Monoamine oxidase B, also known as MAOB, is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

that in humans is encoded by the ''MAOB''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. The protein encoded by this gene belongs to the flavin

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The firs ...

family. It is an

located in the

outer mitochondrial membrane A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...

. It catalyzes the

oxidative deamination Oxidative deamination is a form of deamination that generates α-keto acids and other oxidized products from amine-containing compounds, and occurs primarily in the liver. Oxidative deamination is stereospecific, meaning it contains different stere ...

of biogenic and

xenobiotic A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...

s and plays an important role in the catabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues (such as dopamine). This protein preferentially degrades benzylamine and

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace am ...

. Similarly to

monoamine oxidase A Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamination of amines, ...

(MAOA), it also degrades

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% o ...

hough some new research contradicts this, suggesting that MAOB does ''not'' directly degrade dopamine, but is responsible for GABA synthesis

Structure

Monoamine oxidase B has a hydrophobic bipartite elongated cavity that (for the "open" conformation) occupies a combined volume close to 700 Å³. h

MAO-A Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamination of amines, s ...

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

isoleucine Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depr ...

199 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''.

Differences between MAOA and MAOB

MAO-A is involved in the metabolism of

tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood ...

; 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 (informally known as the "cheese effect"). 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 arylalkylamine neurotransmitters Monoamine oxidase A (MAOA) generally metabolizes tyramine,

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

(NE),

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and va ...

(5-HT), and

(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

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

(AD) and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...

(PD) are both associated with elevated levels of MAO-B in the brain. The normal activity of MAO-B creates

reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

, 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 MAO-B 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. Over- expression and increased levels of MAO-B in the brain have also been linked to the accumulation of amyloid β-peptides (

Aβ Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...

), 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 Silencing is a visual illusion in which a set of objects that change iluminancehueinhibition of MAO-B through MAOI-B ( Selegline, Rasagiline), slows the progression, improves and reverses the symptoms, associated with AD and PD, including the reduction of

plaques in the brain.

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 A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

) 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

intellectual disabilities Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

and behavioral abnormalities, people lacking the gene for MAO-B display no abnormalities except elevated

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 amine Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to th ...

s, which are now known to regulate

catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a su ...

and

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...

through the same receptor as

amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

TAAR1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily ex ...

. 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.

Reversible

Natural

* Geiparvarin * Desmethoxyyangonin, a constituent of

kava Kava or kava kava ('' Piper methysticum'': Latin 'pepper' and Latinized Greek 'intoxicating') is a crop of the Pacific Islands. The name ''kava'' is from Tongan and Marquesan, meaning 'bitter'; other names for kava include ''ʻawa'' ( Hawai� ...

extract; modest affinity *

Catechin Catechin is a flavan-3-ol, a type of secondary metabolite providing antioxidant roles in plants. It belongs to the subgroup of polyphenols called flavonoids. The name of the catechin chemical family derives from ''catechu'', which is the tanni ...

and epicatechin. *

Garlic Garlic (''Allium sativum'') is a species of bulbous flowering plant in the genus '' Allium''. Its close relatives include the onion, shallot, leek, chive, Welsh onion and Chinese onion. It is native to South Asia, Central Asia and northeas ...

* Rosiridin (''in vitro'')

Synthetic

Safinamide Safinamide (INN; brand name Xadago) is a drug used as an add-on treatment for Parkinson's disease with "off" episodes; it has multiple modes of action, including the inhibition of monoamine oxidase B. SeFDA index page for NDA 207145for updates. ...

and analogs * 5''H''-Indeno

,2-c The comma is a punctuation mark that appears in several variants in different languages. It has the same shape as an apostrophe or single closing quotation mark () in many typefaces, but it differs from them in being placed on the baseline o ...

yridazin-5-onescompound #2d, (see 3d model) * Substituted

chalcone Chalcone is the organic compound C6H5C(O)CH=CHC6H5. It is an α,β-unsaturated ketone. A variety of important biological compounds are known collectively as chalcones or chalconoids. Chemical properties Chalcones have two absorption maxima at ...

s * 2-(''N''-Methyl-''N''-benzylaminomethyl)-1''H''-pyrrolecompound #21, * 1-(4-Arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazinecompound # (''R'')-8b, * 2-Thiazolylhydrazonecompound #18, * 3,5-Diaryl

pyrazole Pyrazole is an organic compound with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in ortho-substitution. Pyrazole is a weak base, with p''K''b 11.5 ( ...

compound #3g, *

Pyrazoline Pyrazoline is a heterocyclic A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with ...

derivativescompound #(''S'')-1, * Several

coumarin Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by a lactone-like chain , forming a second six-membered h ...

derivativescompound #41, and #C19* (see 3d model) * Phenylcoumarins, extremely subtype selectivecompound #2, and further analogs (see 3d model) *

Chromone Chromone (or 1,4-benzopyrone) is a derivative of benzopyran with a substituted keto group on the pyran ring. It is an isomer of coumarin. Derivatives of chromone are collectively known as ''chromones''. Most, though not all, chromones are also ...

-3-phenylcarboxamidescompound #9, #12, *

Isatin Isatin, also known as tribulin, is an organic compound derived from indole with formula C8H5NO2. The compound was first obtained by Otto Linné Erdman and Auguste Laurent in 1840 as a product from the oxidation of indigo dye by nitric acid and ...

scompound #9i, *

Phthalimide Phthalimide is the organic compound with the formula C6H4(CO)2NH. It is the imide derivative of phthalic anhydride. It is a sublimable white solid that is slightly soluble in water but more so upon addition of base. It is used as a precursor ...

scompound #5c, * 8-Benzyloxycaffeines and CSC analogs * (''E,E'')-8-(4-phenylbutadien-1-yl)caffeines, with A_2A antagonistic component * Indazole- and Indole-5-carboxamides

Irreversible (covalent)

Selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or ...

(Eldepryl, Zelapar, Emsam) * Rasagiline (Azilect)

References

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