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Monoamine oxidase B

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MAOB
Available structures
PDBOrtholog search: PDBe RCSB
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
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Monoamine oxidase B, also known as MAO-B, is an enzyme that in humans is encoded by the MAOB gene.

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]

Structure and Function

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Monoamine oxidase 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]

Differences between MAOA and MAOB

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MAO-A generally metabolizes tyramine, norepinephrine, serotonin, and dopamine (and other less clinically relevant chemicals). In contrast, MAO-B metabolizes dopamine and 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]

Roles in disease and aging

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Alzheimer's disease (AD) and Parkinson's disease (PD) are both associated with elevated levels of MAO-B in the brain.[13][14] The normal activity of MAO-B creates reactive oxygen species, which directly damage cells.[15] 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.[16] More active polymorphisms of the MAO-B gene have been linked to negative emotionality, and suspected as an underlying factor in depression.[17] Activity of MAO-B has also been shown to play a role in stress-induced cardiac damage.[18][19] 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.[20][21]

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.[22][23][24] They also demonstrate increased responsiveness to stress (as with MAO-A knockout mice)[25] and increased β-PEA.[23][25] In addition, they exhibit behavioral disinhibition and reduced anxiety-like behaviors.[26]

Inhibition of MAO-B 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%.[27][28]

Effects of deficiency in humans

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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.[29][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][30]

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.[31][32]

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.[33]

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. ^ a b c GRCh38: Ensembl release 89: ENSG00000069535 – Ensembl, May 2017
  2. ^ a b c GRCm38: 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. ^ a b c 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].
  7. ^ a b c Edmondson 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. PMC 1993809. PMID 17573034.
  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. PMID 12015330.
  9. ^ a b c 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.
  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. PMID 8313400.
  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. PMC 3213739. PMID 22110357.
  12. ^ a b c 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).
  13. ^ 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.
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  15. ^ 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. ISBN 978-3-211-33327-3. PMID 17447416. {{cite book}}: |journal= ignored (help)
  16. ^ 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. PMID 15247489. S2CID 19776473.
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  20. ^ 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. PMC 5540560. PMID 28764767.
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  22. ^ 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.
  23. ^ a b 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.
  24. ^ Shih JC, Chen K, Ridd MJ (1999). "Monoamine oxidase: from genes to behavior". Annual Review of Neuroscience. 22: 197–217. doi:10.1146/annurev.neuro.22.1.197. PMC 2844879. PMID 10202537.
  25. ^ a b Shih JC (January 2004). "Cloning, after cloning, knock-out mice, and physiological functions of MAO A and B.". Neurotoxicology. 25 (1–2): 21–30. doi:10.1016/s0161-813x(03)00112-8. PMID 14697877.
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  27. ^ 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. PMC 3521895. PMID 23082958.
  28. ^ 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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  30. ^ Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
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