MAOs are important in the breakdown of monoamines ingested in food, and also serve to inactivate monoamine neurotransmitters. 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.[6]
Subtypes and tissue distribution
In humans there are two types of MAO: MAO-A and MAO-B.[7]
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.[8]
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.[9][10] 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).[10] Pituitary has the lowest level of MAO-B activity when compared with brain areas studied.[9]
Function
Monoamine oxidases catalyze the oxidative deamination of monoamines. In the first part of the reaction, cofactorFAD 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 FADH2 cofactor back to the active FAD form. Monoamine oxidases contain the covalently bound cofactorFAD and are, thus, classified as flavoproteins. 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 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[12]) although there is insufficient evidence to support any of them.[13]
Both forms metabolize dopamine, tyramine, and tryptamine;[16] however, some evidence suggests MAO-B may not be responsible for a significant amount of dopamine degradation.[17]
Specific reactions catalyzed by MAO include:[18][19]
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.[42] 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.[43] MAOIs may be effective in treatment resistant depression, especially when it does not respond to tricyclic antidepressants.[44]
Parasite interactions
Sleeping sickness - caused by 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.[45]
Animal models
There are significant differences in MAO activity in different species. Dopamine is primarily deaminated by MAO-A in rats, but by MAO-B in vervet monkeys and humans.[46]
Mice unable to produce either MAO-A or MAO-B display autistic-like traits.[47] These knockout mice display an increased response to stress.[48]
The genes 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]
A study based on the Dunedin cohort concluded that maltreated children with a low-activity polymorphism in the promoter region of the MAO-A gene were more likely to develop antisocial conduct disorders than maltreated children with the high-activity variant.[56] 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 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 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]
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.[57]
A possible link between predisposition to novelty seeking and a genotype of the MAO-A gene has been found.[58]
A particular variant (or genotype), dubbed "warrior gene" in the popular press, was over-represented in 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 variant.[59]
Aging
Unlike many other enzymes, MAO-B activity is increased during aging in the brain of humans and other mammals.[60] Increased MAO-B activity was also found in the pineal gland of aging rats.[10] This may contribute to lowered levels of monoamines in aged brain and pineal gland.[10][61]
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^ abcdKawamura M, Eisenhofer G, Kopin IJ, Kador PF, Lee YS, Fujisawa S, et al. (March 2002). "Aldose reductase: an aldehyde scavenging enzyme in the intraneuronal metabolism of norepinephrine in human sympathetic ganglia". Auton Neurosci. 96 (2): 131–139. doi:10.1016/s1566-0702(01)00385-x. PMID11958479.
^Holt A (November 2018). "On the practical aspects of characterising monoamine oxidase inhibition in vitro". J Neural Transm (Vienna). 125 (11): 1685–1705. doi:10.1007/s00702-018-1943-8. PMID30374594.
^ abcdBenedetti MS, Dostert P (1994). "Contribution of amine oxidases to the metabolism of xenobiotics". Drug Metab Rev. 26 (3): 507–535. doi:10.3109/03602539408998316. PMID7924902.
^Ambroziak W, Maśliński C (April 1988). "Participation of aldehyde dehydrogenase in the oxidative deamination pathway of histamine and putrescine". Agents Actions. 23 (3–4): 311–313. doi:10.1007/BF02142573. PMID3394581.
^Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H (2002). "GABA and GABA Receptors in the Central Nervous System and Other Organs". A Survey of Cell Biology. International Review of Cytology. Vol. 213. pp. 1–47. doi:10.1016/s0074-7696(02)13011-7. ISBN978-0-12-364617-0. PMID11837891. {{cite book}}: |journal= ignored (help)
^ abPang X, Tang C, Guo R, Chen X (May 2022). "Non-cytochrome P450 enzymes involved in the oxidative metabolism of xenobiotics: Focus on the regulation of gene expression and enzyme activity". Pharmacol Ther. 233: 108020. doi:10.1016/j.pharmthera.2021.108020. PMID34637840.
^ abStrolin Benedetti M, Dostert P, Tipton KF. "Contributions of monoamine oxidase to the metabolism of xenobiotics". In Gibson GG (ed.). Progress in Drug Metabolism. Vol. 11. pp. 149–174.
^Domino EF, Khanna SS (March 1976). "Decreased blood platelet MAO activity in unmedicated chronic schizophrenic patients". The American Journal of Psychiatry. 133 (3): 323–6. doi:10.1176/ajp.133.3.323. PMID943955.
^Schildkraut JJ, Herzog JM, Orsulak PJ, Edelman SE, Shein HM, Frazier SH (April 1976). "Reduced platelet monoamine oxidase activity in a subgroup of schizophrenic patients". The American Journal of Psychiatry. 133 (4): 438–40. doi:10.1176/ajp.133.4.438. PMID1267046.
^Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, et al. (November 2006). "Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression". Archives of General Psychiatry. 63 (11): 1209–16. doi:10.1001/archpsyc.63.11.1209. PMID17088501.
^Domschke K, Sheehan K, Lowe N, Kirley A, Mullins C, O'sullivan R, et al. (April 2005). "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". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 134B (1): 110–4. doi:10.1002/ajmg.b.30158. PMID15717295. S2CID24453719.
^Bussone G, Boiardi A, Cerrati A, Girotti F, Merati B, Rivolta G (1 October 2016). "Monoamine oxidase activities in patients with migraine or with cluster headache during the acute phases and after treatment with L-5-hydroxytryptophan". Rivista di Patologia Nervosa e Mentale. 100 (5): 269–74. PMID318025.
^Filic V, Vladic A, Stefulj J, Cicin-Sain L, Balija M, Sucic Z, et al. (February 2005). "Monoamine oxidases A and B gene polymorphisms in migraine patients". Journal of the Neurological Sciences. 228 (2): 149–53. doi:10.1016/j.jns.2004.11.045. PMID15694196. S2CID572208.
^Riederer P, Lachenmayer L, Laux G (August 2004). "Clinical applications of MAO-inhibitors". Current Medicinal Chemistry. 11 (15): 2033–43. doi:10.2174/0929867043364775 (inactive 2024-11-02). PMID15279566.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
^Kristensson K, Nygård M, Bertini G, Bentivoglio M (June 2010). "African trypanosome infections of the nervous system: parasite entry and effects on sleep and synaptic functions". Progress in Neurobiology. 91 (2): 152–71. doi:10.1016/j.pneurobio.2009.12.001. PMID19995590. S2CID207406469.
^Garrick NA, Murphy DL (1980). "Species differences in the deamination of dopamine and other substrates for monoamine oxidase in brain". Psychopharmacology. 72 (1): 27–33. doi:10.1007/bf00433804. PMID6781004. S2CID30722852.
^ abGripois D, Moreteau B, Ramade F (March 1977). "Sur l'activité monoaminoxydasique du cerveau de Locusta migratoria dans les conditions normales et après intoxication par deux insecticides: le chlordiméform et la diéldrine" [Monoamine oxidase activity of the brain of Locusta migratoria in normal conditions and after intoxication by two insecticides: chlordimeform and dieldrin]. Comptes Rendus de l'Académie des Sciences, Série D. 284 (12): 1079–82. PMID406057. S2CID29861405.
^Razygraev AV, Arutiunian AV (2008). "[Pineal gland and brain structures monoamine oxidase activity in rats of different age]". Advances in Gerontology = Uspekhi Gerontologii (in Russian). 21 (3): 402–5. PMID19432173.
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