Monoamine oxidase A

Last updated
MAOA
Monoamine oxidase A 2BXS.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MAOA , MAO-A, monoamine oxidase A, BRNRS
External IDs OMIM: 309850 MGI: 96915 HomoloGene: 203 GeneCards: MAOA
Orthologs
SpeciesHumanMouse
Entrez

4128

17161

Ensembl

ENSG00000189221

ENSMUSG00000025037

UniProt

P21397

Q64133

RefSeq (mRNA)

NM_001270458
NM_000240

NM_173740

RefSeq (protein)

NP_000231
NP_001257387

NP_776101

Location (UCSC) Chr X: 43.65 – 43.75 Mb Chr X: 16.49 – 16.55 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
MAOA gene is located on the short (p) arm of the X chromosome at position 11.3. MAOA Gene with ChrX Ideogram.svg
MAOA gene is located on the short (p) arm of the X chromosome at position 11.3.

Monoamine oxidase A, also known as MAO-A, is an enzyme (E.C. 1.4.3.4) that in humans is encoded by the MAOA gene. [5] [6] This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamination of amines, such as dopamine, norepinephrine, and serotonin. A mutation of this gene results in Brunner syndrome. This gene has also been associated with a variety of other psychiatric disorders, including antisocial behavior. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [7]

Contents

Structures

Gene

Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the MAOA gene. [5] [6] The promoter of MAOA contains conserved binding sites for Sp1, GATA2, and TBP. [8] This gene is adjacent to a related gene ( MAOB ) on the opposite strand of the X chromosome. [9]

In humans, there is a 30-base repeat sequence repeated several different numbers of times in the promoter region of MAO-A. There are 2R (two repeats), 3R, 3.5R, 4R, and 5R variants of the repeat sequence, with the 3R and 4R variants most common in all populations. The variants of the promoter have been found to appear at different frequencies in different ethnic groups in an American sample cohort. [10]

The epigenetic modification of MAOA gene expression through methylation likely plays an important role in women. A study from 2010 found epigenetic methylation of MAOA in men to be very low and with little variability compared to women, while having higher heritability in men than women. [11] [12]

Protein

MAO-A shares 70% amino acid sequence identity with its homologue MAO-B. [13] Accordingly, both proteins have similar structures. Both MAO-A and MAO-B exhibit an N-terminal domain that binds flavin adenine dinucleotide (FAD), a central domain that binds the amine substrate, and a C-terminal α-helix that is inserted in the outer mitochondrial membrane. [13] [14] MAO-A has a slightly larger substrate-binding cavity than MAO-B, which may be the cause of slight differences in catalytic activity between the two enzymes, as shown in quantitative structure-activity relationship experiments. [15] Both enzymes are relatively large, about 60 kilodaltons in size, and are believed to function as dimers in living cells. [14]

Function

Monoamine oxidase A catalyzes O2-dependent oxidation of primary arylalkyl amines, most importantly neurotransmitters such as dopamine and serotonin. This is the initial step in the breakdown of these molecules. The products are the corresponding aldehyde, hydrogen peroxide, and ammonia:

RCH
2-Amine + O
2 + H
2O → R-Aldehyde + H
2O
2 + NH
3

This reaction is believed to occur in three steps, using FAD as an electron-transferring cofactor. First, the amine is oxidized to the corresponding imine, with reduction of FAD 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. [15] [16]

Compared to MAO-B, MAO-A has a higher specificity for serotonin and norepinephrine, while the two enzymes have similar affinity for dopamine and tyramine. [17]

MAO-A is a key regulator for normal brain function. In the brain, the highest levels of transcription occur in the brain stem, hypothalamus, amygdala, habenula, and nucleus accumbens, and the lowest in the thalamus, spinal cord, pituitary gland, and cerebellum. [17] Its expression is regulated by the transcription factors SP1, GATA2, and TBP via cAMP-dependent regulation. [8] [17] MAO-A is also expressed in cardiomyocytes, where it is induced in response to stress such as ischemia and inflammation. [8]

Clinical significance

Cancer

MAO-A produces an amine oxidase, which is a class of enzyme known to affect carcinogenesis. Clorgyline, an MAO-A enzyme inhibitor, prevents apoptosis in melanoma cells, in vitro. [18] Cholangiocarcinoma suppresses MAO-A expression, and those patients with higher MAO-A expression had less adjacent organ invasion and better prognosis and survival. [19]

Cardiovascular disease

MAOA activity is linked to apoptosis and cardiac damage during cardiac injury following ischemic-reperfusion. [8]

Behavioral and neurological disorders

There is some association between low activity forms of the MAOA gene and autism. [20] Mutations in the MAOA gene results in monoamine oxidase deficiency, or Brunner syndrome. [7] Other disorders associated with MAO-A include Alzheimer's disease, aggression, panic disorder, bipolar disorder, major depressive disorder, and attention deficit hyperactivity disorder. [8] Effects of parenting on self-regulation in adolescents appear to be moderated by 'plasticity alleles', of which the 2R and 3R alleles of MAOA are two, with "the more plasticity alleles males (but not females) carried, the more and less self-regulation they manifested under, respectively, supportive and unsupportive parenting conditions." [21]

Depression

MAO-A levels in the brain as measured using positron emission tomography are elevated by an average of 34% in patients with major depressive disorder. [22] Genetic association studies examining the relationship between high-activity MAOA variants and depression have produced mixed results, with some studies linking the high-activity variants to major depression in females, [23] depressed suicide in males, [24] major depression and sleep disturbance in males [25] and major depressive disorder in both males and females. [26]

Other studies failed to find a significant relationship between high-activity variants of the MAOA gene and major depressive disorder. [27] [28] In patients with major depressive disorder, those with MAOA G/T polymorphisms (rs6323) coding for the highest-activity form of the enzyme have a significantly lower magnitude of placebo response than those with other genotypes. [29]

Antisocial behavior

In humans, an association between the 2R allele of the VNTR region of the gene and an increase in the likelihood of committing serious crime or violence has been found. The VNTR 2R allele of MAOA has been found to be a risk factor for violent delinquency, when present in association with stresses, i.e. family issues, low popularity or failing school. [30] [31] [32] [33]

A connection between the MAO-A gene 3R version and several types of anti-social behaviour has been found: Maltreated children with genes causing high levels of MAO-A were less likely to develop antisocial behavior. [34] Low MAO-A activity alleles which are overwhelmingly the 3R allele in combination with abuse experienced during childhood resulted in an increased risk of aggressive behaviour as an adult, [35] and men with the low activity MAOA allele were more genetically vulnerable even to punitive discipline as a predictor of antisocial behaviour. [36] High testosterone, maternal tobacco smoking during pregnancy, poor material living standards, dropping out of school, and low IQ predicted violent behavior are associated with men with the low-activity alleles. [37] [38] According to a large meta-analysis in 2014, the 3R allele had a small, nonsignificant effect on aggression and antisocial behavior, in the absence of other interaction factors. Owing to methodological concerns, the authors do not view this as evidence in favor of an effect. [39]

The MAO-A gene was the first candidate gene for antisocial behavior and was identified during a "molecular genetic analysis of a large, multigenerational, and notoriously violent, Dutch kindred". [40] A study of Finnish prisoners revealed that a MAOA-L (low-activity) genotype, which contributes to low dopamine turnover rate, was associated with extremely violent behavior. [41] For the purpose of the study, "extremely violent behavior" was defined as at least ten committed homicides, attempted homicides or batteries.

However, a large genome-wide association study has failed to find any large or statistically significant effects of the MAOA gene on aggression. [42] A separate GWAS on antisocial personality disorder likewise did not report a significant effect of MAOA. [43] Another study, while finding effects from a candidate gene search, failed to find any evidence in a large GWAS. [41] A separate analysis of human and rat genome wide association studies, Mandelian randomization studies, and causal pathway analyses likewise failed to reveal robust evidence of MAOA in aggression. [44] This lack of replication is predicted from the known issues of candidate gene research, which can produce many substantial false positives. [45]

Aggression and the "Warrior gene"

Low-activity variants of the VNTR promoter region of the MAO-A gene have been referred to as the warrior gene. [46] When faced with social exclusion or ostracism, individuals with the low activity MAO-A variants showed higher levels of aggression than individuals with the high activity MAO-A gene. [47] Low activity MAO-A could significantly predict aggressive behaviour in a high provocation situation: Individuals with the low activity variant of the MAO-A gene were more likely (75% as opposed to 62%, out of a sample size of 70) to retaliate, and with greater force, as compared to those with a normal MAO-A variant if the perceived loss was large. [48]

The effects of MAOA genes on aggression have also been criticized for being heavily overstated. [49] Indeed, the MAOA gene, even in conjunction with childhood adversity, is known to have a very small effect. [50] The vast majority of people with the associated alleles have not committed any violent acts. [51] [52]

In a 2009 criminal trial in the United States, an argument based on a combination of "warrior gene" and history of child abuse was successfully used to avoid a conviction of first-degree murder and the death penalty; however, the convicted murderer was sentenced to 32 years in prison. [53] [54] In a second case, an individual was convicted of second-degree murder, rather than first-degree murder, based on a genetic test that revealed he had the low-activity MAOA variant. [55] Judges in Germany are more likely to sentence offenders to involuntary psychiatric hospitalization on hearing an accused's MAOA-L genotype. [56]

Epigenetics

Studies have linked methylation of the MAOA gene with nicotine and alcohol dependence in women. [57] A second MAOA VNTR promoter, P2, influences epigenetic methylation and interacts with having experienced child abuse to influence antisocial personality disorder symptoms, only in women. [58] A study of 34 non-smoking men found that methylation of the gene may alter its expression in the brain. [59]

Animal studies

A dysfunctional MAOA gene has been correlated with increased aggression levels in mice, [60] [61] and has been correlated with heightened levels of aggression in humans. [62] In mice, a dysfunctional MAOA gene is created through insertional mutagenesis (called 'Tg8'). [60] Tg8 is a transgenic mouse strain that lacks functional MAO-A enzymatic activity. Mice that lacked a functional MAOA gene exhibited increased aggression towards intruder mice. [60] [63]

Some types of aggression exhibited by these mice were territorial aggression, predatory aggression, and isolation-induced aggression. [61] The MAO-A deficient mice that exhibited increased isolation-induced aggression reveals that an MAO-A deficiency may also contribute to a disruption in social interactions. [64] There is research in both humans and mice to support that a nonsense point mutation in the eighth exon of the MAOA gene is responsible for impulsive aggressiveness due to a complete MAO-A deficiency. [60] [62]

Interactions

Transcription factors

A number of transcription factors bind to the promoter region of MAO-A and upregulate its expression. These include:Sp1 transcription factor, GATA2, TBP. [8]

Inducers

Synthetic compounds that up-regulate the expression of MAO-A include Valproic acid (Depakote) [65]

Inhibitors

Substances that inhibit the enzymatic activity of MAO-A include:

See also

Related Research Articles

An allele, or allelomorph, is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule.

<span class="mw-page-title-main">Monoamine oxidase</span> Family of enzymes

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.

Antisocial personality disorder is a personality disorder characterized by a limited capacity for empathy and a long-term pattern of disregard or violation of the rights of others. Other notable symptoms include impulsivity and reckless behavior, a lack of remorse after hurting others, deceitfulness, irresponsibility, and aggressive behavior.

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

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.

<span class="mw-page-title-main">Serotonin transporter</span> Mammalian protein found in humans

The serotonin transporter also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein that transports the neurotransmitter serotonin from the synaptic cleft back to the presynaptic neuron, in a process known as serotonin reuptake.

Catechol-<i>O</i>-methyltransferase Class of enzymes

Catechol-O-methyltransferase is one of several enzymes that degrade catecholamines, catecholestrogens, and various drugs and substances having a catechol structure. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene. Two isoforms of COMT are produced: the soluble short form (S-COMT) and the membrane bound long form (MB-COMT). As the regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines. COMT was first discovered by the biochemist Julius Axelrod in 1957.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter (DAT) also is a membrane-spanning protein coded for in the human by the SLC6A3 gene,, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

Dopamine receptor D<sub>4</sub> Protein-coding gene in the species Homo sapiens

The dopamine receptor D4 is a dopamine D2-like G protein-coupled receptor encoded by the DRD4 gene on chromosome 11 at 11p15.5.

<span class="mw-page-title-main">Gene–environment interaction</span> Response to the same environmental variation differently by different genotypes

Gene–environment interaction is when two different genotypes respond to environmental variation in different ways. A norm of reaction is a graph that shows the relationship between genes and environmental factors when phenotypic differences are continuous. They can help illustrate GxE interactions. When the norm of reaction is not parallel, as shown in the figure below, there is a gene by environment interaction. This indicates that each genotype responds to environmental variation in a different way. Environmental variation can be physical, chemical, biological, behavior patterns or life events.

<span class="mw-page-title-main">CYP2A6</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2A6 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. CYP2A6 is the primary enzyme responsible for the oxidation of nicotine and cotinine. It is also involved in the metabolism of several pharmaceuticals, carcinogens, and a number of coumarin-type alkaloids. CYP2A6 is the only enzyme in the human body that appreciably catalyzes the 7-hydroxylation of coumarin, such that the formation of the product of this reaction, 7-hydroxycoumarin, is used as a probe for CYP2A6 activity.

<span class="mw-page-title-main">CYP2C19</span> Mammalian protein found in humans

Cytochrome P450 2C19 is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some proton pump inhibitors and antiepileptic drugs. In humans, it is the CYP2C19 gene that encodes the CYP2C19 protein. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, most notably the antiplatelet treatment clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.

The field of psychology has been greatly influenced by the study of genetics. Decades of research have demonstrated that both genetic and environmental factors play a role in a variety of behaviors in humans and animals. The genetic basis of aggression, however, remains poorly understood. Aggression is a multi-dimensional concept, but it can be generally defined as behavior that inflicts pain or harm on another.

<span class="mw-page-title-main">Brunner syndrome</span> X-linked recessive disorder characterised by impulsive behaviour

Brunner syndrome is a rare genetic disorder associated with a mutation in the MAOA gene. It is characterized by lower than average IQ, problematic impulsive behavior, sleep disorders and mood swings. It was identified in fourteen males from one family in 1993. It has since been discovered in additional families.

<span class="mw-page-title-main">NPAS2</span> Protein-coding gene in the species Homo sapiens

Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.

Gene–environment correlation is said to occur when exposure to environmental conditions depends on an individual's genotype.

<span class="mw-page-title-main">Monoamine oxidase B</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">Proline oxidase</span> Protein-coding gene in the species Homo sapiens

Proline dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the PRODH gene.

Rs6265, also called Val66Met or G196A, is a gene variation, a single nucleotide polymorphism (SNP) in the BDNF gene that codes for brain-derived neurotrophic factor.

<span class="mw-page-title-main">ANKK1</span> Protein-coding gene in the species Homo sapiens

Ankyrin repeat and kinase domain containing 1 (ANKK1) also known as protein kinase PKK2 or sugen kinase 288 (SgK288) is an enzyme that in humans is encoded by the ANKK1 gene. The ANKK1 is a member of an extensive family of the Ser/Thr protein kinase family, and protein kinase superfamily involved in signal transduction pathways.

A behaviour mutation is a genetic mutation that alters genes that control the way in which an organism behaves, causing their behavioural patterns to change.

References

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