Monoamine oxidase B (MAO-B) is an enzyme that in humans is encoded by the MAOB gene.
Quick Facts MAOB, Available structures ...
| MAOB |
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| Available structures |
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| PDB | Ortholog search: PDBe RCSB |
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| List of PDB id codes |
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1GOS, 1OJ9, 1OJA, 1OJC, 1OJD, 1S2Q, 1S2Y, 1S3B, 1S3E, 2BK3, 2BK4, 2BK5, 2BYB, 2C64, 2C65, 2C66, 2C67, 2C70, 2C72, 2C73, 2C75, 2C76, 2V5Z, 2V60, 2V61, 2VRL, 2VRM, 2VZ2, 2XCG, 2XFN, 2XFO, 2XFP, 2XFQ, 2XFU, 3PO7, 3ZYX, 4A79, 4A7A, 4CRT |
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| Identifiers |
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| Aliases | MAOB, Monoamine oxidase B |
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| External IDs | OMIM: 309860; MGI: 96916; HomoloGene: 20251; GeneCards: MAOB; OMA:MAOB - orthologs |
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| RNA expression pattern |
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| Bgee | | Human | Mouse (ortholog) |
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| Top expressed in | - saphenous vein
- external globus pallidus
- decidua
- tail of epididymis
- middle frontal gyrus
- hypothalamus
- left ovary
- superior vestibular nucleus
- liver
- right lobe of liver
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| | Top expressed in | - epithelium of small intestine
- left lobe of liver
- Epithelium of choroid plexus
- upper respiratory tract
- nasal epithelium
- olfactory epithelium
- medial dorsal nucleus
- islet of Langerhans
- interventricular septum
- myocardium of ventricle
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| | More reference expression data |
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| BioGPS | |
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| Wikidata |
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Close
The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. It catalyzes the oxidative deamination of biogenic and xenobiotic amines and plays an important role in the catabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. This protein preferentially degrades benzylamine and phenethylamine.[5] Similar to monoamine oxidase A (MAO-A), MAO-B is also involved in the catabolism of dopamine.[6]
MAO-B has a hydrophobic bipartite elongated cavity that (for the "open" conformation) occupies a combined volume close to 700 Å3. hMAO-A has a single cavity that exhibits a rounder shape and is larger in volume than the "substrate cavity" of hMAO-B.[7]
The first cavity of hMAO-B has been termed the entrance cavity (290 Å3), the second substrate cavity or active site cavity (~390 Å3) – between both an isoleucine199 side-chain serves as a gate. Depending on the substrate or bound inhibitor, it can exist in either an open or a closed form, which has been shown to be important in defining the inhibitor specificity of hMAO-B. At the end of the substrate cavity is the FAD cofactor with sites for favorable amine binding about the flavin involving two nearly parallel tyrosyl (398 and 435) residues that form what has been termed an aromatic cage.[7]
Like MAO-A, MAO-B catalyzes O2-dependent oxidation of primary arylalkyl amines, the initial step in the breakdown of these molecules. The products are the corresponding aldehyde, hydrogen peroxide, and ammonia:
- Amine + O
2 + H
2O → Aldehyde + H
2O
2 + NH
3
This reaction is believed to occur in three steps. First, the amine is oxidized to the corresponding imine, with reduction of the FAD cofactor to FADH2. Second, O2 accepts two electrons and two protons from FADH2, forming H
2O
2 and regenerating FAD. Third, the imine is hydrolyzed by water, forming ammonia and the aldehyde.[7][8]
MAO-A generally metabolizes tyramine, norepinephrine, serotonin, and dopamine (and other less clinically relevant chemicals). In contrast, MAO-B metabolizes dopamine and β-phenethylamine, as well as other less clinically relevant chemicals.[9] The differences between the substrate selectivity of the two enzymes are utilized clinically when treating specific disorders; MAO-A inhibitors have been typically used in the treatment of depression, whereas MAO-B inhibitors are typically used in the treatment of Parkinson's disease.[10][11] Concurrent use of MAO-A inhibitors with sympathomimetic drugs can induce a hypertensive crisis as a result of excessive norepinephrine.[12] Likewise, the consumption of tyramine-containing substances, such as cheese, whilst using MAO-A inhibitors also carries the risk of hypertensive crisis.[6][12] Selective MAO-B inhibitors bypass this problem by preferentially inhibiting MAO-B, which allows tyramine to be metabolized freely by MAO-A in the gastrointestinal tract.[6][12]
In 2021, it was discovered that MAO-A completely or almost completely mediates striatal dopamine catabolism in the rodent brain and that MAO-B is not importantly involved.[13][14] In contrast, MAO-B appears to mediate γ-aminobutyric acid (GABA) synthesis from putrescine in the striatum, a minor and alternative metabolic pathway of GABA synthesis, and this synthesized GABA in turn inhibits dopaminergic neurons in this brain area.[13][14][15] MAO-B specifically mediates the transformations of putrescine into γ-aminobutyraldehyde (GABAL or GABA aldehyde) and N-acetylputrescine into N-acetyl-γ-aminobutyraldehyde (N-acetyl-GABAL or N-acetyl-GABA aldehyde).[15][16][13][14] These findings may warrant a rethinking of the actions of MAO-B inhibitors in the treatment of Parkinson's disease.[13][14]
Alzheimer's disease (AD) and Parkinson's disease (PD) are both associated with elevated levels of MAO-B in the brain.[17][18] The normal activity of MAO-B creates reactive oxygen species, which directly damage cells.[19] MAO-B levels have been found to increase with age, suggesting a role in natural age related cognitive decline and the increased likelihood of developing neurological diseases later in life.[20] More active polymorphisms of the MAO-B gene have been linked to negative emotionality, and suspected as an underlying factor in depression.[21] Activity of MAO-B has also been shown to play a role in stress-induced cardiac damage.[22][23] Over-expression and increased levels of MAO-B in the brain have also been linked to the accumulation of amyloid β-peptides (Aβ), through mechanisms of the amyloid precursor protein secretase, γ-secretase, responsible for the development of plaques, observed in Alzheimer's and Parkinson's patients. Evidence suggests that siRNA silencing of MAO-B, or inhibition of MAO-B through MAO-B inhibitors (Selegline, Rasagiline), slows the progression, improves and reverses the symptoms, associated with AD and PD, including the reduction of Aβ plaques in the brain.[24][25]
Animal models
Transgenic mice that are unable to produce MAO-B are shown to be resistant to a mouse model of Parkinson's disease.[26][27][28] They also demonstrate increased responsiveness to stress (as with MAO-A knockout mice)[29] and increased β-PEA.[27][29] In addition, they exhibit behavioral disinhibition and reduced anxiety-like behaviors.[30]
Treatment with selegiline, an MAO-B inhibitor, in rats has been shown to prevent many age-related biological changes, such as optic nerve degeneration, and extend average lifespan by up to 39%.[31][32] However, subsequent research suggests that the anti-aging effects of selegiline in animals are due to its catecholaminergic activity enhancer actions rather than MAO-B inhibition.[33]
Effects of deficiency in humans
While people lacking the gene for MAO-A display intellectual disabilities and behavioral abnormalities, people lacking the gene for MAO-B display no abnormalities except elevated phenethylamine levels in urine.[34][9] Newer research indicates the importance of phenethylamine and other trace amines, which are now known to regulate catecholamine and serotonin neurotransmission through the same receptor as amphetamine, TAAR1.[9][35]
The prophylactic use of MAO-B inhibitors to slow natural human aging in otherwise healthy individuals has been proposed, but remains a highly controversial topic.[36][37]
Tan YY, Jenner P, Chen SD (2022). "Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease: Past, Present, and Future". Journal of Parkinson's Disease. 12 (2): 477–493. doi:10.3233/JPD-212976. PMC 8925102. PMID 34957948. There are two MAO isoenzymes: MAO-A and MAO-B. MAO-A is mainly distributed in the gastrointestinal tract, platelets, and heart, and can promote the metabolism of tyramine-containing substances in food so avoiding hypertensive crises caused by the accumulation of tyramine ("cheese reaction"). MAO-A also exists in catecholaminergic neurons, such as dopaminergic neurons in SN, norepinephrine neurons in locus coeruleus, etc. [18]. MAO-B is mainly distributed in platelets and glial cells, and total MAO activity within the brain is composed of approximately 20% MAO-A and 80% MAO-B [19–22]. Both MAO-A and MAO-B regulate the amine neurotransmitters, including dopamine. MAO-A metabolizes dopamine in presynaptic neurons, while MAO-B metabolizes dopamine released to synaptic cleft and taken up by glial cells. The number of glial cells was shown to increase with age, and in neurodegenerative diseases, as expected, the activity of MAO-B also increased [23–25]. MAO-B inhibitors inhibit MAO-B activity in the brain, block dopamine catabolism, enhance dopamine signaling, and selectively enhance dopamine levels at synaptic cleft [21].
Bortolato M, Floris G, Shih JC (November 2018). "From aggression to autism: new perspectives on the behavioral sequelae of monoamine oxidase deficiency". Journal of Neural Transmission. 125 (11): 1589–1599. doi:10.1007/s00702-018-1888-y. PMC 6215718. PMID 29748850. In striking contrast with the evidence on MAOA deficiency, the clinical consequences of low MAO B activity remain partially elusive. Indeed, the only cases with a documented loss-of-function mutation were described in atypical Norrie disease patients, harboring deletions of both the ND gene as well as the (adjacent) MAOB gene (Lenders et al., 1996). These patients did not exhibit any overt psychopathological alterations, pointing to a lack of overt clinical sequelae of MAOB deficiency (Lenders et al., 1996). ... The behavioral sequelae of MAO B deficiency are unlikely to be reflective of early neurodevelopmental problems (given the lower expression of this enzyme in perinatal stages), but may instead reflect tonic enhancements of PEA and/or other MAO B substrates. PEA is a trace amine that has been involved in several neuropsychiatric disorders (Beckmann et al., 1983; Szymanski et al., 1987; O'Reilly et al., 1991; Berry, 2007). The effects of PEA are not fully clear, but its chemical similarity with d-amphetamine (in which a methyl group is substituted at the α-carbon) underlines the possibility that this molecule may serve as a facilitator of catecholamine and serotonin release. On the other hand, the identification of TAAR1 as the endogenous receptor for PEA, as well as other monoamines metabolized by MAO B (such as tyramine and 3-iodothyronamine), calls into question whether the effects of PEA may result from a combination of different mechanisms.
Nolen WA, Hoencamp E, Bouvy PF, Haffmans PM (1993). "Reversible monoamine oxidase-A inhibitors in resistant major depression". Clin Neuropharmacol. 16 (Suppl 2): S69–76. PMID 8313400. Calvi A, Fischetti I, Verzicco I, Belvederi Murri M, Zanetidou S, Volpi R, et al. (2021). "Antidepressant Drugs Effects on Blood Pressure". Frontiers in Cardiovascular Medicine. 8: 704281. doi:10.3389/fcvm.2021.704281. PMC 8370473. PMID 34414219. The risk of developing the "cheese reaction" during treatment with MAOIs depends on the concurrent consumption of meals containing tyramine or sympathomimetic drugs (Table 3). Tyramine is normally metabolized by MAO-A located on the gut wall and by MAO-B in the liver; if MAO-A is inhibited, the bioavailability of tyramine is increased, which leads to an excess in NE, resulting in a hypertensive crisis (55, 217). Currently, they are not first-line antidepressant medications, and their use is limited to treatment-resistant or atypical depression. ... Selegiline is a selective MAO-B at low doses and a non-selective MAOI at higher doses; it also induces dopaminergic activity at low doses. This different action, depending on the dose, implies different use: low doses (up to 10 mg/day) for Parkinson's disease and higher doses as antidepressant treatment (Table 1) (55). ... Higher doses of oral and transdermal selegiline have been linked to a major frequency of orthostatic hypotension (227). No hypertensive crisis was reported with patch administration, but a small portion of patients with preexisting hypertension showed a worse BP control (224).
Saura J, Luque JM, Cesura AM, Da Prada M, Chan-Palay V, Huber G, et al. (September 1994). "Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography". Neuroscience. 62 (1): 15–30. doi:10.1016/0306-4522(94)90311-5. PMID 7816197. S2CID 38740469. Shih JC, Chen K (1999). "MAO-A and -B gene knock-out mice exhibit distinctly different behavior". Neurobiology (Bp). 7 (2): 235–46. PMID 10591056. Grimsby J, Toth M, Chen K, Kumazawa T, Klaidman L, Adams JD, Karoum F, Gal J, Shih JC (October 1997). "Increased stress response and beta-phenylethylamine in MAOB-deficient mice". Nature Genetics. 17 (2): 206–10. doi:10.1038/ng1097-206. PMID 9326944. S2CID 31804364. Kitani K, Kanai S, Sato Y, Ohta M, Ivy GO, Carrillo MC (1993). "Chronic treatment of (-)deprenyl prolongs the life span of male Fischer 344 rats. Further evidence". Life Sci. 52 (3): 281–8. doi:10.1016/0024-3205(93)90219-S. PMID 8423709. 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Bioorg. Med. Chem. Lett. 12 (24): 3551–5. doi:10.1016/S0960-894X(02)00798-9. PMID 12443774. Uebelhack R, Franke L, Schewe HJ (September 1998). "Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava)". Pharmacopsychiatry. 31 (5): 187–92. doi:10.1055/s-2007-979325. PMID 9832350. S2CID 25270815. van Diermen D, Marston A, Bravo J, Reist M, Carrupt PA, Hostettmann K (March 2009). "Monoamine oxidase inhibition by Rhodiola rosea L. roots". Journal of Ethnopharmacology. 122 (2): 397–401. doi:10.1016/j.jep.2009.01.007. PMID 19168123. Leonetti F, Capaldi C, Pisani L, Nicolotti O, Muncipinto G, Stefanachi A, Cellamare S, Caccia C, Carotti A (October 2007). "Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase". Journal of Medicinal Chemistry. 50 (20): 4909–16. doi:10.1021/jm070725e. PMID 17824599. compound #2d, Frédérick R, Dumont W, Ooms F, Aschenbach L, Van der Schyf CJ, Castagnoli N, Wouters J, Krief A (June 2006). "Synthesis, structural reassignment, and biological activity of type B MAO inhibitors based on the 5H-indeno[1,2-c]pyridazin-5-one core". J. Med. Chem. 49 (12): 3743–7. doi:10.1021/jm051091j. PMID 16759116. Carotti A, Catto M, Leonetti F, Campagna F, Soto-Otero R, Méndez-Alvarez E, Thull U, Testa B, Altomare C (November 2007). "Synthesis and monoamine oxidase inhibitory activity of new pyridazine-, pyrimidine- and 1,2,4-triazine-containing tricyclic derivatives". Journal of Medicinal Chemistry. 50 (22): 5364–71. doi:10.1021/jm070728r. PMID 17910428. Chimenti F, Fioravanti R, Bolasco A, Chimenti P, Secci D, Rossi F, Yáñez M, Orallo F, Ortuso F, Alcaro S (May 2009). "Chalcones: a valid scaffold for monoamine oxidases inhibitors". J. Med. Chem. 52 (9): 2818–24. doi:10.1021/jm801590u. PMID 19378991. compound #21, Silvestri R, La Regina G, De Martino G, Artico M, Befani O, Palumbo M, Agostinelli E, Turini P (March 2003). "Simple, potent, and selective pyrrole inhibitors of monoamine oxidase types A and B". J. Med. Chem. 46 (6): 917–20. doi:10.1021/jm0256124. PMID 12620068. compound # (R)-8b, Chimenti F, Secci D, Bolasco A, Chimenti P, Granese A, Carradori S, Yáñez M, Orallo F, Sanna ML, Gallinella B, Cirilli R (September 2010). "Synthesis, stereochemical separation, and biological evaluation of selective inhibitors of human MAO-B: 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazines". J. Med. Chem. 53 (17): 6516–20. doi:10.1021/jm100120s. hdl:11573/360702. PMID 20715818. compound #18, Chimenti F, Maccioni E, Secci D, Bolasco A, Chimenti P, Granese A, Befani O, Turini P, Alcaro S, Ortuso F, Cardia MC, Distinto S (February 2007). "Selective inhibitory activity against MAO and molecular modeling studies of 2-thiazolylhydrazone derivatives". J. Med. 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Med. Chem. Lett. 21 (7): 1969–73. doi:10.1016/j.bmcl.2011.02.030. PMID 21377879. compound #41, Catto M, Nicolotti O, Leonetti F, Carotti A, Favia AD, Soto-Otero R, Méndez-Alvarez E, Carotti A (2006). "Structural insights into monoamine oxidase inhibitory potency and selectivity of 7-substituted coumarins from ligand- and target-based approaches". Journal of Medicinal Chemistry. 49 (16): 4912–25. doi:10.1021/jm060183l. PMID 16884303. compound #2, Matos MJ, Vazquez-Rodriguez S, Uriarte E, Santana L, Viña D (July 2011). "MAO inhibitory activity modulation: 3-Phenylcoumarins versus 3-benzoylcoumarins". Bioorg. Med. Chem. Lett. 21 (14): 4224–7. doi:10.1016/j.bmcl.2011.05.074. PMID 21684743. Matos MJ, Viña D, Janeiro P, Borges F, Santana L, Uriarte E (September 2010). "New halogenated 3-phenylcoumarins as potent and selective MAO-B inhibitors". Bioorg. Med. Chem. Lett. 20 (17): 5157–60. doi:10.1016/j.bmcl.2010.07.013. PMID 20659799. 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Chem. 19 (1): 261–74. doi:10.1016/j.bmc.2010.11.028. PMID 21134756. compound #5c, Manley-King CI, Bergh JJ, Petzer JP (August 2011). "Inhibition of monoamine oxidase by C5-substituted phthalimide analogues". Bioorg. Med. Chem. 19 (16): 4829–40. doi:10.1016/j.bmc.2011.06.070. PMID 21778064. Strydom B, Malan SF, Castagnoli N, Bergh JJ, Petzer JP (February 2010). "Inhibition of monoamine oxidase by 8-benzyloxycaffeine analogues". Bioorg. Med. Chem. 18 (3): 1018–28. doi:10.1016/j.bmc.2009.12.064. PMID 20093036. Vlok N, Malan SF, Castagnoli N, Bergh JJ, Petzer JP (May 2006). "Inhibition of monoamine oxidase B by analogues of the adenosine A2A receptor antagonist (E)-8-(3-chlorostyryl)caffeine (CSC)". Bioorg. Med. Chem. 14 (10): 3512–21. doi:10.1016/j.bmc.2006.01.011. PMID 16442801. Pretorius J, Malan SF, Castagnoli N, Bergh JJ, Petzer JP (September 2008). "Dual inhibition of monoamine oxidase B and antagonism of the adenosine A(2A) receptor by (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues". Bioorganic & Medicinal Chemistry. 16 (18): 8676–84. doi:10.1016/j.bmc.2008.07.088. PMID 18723354. Tzvetkov NT, Hinz S, Küppers P, Gastreich M, Müller CE (August 2014). "Indazole- and indole-5-carboxamides: selective and reversible monoamine oxidase B inhibitors with subnanomolar potency". Journal of Medicinal Chemistry. 57 (15): 6679–6703. doi:10.1021/jm500729a. PMID 24955776.
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