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 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 phenethylamine. [5] Similar to monoamine oxidase A (MAO-A), MAO-B is also involved in the catabolism of dopamine. [6]
Monoamine oxidase B has a hydrophobic bipartite elongated cavity that (for the "open" conformation) occupies a combined volume close to 700 Å 3. hMAO-A has a single cavity that exhibits a rounder shape and is larger in volume than the "substrate cavity" of hMAO-B. [7]
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 O2-dependent oxidation of primary arylalkyl amines, the initial step in the breakdown of these molecules. The products are the corresponding aldehyde, hydrogen peroxide, and ammonia:
This reaction is believed to occur in three steps. First, the amine is oxidized to the corresponding imine, with reduction of the FAD cofactor to FADH2. Second, O2 accepts two electrons and two protons from FADH2, forming H
2O
2 and regenerating FAD. Third, the imine is hydrolyzed by water, forming ammonia and the aldehyde. [7] [8]
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]
Alzheimer's disease (AD) and Parkinson's disease (PD) are both associated with elevated levels of MAO-B in the brain. [13] [14] The normal activity of MAO-B creates reactive oxygen species, which directly damage cells. [15] 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. [16] More active polymorphisms of the MAO-B gene have been linked to negative emotionality, and suspected as an underlying factor in depression. [17] Activity of MAO-B has also been shown to play a role in stress-induced cardiac damage. [18] [19] Over-expression and increased levels of MAO-B in the brain have also been linked to the accumulation of amyloid β-peptides (Aβ), 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 of MAO-B, or inhibition of MAO-B through MAO-B inhibitors (Selegline, Rasagiline), slows the progression, improves and reverses the symptoms, associated with AD and PD, including the reduction of Aβ plaques in the brain. [20] [21]
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]
While people lacking the gene for MAO-A display intellectual disabilities and behavioral abnormalities, people lacking the gene for MAO-B display no abnormalities except elevated phenethylamine levels in urine. [29] [9] 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. [9] [30]
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]
Species-dependent divergences may hamper the extrapolation of inhibitor potencies. [33]
Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especially for treatment-resistant depression and atypical depression. They are also used to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders.
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 first such enzyme was discovered in 1928 by Mary Bernheim in the liver and was named tyramine oxidase. The MAOs belong to the protein family of flavin-containing amine oxidoreductases.
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.
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 amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.
Tranylcypromine, sold under the brand name Parnate among others, is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.
Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.
A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic bases with low molecular weight and are synthesized by microbial, vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw material or are generated by microbial decarboxylation of amino acids.
Tyramine, 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-brain barrier, resulting in only non-psychoactive peripheral sympathomimetic effects following ingestion. A hypertensive crisis can result, however, from ingestion of tyramine-rich foods in conjunction with the use of monoamine oxidase inhibitors (MAOIs).
β-Carboline (9H-pyrido[3,4-b]indole) represents the basic chemical structure for more than one hundred alkaloids and synthetic compounds. The effects of these substances depend on their respective substituent. Natural β-carbolines primarily influence brain functions but can also exhibit antioxidant effects. Synthetically designed β-carboline derivatives have recently been shown to have neuroprotective, cognitive enhancing and anti-cancer properties.
Harmala alkaloids are several alkaloids that increase effects of reward system neurotransmitter dopamine by acting as monoamine oxidase inhibitors (MAOIs). These alkaloids are found in the seeds of Peganum harmala, as well as leaves of tobacco and coffee beans. The alkaloids include harmine, harmaline, harmalol, and their derivatives, which have similar chemical structures, hence the name "harmala alkaloids". These alkaloids are of interest for their use in Amazonian shamanism, where they are derived from other plants. Harmine, once known as telepathine and banisterine, is a naturally occurring beta-carboline alkaloid that is structurally related to harmaline, and also found in the vine Banisteriopsis caapi. Tetrahydroharmine is also found in B. caapi and P. harmala. Dr. Alexander Shulgin has suggested that harmine may be a breakdown product of harmaline. Harmine and harmaline are reversible inhibitors of monoamine oxidase A (RIMAs). They can stimulate the central nervous system by inhibiting the metabolism of monoamine compounds such as serotonin and norepinephrine.
Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Emsam, Selgin, among other names, 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 tablet taken by mouth or orally disintegrating tablets taken on the tongue for Parkinson's disease and as a patch applied to skin for depression.
Isocarboxazid is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class used as an antidepressant. Along with phenelzine and tranylcypromine, it is one of only three classical MAOIs still available for clinical use in the treatment of psychiatric disorders in the United States, though it is not as commonly employed in comparison to the others.
Moclobemide, sold under the brand names Amira, Aurorix, Clobemix, Depnil and Manerix among others, is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat depression and social anxiety. It is not approved for use in the United States, but is approved in other Western countries such as Canada, the UK and Australia. It is produced by affiliates of the Hoffmann–La Roche pharmaceutical company. Initially, Aurorix was also marketed by Roche in South Africa, but was withdrawn after its patent rights expired and Cipla Medpro's Depnil and Pharma Dynamic's Clorix became available at half the cost.
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 the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.
Rasagiline is an irreversible inhibitor of monoamine oxidase-B used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases.
N-Methylphenethylamine (NMPEA) is a naturally occurring trace amine neuromodulator in humans that is derived from the trace amine, phenethylamine (PEA). It has been detected in human urine and is produced by phenylethanolamine N-methyltransferase with phenethylamine as a substrate, which significantly increases PEA's effects. PEA breaks down into phenylacetaldehyde which is further broken down into phenylacetic acid by monoamine oxidase. When this is inhibited by monoamine oxidase inhibitors, it allows more of the PEA to be metabolized into nymphetamine (NMPEA) and not wasted on the weaker inactive metabolites.
Benzofuranylpropylaminopentane is a drug with an unusual monoamine-release potentiating mechanism of action. It can loosely be grouped with the stimulant or antidepressant drug families, but its mechanism of action is quite different.
Safinamide 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.
Geiparvarin is a coumarin derivative found in the leaves of the Australian Willow. It is a monoamine oxidase inhibitor.
Mofegiline (MDL-72,974) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) and semicarbazide-sensitive amine oxidase (SSAO) which was under investigation for the treatment of Parkinson's disease and Alzheimer's disease, but was never marketed.
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].
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.
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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ignored (help)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).