp Mol Med | volume = 53 | issue = 7 | pages = 1148–1158 | date = July 2021 | pmid = 34244591 | pmc = 8333267 | doi = 10.1038/s12276-021-00646-3 | url = }}</ref>

Besides [[endogenous]] compounds, a variety of [[exogenous]] compounds and [[drug]]s are substrates of the MAOs.<ref name="BenedettiDostert1994">{{cite journal | vauthors = Benedetti MS, Dostert P | title = Contribution of amine oxidases to the metabolism of xenobiotics | journal = Drug Metab Rev | volume = 26 | issue = 3 | pages = 507–535 | date = 1994 | pmid = 7924902 | doi = 10.3109/03602539408998316 | url = }}</ref><ref name="PangTangGuo2022">{{cite journal | vauthors = Pang X, Tang C, Guo R, Chen X | title = Non-cytochrome P450 enzymes involved in the oxidative metabolism of xenobiotics: Focus on the regulation of gene expression and enzyme activity | journal = Pharmacol Ther | volume = 233 | issue = | pages = 108020 | date = May 2022 | pmid = 34637840 | doi = 10.1016/j.pharmthera.2021.108020 | url = }}</ref><ref name="StrolinBenedettiDostertTipton1988">{{cite book | veditors = Gibson GG | vauthors = Strolin Benedetti M, Dostert P, Tipton KF | chapter = Contributions of monoamine oxidase to the metabolism of xenobiotics | title = Progress in Drug Metabolism | volume = 11 | pages = 149–174 | url = https://scholar.google.com/scholar?cluster=4712296110836164590}}</ref><ref name="Zetin2013">{{cite journal | last=Zetin | first=Mark | title=A Clinician's Guide to Monoamine Oxidase Inhibitors | journal=Current Psychiatry Reviews | volume=9 | issue=4 | date=2013-08-31 | issn=1573-4005 | doi=10.2174/15734005113096660013 | pages=353–364}}</ref> Examples include [[substituted phenethylamine]] [[sympathomimetic]]s and [[sympatholytic]]s like [[phenylephrine]], [[propranolol]], and [[pronethalol]], [[substituted tryptamine]] [[serotonergic drug|serotonergic agent]]s like [[dimethyltryptamine]] (DMT), [[5-MeO-DMT]], [[bufotenin]], [[almotriptan]], [[rizatriptan]], and [[sumatriptan]], and other compounds like [[bicifadine]], [[citalopram]], [[CP-409092]], [[KW-2449]], [[milacemide]], [[MPTP]], [[nomifensine]], [[primaquine]], [[rivaroxaban]], [[sertraline]], and [[ticlopidine]], among others.<ref name="BenedettiDostert1994" /><ref name="PangTangGuo2022" /><ref name="StrolinBenedettiDostertTipton1988" /><ref name="Zetin2013" /> [[Haloperidol]] is another possible substrate of MAO, which may contribute to formation of its [[monoaminergic neurotoxin|neurotoxic]] metabolite [[HPP+|HPP<sup>+</sup>]].<ref name="BenedettiDostert1994" />

== Clinical significance ==
Because of the vital role that MAOs play in the inactivation of [[neurotransmitter]]s, MAO dysfunction (too much or too little MAO activity) is thought to contribute to a number of psychiatric and neurological disorders. Unusually high or low levels of MAOs in the body have been associated with [[schizophrenia]],<ref name="pmid943955">{{cite journal | vauthors = Domino EF, Khanna SS | title = Decreased blood platelet MAO activity in unmedicated chronic schizophrenic patients | journal = The American Journal of Psychiatry | volume = 133 | issue = 3 | pages = 323–6 | date = March 1976 | pmid = 943955 | doi = 10.1176/ajp.133.3.323 }}</ref><ref name="pmid1267046">{{cite journal | vauthors = Schildkraut JJ, Herzog JM, Orsulak PJ, Edelman SE, Shein HM, Frazier SH | title = Reduced platelet monoamine oxidase activity in a subgroup of schizophrenic patients | journal = The American Journal of Psychiatry | volume = 133 | issue = 4 | pages = 438–40 | date = April 1976 | pmid = 1267046 | doi = 10.1176/ajp.133.4.438 }}</ref> [[clinical depression|depression]],<ref name="pmid17088501">{{cite journal | vauthors = Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, Young T, Praschak-Rieder N, Wilson AA, Houle S | title = Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression | journal = Archives of General Psychiatry | volume = 63 | issue = 11 | pages = 1209–16 | date = November 2006 | pmid = 17088501 | doi = 10.1001/archpsyc.63.11.1209 | doi-access =  }}</ref> [[attention deficit disorder]],<ref>{{cite journal | vauthors = Domschke K, Sheehan K, Lowe N, Kirley A, Mullins C, O'sullivan R, Freitag C, Becker T, Conroy J, Fitzgerald M, Gill M, Hawi Z | title = Association analysis of the monoamine oxidase A and B genes with attention deficit hyperactivity disorder (ADHD) in an Irish sample: preferential transmission of the MAO-A 941G allele to affected children | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 134B | issue = 1 | pages = 110–4 | date = April 2005 | pmid = 15717295 | doi = 10.1002/ajmg.b.30158 | s2cid = 24453719 }}</ref>  [[substance abuse]],<ref>{{cite journal | vauthors = Oreland L | title = Platelet monoamine oxidase, personality and alcoholism: the rise, fall and resurrection | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 79–89 | date = January 2004 | pmid = 14697883 | doi = 10.1016/S0161-813X(03)00115-3 | bibcode = 2004NeuTx..25...79O }}</ref> migraines,<ref>{{cite journal | vauthors = Bussone G, Boiardi A, Cerrati A, Girotti F, Merati B, Rivolta G | title = Monoamine oxidase activities in patients with migraine or with cluster headache during the acute phases and after treatment with L-5-hydroxytryptophan | journal = Rivista di Patologia Nervosa e Mentale | volume = 100 | issue = 5 | pages = 269–74 | date = 1 October 2016 | pmid = 318025 }}</ref><ref>{{cite journal | vauthors = Filic V, Vladic A, Stefulj J, Cicin-Sain L, Balija M, Sucic Z, Jernej B | title = Monoamine oxidases A and B gene polymorphisms in migraine patients | journal = Journal of the Neurological Sciences | volume = 228 | issue = 2 | pages = 149–53 | date = February 2005 | pmid = 15694196 | doi = 10.1016/j.jns.2004.11.045 | s2cid = 572208 }}</ref> and irregular sexual maturation.{{citation needed|date=April 2013}} [[Monoamine oxidase inhibitor]]s are one of the major classes of drug prescribed for the treatment of depression, although they are often last-line treatment due to risk of the drug's interaction with diet or other drugs. Excessive levels of [[catecholamine]]s ([[epinephrine]], [[norepinephrine]], and [[dopamine]]) may lead to a [[Hypertensive emergency|hypertensive crisis]], and excessive levels of [[serotonin]] may lead to [[serotonin syndrome]].{{medical citation needed|date=May 2024}}

In fact, MAO-A inhibitors act as antidepressant and anti-anxiety agents, whereas MAO-B inhibitors are used alone or in combination to treat [[Alzheimer's disease]] and [[Parkinson's disease]].<ref name="pmid15279566">{{cite journal | vauthors = Riederer P, Lachenmayer L, Laux G | title = Clinical applications of MAO-inhibitors | journal = Current Medicinal Chemistry | volume = 11 | issue = 15 | pages = 2033–43 | date = August 2004 | pmid = 15279566 | doi = 10.2174/0929867043364775 | doi-broken-date = 2024-11-02 }}</ref>  Some research suggests that certain phenotypes of depression, such as those with anxiety, and "atypical" symptoms involving psychomotor retardation, weight gain and interpersonal sensitivity respond better to MAO inhibitors than other classes of anti-depressant.  However the findings related to this have not been consistent.<ref name="pmid32931110">{{cite journal | vauthors = Maj M, Stein DJ, Parker G, Zimmerman M, Fava GA, De Hert M, Demyttenaere K, McIntyre RS, Widiger T, Wittchen HU | title = The clinical characterization of the adult patient with depression aimed at personalization of management | journal = World Psychiatry | volume = 19 | issue = 3 | pages = 269–293 | date = October 2020 | pmid = 32931110 | pmc = 7491646 | doi = 10.1002/wps.20771 }}</ref> MAOIs may be effective in treatment resistant depression, especially when it does not respond to tricyclic antidepressants.<ref name="pmid15552546">{{cite journal | vauthors = Fiedorowicz JG, Swartz KL | title = The role of monoamine oxidase inhibitors in current psychiatric practice | journal = Journal of Psychiatric Practice | volume = 10 | issue = 4 | pages = 239–48 | date = July 2004 | pmid = 15552546 | pmc = 2075358 | doi = 10.1097/00131746-200407000-00005 }}</ref>

===Parasite interactions===
[[African trypanosomiasis|Sleeping sickness]] - caused by [[trypanosoma|trypanosomes]] - gets its name from the sleep disruption it causes in mammals. That sleep disruption is caused, at least in part, by trypanosomes' tendency to disrupt MAO activity in the [[orexin]] system.<ref name="Kristensson-et-al-2010" />

===Animal models===
There are significant differences in MAO activity in different species. Dopamine is primarily deaminated by [[monoamine oxidase A|MAO-A]] in rats, but by [[Monoamine oxidase B|MAO-B]] in [[vervet monkey]]s and humans.<ref name="Garrick Murphy">{{cite journal | vauthors = Garrick NA, Murphy DL | title = Species differences in the deamination of dopamine and other substrates for monoamine oxidase in brain | journal = Psychopharmacology | volume = 72 | issue = 1 | pages = 27–33 | year = 1980 | pmid = 6781004 | doi = 10.1007/bf00433804 | s2cid = 30722852 }}</ref>

Mice unable to produce either MAO-A or MAO-B display [[autism spectrum|autistic-like]] traits.<ref name="pmid22850464">{{cite journal | vauthors = Bortolato M, Godar SC, Alzghoul L, Zhang J, Darling RD, Simpson KL, Bini V, Chen K, Wellman CL, Lin RC, Shih JC | title = Monoamine oxidase A and A/B knockout mice display autistic-like features | journal = The International Journal of Neuropsychopharmacology | volume = 16 | issue = 4 | pages = 869–88 | date = May 2013 | pmid = 22850464 | pmc = 3517692 | doi = 10.1017/S1461145712000715 }}</ref> These [[Knockout mouse|knockout mice]] display an increased response to stress.<ref name="pmid14697877">{{cite journal | vauthors = Shih JC | title = Cloning, after cloning, knock-out mice, and physiological functions of MAO A and B | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 21–30 | date = January 2004 | pmid = 14697877 | doi = 10.1016/s0161-813x(03)00112-8 | bibcode = 2004NeuTx..25...21S }}</ref>

====Arthropods====
=====Insects=====
Insect brains express MAOs,<ref name="Gripois-et-al-1977" /><ref name="Evans-1980" /><ref name="Lund-et-al-1979" /> and some [[insecticide]]s<ref name="Aziz-Knowles-1973" /><ref name="Lund-et-al-1979" /> work by inhibiting them. An MAOI effect is especially important for [[chlordimeform]]<ref name="Aziz-Knowles-1973" /><ref name="Lund-et-al-1979" /><ref name="Beeman-Matsumura-1974" /> (although one result shows little or no effect in ''[[American cockroach|Periplaneta americana]]'');<ref name="Sloley-et-al-1985" /> and [[dieldrin]] may<ref name="Gripois-et-al-1977" /> or may not<ref name="Evans-1980" /> be an MAOI in ''[[migratory locust|Locusta migratoria]]''.{{medical citation needed|date=May 2024}}

=====Acari=====
MAO activity has been detected in ''[[Rhipicephalus microplus]]'' and chlordimeform is an MAOI in ''R. m.''.<ref name="Atkinson-et-al-1974" />

== Genetics ==
The [[gene]]s encoding MAO-A and MAO-B are located side-by-side on the short arm of the [[X chromosome]], and have about 70% sequence similarity. Rare mutations in the gene are associated with [[Brunner syndrome]].{{medical citation needed|date=May 2024}}

A study based on the [[Dunedin cohort]] concluded that maltreated children with a low-activity polymorphism in the [[promoter (biology)|promoter]] region of the MAO-A gene were more likely to develop [[conduct disorder|antisocial conduct disorders]] than maltreated children with the high-activity variant.<ref name="pmid12161658">{{cite journal | vauthors = Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R | title = Role of genotype in the cycle of violence in maltreated children | journal = Science | volume = 297 | issue = 5582 | pages = 851–4 | date = August 2002 | pmid = 12161658 | doi = 10.1126/science.1072290 | bibcode = 2002Sci...297..851C | s2cid = 7882492 }}</ref> Out of the 442 total males in the study (maltreated or not), 37% had the low activity variant. Of the 13 maltreated males with low MAO-A activity, 11 had been assessed as exhibiting [[conduct disorder|adolescent conduct disorder]] and 4 were convicted for violent offenses. The suggested mechanism for this effect is the decreased ability of those with low MAO-A activity to quickly degrade norepinephrine, the synaptic neurotransmitter involved in [[sympathetic nervous system|sympathetic]] arousal and rage. This is argued to provide direct support for the idea that genetic susceptibility to disease is not determined at birth, but varies with exposure to environmental influences. However, most individuals with conduct disorder or convictions did not have low activity of MAO-A; maltreatment was found to have caused stronger predisposition for antisocial behavior than differences in MAO-A activity.{{medical citation needed|date=May 2024}}

The claim that an interaction between low MAO-A activity and maltreatment would cause anti-social behavior has been criticized since the predisposition towards anti-social behavior could equally well have been caused by ''other'' genes inherited from abusive parents.<ref name="isbn0-521-82818-X">{{cite book | vauthors =  Sesardic N | title = Making sense of heritability | publisher = Cambridge University Press | location = Cambridge, UK | year = 2005 | isbn = 978-0-521-82818-5 }}</ref>

A possible link between predisposition to [[neophilia|novelty seeking]] and a [[genotype]] of the MAO-A gene has been found.<ref name="pmid16538181">{{cite journal | vauthors = Shiraishi H, Suzuki A, Fukasawa T, Aoshima T, Ujiie Y, Ishii G, Otani K | title = Monoamine oxidase A gene promoter polymorphism affects novelty seeking and reward dependence in healthy study participants | journal = Psychiatric Genetics | volume = 16 | issue = 2 | pages = 55–8 | date = April 2006 | pmid = 16538181 | doi = 10.1097/01.ypg.0000199447.62044.ef | s2cid = 25418973}}
* {{cite magazine |author=Heidi Dawley |date=June 18, 2006 |title=The disorder of these times, neophilia |magazine=Media Life |url=http://www.medialifemagazine.com/cgi-bin/artman/exec/view.cgi?archive=226&num=5439 |archive-url=https://web.archive.org/web/20070930153607/http://www.medialifemagazine.com/cgi-bin/artman/exec/view.cgi?archive=226&num=5439 |archive-date=2007-09-30}}</ref>

A particular variant (or [[genotype]]), dubbed "[[warrior gene]]" in the popular press, was over-represented in [[Māori people|Māori]]. This supported earlier studies finding different proportions of variants in different ethnic groups. This is the case for many genetic variants, with 33% White/Non-Hispanic, 61% Asian/Pacific Islanders having the low-activity MAO-A [[promoter (biology)|promoter]] variant.<ref name="pmid9799080">{{cite journal | vauthors = Sabol SZ, Hu S, Hamer D | title = A functional polymorphism in the monoamine oxidase A gene promoter | journal = Human Genetics | volume = 103 | issue = 3 | pages = 273–9 | date = September 1998 | pmid = 9799080 | doi = 10.1007/s004390050816 | s2cid = 29954052 | url = https://zenodo.org/record/1232725 | access-date = 2021-03-30 | archive-date = 2021-04-04 | archive-url = https://web.archive.org/web/20210404203313/https://zenodo.org/record/1232725 | url-status = live }}</ref>

== Aging ==
Unlike many other enzymes, MAO-B activity is increased during aging in the brain of humans and other mammals.<ref>{{cite journal | vauthors = Nicotra A, Pierucci F, Parvez H, Senatori O | title = Monoamine oxidase expression during development and aging | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 155–65 | date = January 2004 | pmid = 14697890 | doi = 10.1016/S0161-813X(03)00095-0 | bibcode = 2004NeuTx..25..155N }}</ref> Increased MAO-B activity was also found in the [[pineal gland]] of aging rats.<ref name=":1" /> This may contribute to lowered levels of monoamines in aged brain and pineal gland.<ref name=":1" /><ref>{{cite journal | vauthors = Razygraev AV, Arutiunian AV | title = [Pineal gland and brain structures monoamine oxidase activity in rats of different age] | language = Russian | journal = Advances in Gerontology = Uspekhi Gerontologii | volume = 21 | issue = 3 | pages = 402–5 | date = 2008 | pmid = 19432173 }}</ref>

== See also ==
* [[Cheese effect]]
* [[Imidazoline receptor|I<sub>2</sub> receptor]]
* [[Monoamine oxidase inhibitor]]

{{Clear}}

== References ==
{{Reflist|32em|refs=

<ref name="Gripois-et-al-1977">{{cite journal | vauthors = Gripois D, Moreteau B, Ramade F | trans-title = Monoamine oxidase activity of the brain of ''Locusta migratoria'' in normal conditions and after intoxication by two insecticides: chlordimeform and dieldrin | journal = Comptes Rendus de l'Académie des Sciences, Série D  | volume = 284 | issue = 12 | pages = 1079–82 | date = March 1977 | pmid = 406057 | title=Sur l'activité monoaminoxydasique du cerveau de ''Locusta migratoria'' dans les conditions normales et après intoxication par deux insecticides: le chlordiméform et la diéldrine | s2cid = 29861405 }}</ref>

<ref name="Evans-1980">{{cite book | vauthors = Evans PD | title=[[Advances in Insect Physiology]] | volume=15 | chapter=Biogenic Amines in the Insect Nervous System | year=1980 | isbn=978-0-12-024215-3 | issn=0065-2806 | doi=10.1016/s0065-2806(08)60143-5 | pages=317–473 | s2cid=83010475}}</ref>

<ref name="Kristensson-et-al-2010">{{cite journal | vauthors = Kristensson K, Nygård M, Bertini G, Bentivoglio M | title = African trypanosome infections of the nervous system: parasite entry and effects on sleep and synaptic functions | journal = Progress in Neurobiology | volume = 91 | issue = 2 | pages = 152–71 | date = June 2010 | pmid = 19995590 | doi = 10.1016/j.pneurobio.2009.12.001 | s2cid = 207406469 }}</ref>

<ref name="Aziz-Knowles-1973">{{cite journal | vauthors = Aziz SA, Knowles CO | title = Inhibition of monoamine oxidase by the pesticide chlordimeform and related compounds | journal = Nature | volume = 242 | issue = 5397 | pages = 417–8 | date = April 1973 | pmid = 4701207 | doi = 10.1038/242417a0 | bibcode = 1973Natur.242..417A | s2cid = 4162760 }}</ref>

<ref name="Atkinson-et-al-1974">{{cite journal|title=High monoamine oxidase activity in the tick ''Boophilus Microplus'' and inhibition by chlordimeform and related pesticides |author=P. Atkinson |author2=K. Binnington |author3=W. J. Roulston |date=1974|journal=[[Australian Journal of Entomology]]|volume=13|issue=3|pages=207–210 |doi=10.1111/j.1440-6055.1974.tb02174.x|s2cid=83731654}}</ref>

<ref name="Lund-et-al-1979">{{cite journal | vauthors = Lund AE, Hollingworth RM, Shankland DL | title=Chlordimeform: Plant protection by a sublethal, noncholinergic action on the central nervous system | journal=[[Pesticide Biochemistry and Physiology]] | volume=11 | issue=1–3 | year=1979 | issn=0048-3575 | doi=10.1016/0048-3575(79)90052-x | pages=117–128| bibcode=1979PBioP..11..117L }}</ref>

<ref name="Sloley-et-al-1985">{{cite journal | vauthors = Sloley BD, Bailey BA, Downer RG | title=Effects of chlordimeform and lindane on monoamine levels in the central nervous system of the american cockroach, ''Periplaneta americana'' L. | journal=[[Pesticide Biochemistry and Physiology]] | volume=24 | issue=2 | year=1985 | issn=0048-3575 | doi=10.1016/0048-3575(85)90131-2 | pages=213–219 | bibcode=1985PBioP..24..213S | s2cid=84947221}}</ref>

<ref name="Beeman-Matsumura-1974">{{cite journal | vauthors = Beeman RW, Matsumura F | title=Studies on the action of chlordimeform in cockroaches | journal=[[Pesticide Biochemistry and Physiology]] | volume=4 | issue=3 | year=1974 | issn=0048-3575 | doi=10.1016/0048-3575(74)90115-1 | pages=325–336 | bibcode=1974PBioP...4..325B | s2cid=83944360}}</ref>

}}

{{Mitochondrial enzymes}}
{{Neurotransmitter metabolism enzymes}}
{{CH-NH2 oxidoreductases}}
{{Enzymes}}
{{Monoamine metabolism modulators}}
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