Monoamine oxidase B

MAOB
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases MAOB, Monoamine oxidase B
External IDs MGI: 96916 HomoloGene: 20251 GeneCards: MAOB
Targeted by Drug
lazabemide, moclobemide, rasagiline, safinamide, tranylcypromine, phenelzine[1]
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez

4129

109731

Ensembl

ENSG00000069535

ENSMUSG00000040147

UniProt

P27338

Q8BW75

RefSeq (mRNA)

NM_000898

NM_172778

RefSeq (protein)

NP_000889.3

NP_766366.2

Location (UCSC) Chr X: 43.77 – 43.88 Mb Chr X: 16.71 – 16.82 Mb
PubMed search [2] [3]
Wikidata
View/Edit HumanView/Edit Mouse

Monoamine oxidase B, also known as MAOB, 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 phenylethylamine.[4] Like MAOA, it also degrades dopamine.

Structure

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.[5]

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 coenzyme 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.[5]

Differences between MAOA and MAOB

MAO-A is involved in the metabolism of tyramine; inhibition, in particular irreversible inhibition of MAO-A can result in a dangerous pressor effect when foods high in tyramine are consumed such as cheeses. MAO-A is involved in the metabolism of serotonin, noradrenaline and dopamine whereas MAO-B metabolises the dopamine neurotransmitter.[6] MAO-B is an enzyme on the outer mitochondrial membrane and catalyzes the oxidation of arylalkylamine neurotransmitters[7]

Monoamine oxidase A (MAOA) generally metabolizes tyramine, norepinephrine (NE), serotonin (5-HT), and dopamine (DA) (and other less clinically relevant chemicals). In contrast, Monoamine oxidase B (MAOB) mainly metabolizes dopamine (DA) (and other less clinically relevant chemicals). The differences between the substrate selectivity of the two enzymes are utilized clinically when treating specific disorders: Monoamine oxidase A inhibitors have been typically used in the treatment of depression, and monoamine oxidase B inhibitors are typically used in the treatment of Parkinson's disease.[8][9] Nonspecific (i.e. MAOA/B combined) inhibitors can pose problems when taken concomitantly with tyramine-containing foods such as cheese, because the drug's inhibition of MAOA causes a dangerous elevation of serum tyramine levels, which can lead to hypertensive symptoms. Selective MAOB inhibitors bypass this problem by preferentially inhibiting MAOB, which mostly metabolizes DA. If MAOB is inhibited, then more DA is available for proper neuronal function, especially in Parkinson's Disease.

Roles in disease and aging

Alzheimer's disease and Parkinson's disease are both associated with elevated levels of MAO-B in the brain.[10][11] The normal activity of MAO-B creates reactive oxygen species, which directly damage cells.[12] 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.[13] More active polymorphisms of the MAOB gene have been linked to negative emotionality, and suspected as an underlying factor in depression.[14] Activity of MAO-B has also been shown to play a role in stress-induced cardiac damage.[15][16]

Animal models

Transgenic mice that are unable to produce MAO-B are shown to be resistant to a mouse model of Parkinson's disease.[17][18][19] They also demonstrate increased responsiveness to stress (as with MAO-A knockout mice)[20] and increased β-PEA.[18][20] In addition, they exhibit behavioral disinhibition and reduced anxiety-like behaviors.[21]

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%.[22][23]

Effects of deficiency in humans

While people lacking the gene for MAO-A display mental retardation and behavioral abnormalities, people lacking the gene for MAO-B display no abnormalities except elevated phenethylamine levels in urine, raising the question of whether MAO-B is actually a necessary enzyme. 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.[24][25]

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.[26][27]

Selective inhibitors

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

Species-dependent divergences may hamper the extrapolation of inhibitor potencies.[28]

Reversible

Natural

Synthetic

Irreversible (covalent)

References

  1. "Drugs that physically interact with Amine oxidase [flavin-containing] B view/edit references on wikidata".
  2. "Human PubMed Reference:".
  3. "Mouse PubMed Reference:".
  4. "Entrez Gene: MAOB monoamine oxidase B".
  5. 1 2 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 1993809Freely accessible. PMID 17573034.
  6. Youdim MB, Weinstock M (January 2004). "Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation". Neurotoxicology. 25 (1–2): 243–50. doi:10.1016/S0161-813X(03)00103-7. PMID 14697899.
  7. Binda C, Hubálek F, Li M, Herzig Y, Sterling J, Edmondson DE, Mattevi A (March 2004). "Crystal structures of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class". J. Med. Chem. 47 (7): 1767–74. doi:10.1021/jm031087c. PMID 15027868.
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  21. 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. PMC 2783894Freely accessible. PMID 19710633.
  22. Nebbioso M, Pascarella A, Cavallotti C, Pescosolido N (December 2012). "Monoamine oxidase enzymes and oxidative stress in the rat optic nerve: age-related changes". Int J Exp Pathol. 93 (6): 401–5. doi:10.1111/j.1365-2613.2012.00832.x. PMC 3521895Freely accessible. PMID 23082958.
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  26. Miklya I (December 2009). "[Slowing the age-induced decline of brain function with prophylactic use of (−)-deprenyl (Selegiline, Jumex). Current international view and conclusions 25 years after the Knoll's proposal]". Neuropsychopharmacol Hung (in Hungarian). 11 (4): 217–25. PMID 20150659.
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  29. Carotti A, Carrieri A, Chimichi S, Boccalini M, Cosimelli B, Gnerre C, Carotti A, Carrupt PA, Testa B (December 2002). "Natural and synthetic geiparvarins are strong and selective MAO-B inhibitors. Synthesis and SAR studies". Bioorg. Med. Chem. Lett. 12 (24): 3551–5. doi:10.1016/S0960-894X(02)00798-9. PMID 12443774.
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  40. 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. PMID 16279769.
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  43. 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.
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  45. 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. PMID 19628387.
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  49. 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.
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  52. 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.
  53. 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.
  54. Tzvetkov; et al. (June 23, 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.

Further reading

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