Monoamine oxidase B

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

The protein encoded by this gene belongs to the flavin is_associated_with::monoamine oxidase family. It is an is_associated_with::enzyme located in the is_associated_with::outer mitochondrial membrane. It catalyzes the is_associated_with::oxidative deamination of biogenic and is_associated_with::xenobiotic is_associated_with::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 is_associated_with::benzylamine and is_associated_with::phenylethylamine. Like is_associated_with::MAOA, it also degrades is_associated_with::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.

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 is_associated_with::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 is_associated_with::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.

Differences between MAOA and MAOB
MAO-A is involved in the metabolism of is_associated_with::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. MAO-B is an enzyme on the outer mitochondrial membrane and catalyzes the oxidation of is_associated_with::arylalkylamine neurotransmitters

Monoamine oxidase A (MAOA) generally metabolizes tyramine, is_associated_with::norepinephrine (NE), is_associated_with::serotonin (5-HT), and is_associated_with::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. 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
is_associated_with::Alzheimer's disease and is_associated_with::Parkinson's disease are both associated with elevated levels of MAO-B in the brain. The normal activity of MAO-B creates is_associated_with::reactive oxygen species, which directly damage cells. 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. More active polymorphisms of the MAOB gene have been linked to negative emotionality, and suspected as an underlying factor in depression. Activity of MAO-B has also been shown to play a role in stress-induced cardiac damage.

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

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%.

Effects of deficiency in humans
While people lacking the gene for MAO-A display is_associated_with::mental retardation and behavioral abnormalities, people lacking the gene for MAO-B display no abnormalities except elevated is_associated_with::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 is_associated_with::trace amines, which are now known to regulate is_associated_with::catecholamine and is_associated_with::serotonin is_associated_with::neurotransmission through the same receptor as is_associated_with::amphetamine, is_associated_with::TAAR1.

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.

Selective inhibitors
Species-dependent divergences may hamper the extrapolation of inhibitor potencies.

Natural

 * is_associated_with::Geiparvarin
 * is_associated_with::Desmethoxyyangonin, a constituent of is_associated_with::kava extract; modest affinity
 * is_associated_with::Catechin and epicatechin

Synthetic

 * is_associated_with::Safinamide and analogs
 * 5H-Indeno[1,2-c]pyridazin-5-ones (see 3d model)
 * Substituted is_associated_with::chalcones
 * 2-(N-Methyl-N-benzylaminomethyl)-1H-pyrrole
 * 1-(4-Arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine
 * 2-Thiazolylhydrazone
 * 3,5-Diaryl is_associated_with::pyrazole
 * is_associated_with::Pyrazoline derivatives
 * Several is_associated_with::coumarin derivatives and #C19* (see 3d model)
 * Phenylcoumarins, extremely subtype selective and further analogs  (see 3d model)
 * is_associated_with::Chromone-3-phenylcarboxamides
 * is_associated_with::Isatins
 * is_associated_with::Phthalimides
 * 8-Benzyloxycaffeines and CSC analogs
 * (E,E)-8-(4-phenylbutadien-1-yl)caffeines, with A2A antagonistic component
 * Indazole- and Indole-5-carboxamides

Irreversible (covalent)

 * is_associated_with::Selegiline (Eldepryl, Zelapar, is_associated_with::Emsam)
 * is_associated_with::Rasagiline (Azilect)