Monoamine oxidase B
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| Location (UCSC) | Chr X: 43.77 – 43.88 Mb | Chr X: 16.58 – 16.68 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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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
Structure and Function
Monoamine oxidase B has a hydrophobic bipartite elongated cavity that (for the "open" conformation) occupies a combined volume close to 700
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
- 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
Differences between MAOA and MAOB
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
Animal models
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
While people lacking the gene for MAO-A display
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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Species-dependent divergences may hamper the extrapolation of inhibitor potencies.[33]
Reversible
Natural
- Geiparvarin[34]
- Desmethoxyyangonin,[35] a constituent of kava extract; modest affinity
- Catechin and epicatechin[citation needed].
- Garlic[36]
- Rosiridin[37] (in vitro)
Synthetic
- Safinamide and analogs[38]
- 5H-Indeno[1,2-c]pyridazin-5-ones[33][39][40] (see 3d model)
- Substituted chalcones[41]
- 2-(N-Methyl-N-benzylaminomethyl)-1H-pyrrole[42]
- 1-(4-Arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine[43]
- 2-Thiazolylhydrazone[44]
- 3,5-Diaryl pyrazole[45]
- Pyrazoline derivatives[46][47]
- Several coumarin derivatives[48] and #C19*[33] (see 3d model)
- Phenylcoumarins, extremely subtype selective[49] and further analogs[50][51][52] (see 3d model)
- Chromone-3-phenylcarboxamides[53]
- Isatins[54]
- Phthalimides[55]
- 8-Benzyloxycaffeines[56][57] and CSC analogs[58]
- (E,E)-8-(4-phenylbutadien-1-yl)caffeines,[59] with A2A antagonistic component
- Indazole- and Indole-5-carboxamides[60]
Irreversible (covalent)
- Emsam)
- Rasagiline (Azilect)
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000069535 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040147 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: MAOB monoamine oxidase B".
- ^ 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].
- ^ PMID 17573034.
- PMID 12015330.
- ^ 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.
- PMID 8313400.
- PMID 22110357.
- ^ 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).
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To the best of our knowledge, there have been no reports of clinical conditions characterized by selective MAO-B deficiency. However, in few cases of atypical ND with MAO-B deletion, the latter deficit was reported to result in increased urinary excretion of PEA, but no overt behavioral abnormalities or cognitive deficits (Berger et al., 1992; Lenders et al., 1996).
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