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Monoamine oxidase B

(Redirected fromMAO-B)

Monoamine oxidase B(MAO-B) is anenzymethat in humans is encoded by theMAOBgene.

MAOB
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesMAOB,Monoamine oxidase B
External IDsOMIM:309860;MGI:96916;HomoloGene:20251;GeneCards:MAOB;OMA:MAOB - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4129

109731

Ensembl

ENSG00000069535

ENSMUSG00000040147

UniProt

P27338

Q8BW75

RefSeq (mRNA)

NM_000898

NM_172778

RefSeq (protein)

NP_000889

NP_766366

Location (UCSC)Chr X: 43.77 – 43.88 MbChr X: 16.58 – 16.68 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The protein encoded by this gene belongs to the flavinmonoamine oxidasefamily. It is anenzymelocated in theouter mitochondrial membrane.It catalyzes theoxidative deaminationof biogenic andxenobioticaminesand plays an important role in the catabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. This protein preferentially degradesbenzylamineandphenethylamine.[5]Similar tomonoamine oxidase A(MAO-A), MAO-B is also involved in the catabolism ofdopamine.[6]

Structure and function

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MAO-B has a hydrophobic bipartite elongated cavity that (for the "open" conformation) occupies a combined volume close to 700Å3.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 theentrance cavity(290 Å3), the secondsubstrate cavityoractive site cavity(~390 Å3) – between both anisoleucine199 side-chain serves as agate.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 theFADcofactor with sites for favorable amine binding about the flavin involving two nearly parallel tyrosyl (398 and 435) residues that form what has been termed anaromatic cage.[7]

Like MAO-A, MAO-B catalyzesO2-dependent oxidation of primary arylalkylamines,the initial step in the breakdown of these molecules. The products are the correspondingaldehyde,hydrogen peroxide,andammonia:

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 correspondingimine,with reduction of the FAD cofactor to FADH2.Second, O2accepts two electrons and two protons from FADH2,formingH
2O
2and regenerating FAD. Third, the imine ishydrolyzedby water, forming ammonia and the aldehyde.[7][8]

Differences between MAO-A and MAO-B

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MAO-A generally metabolizestyramine,norepinephrine,serotonin,anddopamine(and other less clinically relevant chemicals). In contrast, MAO-B metabolizes dopamine andβ-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-Ainhibitorshave 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 withsympathomimeticdrugs can induce ahypertensive crisisas 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 thegastrointestinal tract.[6][12]

In 2021, it was discovered that MAO-A completely or almost completely mediatesstriataldopaminecatabolismin the rodent brain and that MAO-B is not importantly involved.[13][14]In contrast, MAO-B appears to mediateγ-aminobutyric acid(GABA) synthesis fromputrescinein the striatum, a minor and alternativemetabolic pathwayof GABA synthesis, and this synthesized GABA in turn inhibitsdopaminergicneuronsin this brain area.[13][14][15]MAO-B specifically mediates thetransformationsof putrescine intoγ-aminobutyraldehyde(GABAL or GABA aldehyde) andN-acetylputrescineintoN-acetyl-γ-aminobutyraldehyde(N-acetyl-GABAL orN-acetyl-GABA aldehyde).[15][16][13][14]These findings may warrant a rethinking of the actions ofMAO-B inhibitorsin the treatment ofParkinson's disease.[13][14]

Roles in disease and aging

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Alzheimer's disease(AD) andParkinson's disease(PD) are both associated with elevated levels of MAO-B in the brain.[17][18]The normal activity of MAO-B createsreactive oxygen species,which directly damage cells.[19]MAO-B levels have been found to increase with age, suggesting a role innatural age related cognitive declineand the increased likelihood of developing neurological diseases later in life.[20]More activepolymorphismsof the MAO-B gene have been linked to negativeemotionality,and suspected as an underlying factor indepression.[21]Activity of MAO-B has also been shown to play a role in stress-induced cardiac damage.[22][23]Over-expressionand increased levels of MAO-B in the brain have also been linked to the accumulation of amyloid β-peptides (Aβ), through mechanisms of theamyloid precursor protein secretase,γ-secretase,responsible for the development of plaques, observed in Alzheimer's and Parkinson's patients. Evidence suggests thatsiRNAsilencingof MAO-B, orinhibitionof MAO-B through MAO-B inhibitors (Selegline,Rasagiline), slows the progression, improves and reverses the symptoms, associated with AD and PD, including the reduction ofAβplaques in the brain.[24][25]

Animal models

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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-Aknockout mice)[29]and increasedβ-PEA.[27][29]In addition, they exhibit behavioral disinhibition and reduced anxiety-like behaviors.[30]

Treatment withselegiline,an MAO-B inhibitor, in rats has been shown to prevent many age-related biological changes, such asoptic nervedegeneration,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 itscatecholaminergic activity enhanceractions rather than MAO-B inhibition.[33]

Effects of deficiency in humans

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While people lacking the gene for MAO-A displayintellectual disabilitiesand 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 othertrace amines,which are now known to regulatecatecholamineand serotoninneurotransmissionthrough the same receptor asamphetamine,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]

Selective inhibitors

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Geiparvarin
(+)-Catechin
Structural formulae of high-affinity reversible MAO inhibitors selective for type B

Species-dependent divergences may hamper the extrapolation of inhibitor potencies.[38]

Reversible

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Natural

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Synthetic

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Irreversible (covalent)

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See also

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References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000069535–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000040147–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^"Entrez Gene: MAOB monoamine oxidase B".
  6. ^abcTan 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.PMC8925102.PMID34957948.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].
  7. ^abcEdmondson DE, Binda C, Mattevi A (August 2007)."Structural insights into the mechanism of amine oxidation by monoamine oxidases A and B".Arch. Biochem. Biophys.464(2): 269–76.doi:10.1016/j.abb.2007.05.006.PMC1993809.PMID17573034.
  8. ^Binda C, Mattevi A, Edmondson DE (5 July 2002)."Structure-function relationships in flavoenzyme-dependent amine oxidations: A comparison of polyamine oxidase and monoamine oxidase".Journal of Biological Chemistry.277(27): 23973–23976.doi:10.1074/jbc.R200005200.PMID12015330.
  9. ^abcBortolato 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.PMC6215718.PMID29748850.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.
  10. ^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.PMID8313400.
  11. ^Riederer P, Laux G (March 2011)."MAO-inhibitors in Parkinson's Disease".Exp Neurobiol.20(1): 1–17.doi:10.5607/en.2011.20.1.1.PMC3213739.PMID22110357.
  12. ^abcCalvi 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.PMC8370473.PMID34414219.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).
  13. ^abcdNam MH, Sa M, Ju YH, Park MG, Lee CJ (April 2022)."Revisiting the Role of Astrocytic MAOB in Parkinson's Disease".Int J Mol Sci.23(8): 4453.doi:10.3390/ijms23084453.PMC9028367.PMID35457272.
  14. ^abcdCho HU, Kim S, Sim J, Yang S, An H, Nam MH, Jang DP, Lee CJ (July 2021)."Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis".Exp Mol Med.53(7): 1148–1158.doi:10.1038/s12276-021-00646-3.PMC8333267.PMID34244591.
  15. ^abWatanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H (2002). "GABA and GABA receptors in the central nervous system and other organs".Int Rev Cytol.International Review of Cytology.213:1–47.doi:10.1016/s0074-7696(02)13011-7.ISBN978-0-12-364617-0.PMID11837891.
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  19. ^Nagatsu T, Sawada M (2006). "Molecular mechanism of the relation of monoamine oxidase B and its inhibitors to Parkinson's disease: Possible implications of glial cells".Oxidative Stress and Neuroprotection.Vol. 71. pp. 53–65.doi:10.1007/978-3-211-33328-0_7.ISBN978-3-211-33327-3.PMID17447416.{{cite book}}:|journal=ignored (help)
  20. ^Kumar MJ, Andersen JK (August 2004). "Perspectives on MAO-B in aging and neurological disease: where do we go from here?".Molecular Neurobiology.30(1): 77–89.doi:10.1385/MN:30:1:077.PMID15247489.S2CID19776473.
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  24. ^Schedin-Weiss S, Inoue M, Hromadkova L, Teranishi Y, Yamamoto NG, Wiehager B, et al. (August 2017)."Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with γ-secretase and regulates neuronal amyloid β-peptide levels".Alzheimer's Research & Therapy.9(1): 57.doi:10.1186/s13195-017-0279-1.PMC5540560.PMID28764767.
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  30. ^Bortolato M, Godar SC, Davarian S, Chen K, Shih JC (December 2009)."Behavioral disinhibition and reduced anxiety-like behaviors in monoamine oxidase B-deficient mice".Neuropsychopharmacology.34(13): 2746–57.doi:10.1038/npp.2009.118.PMC2783894.PMID19710633.
  31. ^Nebbioso M, Pascarella A, Cavallotti C, Pescosolido N (December 2012)."Monoamine oxidase enzymes and oxidative stress in the rat optic nerve: age-related changes".International Journal of Experimental Pathology.93(6): 401–5.doi:10.1111/j.1365-2613.2012.00832.x.PMC3521895.PMID23082958.
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  40. ^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.PMID9832350.S2CID25270815.
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  44. ^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.PMID16759116.
  45. ^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.PMID17910428.
  46. ^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.PMID19378991.
  47. ^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.PMID12620068.
  48. ^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.PMID20715818.
  49. ^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. Chem.50(4): 707–12.doi:10.1021/jm060869d.hdl:11573/231039.PMID17253676.
  50. ^compound #3g,Chimenti F, Fioravanti R, Bolasco A, Manna F, Chimenti P, Secci D, Befani O, Turini P, Ortuso F, Alcaro S (February 2007). "Monoamine oxidase isoform-dependent tautomeric influence in the recognition of 3,5-diaryl pyrazole inhibitors".J. Med. Chem.50(3): 425–8.doi:10.1021/jm060868l.PMID17266193.
  51. ^compound #(S)-1,Chimenti F, Maccioni E, Secci D, Bolasco A, Chimenti P, Granese A, Befani O, Turini P, Alcaro S, Ortuso F, Cirilli R, La Torre F, Cardia MC, Distinto S (November 2005). "Synthesis, molecular modeling studies, and selective inhibitory activity against monoamine oxidase of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)- pyrazole derivatives".J. Med. Chem.48(23): 7113–22.doi:10.1021/jm040903t.PMID16279769.
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  53. ^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.PMID16884303.
  54. ^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.PMID21684743.
  55. ^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.PMID20659799.
  56. ^Matos MJ, Viña D, Picciau C, Orallo F, Santana L, Uriarte E (September 2009). "Synthesis and evaluation of 6-methyl-3-phenylcoumarins as potent and selective MAO-B inhibitors".Bioorg. Med. Chem. Lett.19(17): 5053–5.doi:10.1016/j.bmcl.2009.07.039.PMID19628387.
  57. ^Matos MJ, Viña D, Quezada E, Picciau C, Delogu G, Orallo F, Santana L, Uriarte E (June 2009). "A new series of 3-phenylcoumarins as potent and selective MAO-B inhibitors".Bioorg. Med. Chem. Lett.19(12): 3268–70.doi:10.1016/j.bmcl.2009.04.085.PMID19423346.
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