Monoamine oxidase B

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Monoamine oxidase B
Protein MAOB PDB 1gos.png
PDB rendering based on 1gos.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MAOB ; MGC26382
External IDs OMIM309860 MGI96916 HomoloGene20251 ChEMBL: 2039 GeneCards: MAOB Gene
EC number 1.4.3.4
RNA expression pattern
PBB GE MAOB 204041 at tn.png
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 NP_766366
Location (UCSC) Chr X:
43.63 – 43.74 Mb
Chr X:
16.71 – 16.82 Mb
PubMed search [1] [2]

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[citation needed] role in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. This protein preferentially degrades benzylamine and phenylethylamine.[1] Like MAOA, it also degrades dopamine.

Structure[edit]

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.[2]

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.[2]

Differences between MAOA and MAOB[edit]

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 where as MAO-B metabolises the dopamine neurotransmitter.[3] MAO-B is an enzyme on the outer mitochondrial membrane and catalyzes the oxidation of arylalkylamine neurotransmitters[4]

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.[5][6] 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[edit]

Alzheimer's disease and Parkinson's disease are both associated with elevated levels of MAO-B in the brain.[7][8] The normal activity of MAO-B creates reactive oxygen species, which directly damage cells.[9] 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.[10] More active polymorphisms of the MAOB gene have been linked to negative emotionality, and suspected as an underlying factor in depression.[11] Activity of MAO-B has also been shown to play a role in stress-induced cardiac damage.[12][13]

Animal models[edit]

Transgenic mice that are unable to produce MAO-B are shown to be resistant to a mouse model of Parkinson's disease.[14][15][16] They also demonstrate increased responsiveness to stress (as with MAO-A knockout mice)[17] and increased β-PEA.[15][17] In addition, they exhibit behavioral disinhibition and reduced anxiety-like behaviors.[18]

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%.[19][20]

Effects of deficiency in humans[edit]

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.[21][22]

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.[23][24]

Selective inhibitors[edit]

Species-dependent divergences may hamper the extrapolation of inhibitor potencies.[25]

Reversible[edit]

Natural[edit]

Geiparvarin
(+)-Catechin

Synthetic[edit]

Structural formulae of high-affinity reversible MAO inhibitors selective for type B
3d model of compound 2D (Frédérick, 2006)[28]
3d model of compound 2 (Matos, 2011)[29]
3d model of compound 41 (Catto, 2006)[30]

Irreversible (covalent)[edit]


References[edit]

  1. ^ "Entrez Gene: MAOB monoamine oxidase B". 
  2. ^ a b 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. 
  3. ^ 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. 
  4. ^ 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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  28. ^ a b 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. 
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Further reading[edit]