Monoamine oxidase A

Monoamine oxidase A
Ribbon diagram of an MAO-A monomer, with FAD and clorgiline bound, oriented as if attached to the outer membrane of a mitochondrion.[1]
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1H8Q, 2BXR, 2BXS, 2Z5X, 2Z5Y
Identifiers
Symbols	MAOA ; MAO-A
External IDs	OMIM: 309850 MGI: 96915 HomoloGene: 203 IUPHAR: 2489 ChEMBL: 1951 GeneCards: MAOA Gene
EC number	1.4.3.4
Gene ontology Molecular function • primary amine oxidase activity Cellular component • mitochondrion • mitochondrial outer membrane • integral component of membrane Biological process • cellular biogenic amine metabolic process • xenobiotic metabolic process • synaptic transmission • neurotransmitter secretion • neurotransmitter catabolic process • neurotransmitter biosynthetic process • dopamine catabolic process • small molecule metabolic process • oxidation-reduction process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4128	17161
Ensembl	ENSG00000189221	ENSMUSG00000025037
UniProt	P21397	Q64133
RefSeq (mRNA)	NM_000240	NM_173740
RefSeq (protein)	NP_000231	NP_776101
Location (UCSC)	Chr X: 43.52 – 43.61 Mb	Chr X: 16.62 – 16.69 Mb
PubMed search

Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the MAOA gene.^[2][3] Monoamine oxidase A is an isozyme of monoamine oxidase. It preferentially deaminates norepinephrine (noradrenaline), epinephrine (adrenaline), serotonin, and dopamine (which is equally deaminated by MAO-A and MAO-B).

It is inhibited by clorgyline and befloxatone. Inhibition of both MAO-A and MAO-B using a monoamine oxidase inhibitor (MAO inhibitor) is used in the treatment of clinical depression, erectile dysfunction and anxiety.

Function

Monoamine oxidase A is an enzyme that degrades amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. The protein localizes to the outer mitochondrial membrane. Its encoding gene is adjacent to a related gene (MAOB) on the opposite strand of the X chromosome.

Clinical significance

In humans, there is a 30-base repeat sequence repeated in one of several different numbers of times in the promoter region of the gene coding for 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 Caucasians. The 3.5R and 4R variants have been found to be more highly active than 3R or 5R, in a study which did not examine the 2R variant.^[4] 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.^[4][5][6]

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.^[7] 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,^[8] depressed suicide in males,^[9] major depression and sleep disturbance in males^[10] and major depressive disorder in both males and females.^[11]

Other studies failed to find a significant relationship between high-activity variants of the MAOA gene and major depressive disorder.^[12][13] 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.^[14]

There is a link between low activities forms of the MAOA gene and autism.^[15]

Mutation in the MAOA gene results in monoamine oxidase deficiency, or Brunner syndrome.^[16]

Aggression and the "Warrior gene"

A version of the monoamine oxidase-A gene has been popularly referred to as the warrior gene.^[17] Several different versions of the gene are found in different individuals, although a functional gene is present in most humans (with the exception of a few individuals with Brunner syndrome).^[18] In the variant, the allele associated with behavioural traits is shorter (30 bases) and may produce less MAO-A enzyme.^[19] This gene variation is in a regulatory promoter region about 1000 bases from the start of the region that encodes the MAO-A enzyme.

The frequency distribution of variants of the MAO-A gene differs between ethnic groups.^[19][20] 59% of Black men, 54% of Chinese men, 56% of Maori men, and 34% of Caucasian men carry the 3R allele. 5.5% of Black men, 0.1% of Caucasian men, and 0.00067% of Asian men carry the 2R allele.^{[6][19][20][21][22][23][24][25][26][27]}

A connection between a version of the monoamine oxidase A gene (3R) and several types of antisocial behavior has been found. MAO-A had no statistically significant main effect on antisocial behavior. Maltreated children with genes causing high levels of MAO-A were less likely to develop antisocial behavior.^[28] Low MAO-A activity in combination with abuse experienced during childhood results in an increased risk of aggressive behaviour as an adult.^[29] High testosterone, maternal tobacco smoking during pregnancy, poor material living standards, dropping out of school, and low IQ can also trigger violent behavior in men with the low-activity alleles (which are overwhelmingly the 3R allele).^[30][31]

In individuals with the low activity MAO-A gene, when faced with social exclusion or ostracism showed higher levels of aggression than individuals with the high activity MAO-A gene.^[32] Low activity MAO-A could significantly predict aggressive behaviour in a high provocation situation, but was less associated with aggression in a low provocation situation. Individuals with the low activity variant of the MAO-A gene were just as likely as participants with the high activity variant to retaliate when the loss was small. However, they were more likely to retaliate and with greater force when the loss was large.^[33]

“Monoamine oxidases (MAOs) are enzymes that are involved in the breakdown of neurotransmitters such as serotonin and dopamine and are, therefore, capable of influencing feelings, mood, and behaviour of individuals”.^[34] According to this, if there was a mutation to the gene that is involved in the process of promoting or inhibiting MAO enzymes, it could affect a person’s personality or behaviour and could therefore make them more prone to aggression. A deficiency in the MAO-A gene has shown higher levels of aggression in males, which could further stimulate more research into this controversial topic. “A deficiency in monoamine oxidase A (MAO-A) has been shown to be associated with aggressive behaviour in men of a Dutch family”.^[35]

Animal studies

A dysfunctional MAO-A gene has been correlated with increased aggression levels in mice,^[36][37] and has been correlated with heightened levels of aggression in humans.^[38] In mice, a dysfunctional MAO-A gene is created through insertional mutagenesis (called ‘Tg8’).^[36] Tg8 is a transgenic mouse strain that lacks functional MAO-A enzymatic activity. Mice that lacked a functional MAO-A gene exhibited increased aggression towards intruder mice.^[36][39]

Some types of aggression exhibited by these mice were territorial aggression, predatory aggression, and isolation-induced aggression.^[37] 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.^[40] There is research in both humans and mice to support that a nonsense point mutation in the eighth exon of the MAO-A gene is responsible for impulsive aggressiveness due to a complete MAO-A deficiency.^[36][38]

Epigenetics

Epigenetics likely plays an important role in the expression of the MAO-A gene through methylation in women.^[41] Studies have linked methylation of the MAO-A gene with nicotine and alcohol dependence in women.^[42] A second MAO-A VNTR promoter, P2, influences epigenetic methylation in women only and interacts with having experienced child abuse to influence antisocial personality disorder symptoms, also only in women.^[43] Epigenetic methylation of MAO-A in men is very low and with little variability compared to women. It also has a much higher heritability in men than women.^[44]

Legal implications

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.^[45][46]

Cancer research

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.^[47] Cholangiocarcinoma suppresses MAO-A expression, and those patients with higher MAO-A expression had less adjacent organ invasion and better prognosis and survival.^[48]

MAO-A inhibitors

• Synthetic compounds
  • Befloxatone (MD370503)
  • Brofaromine (Consonar)
  • Cimoxatone
  • Clorgyline (irreversable)
  • Methylene Blue
  • Minaprine (Cantor)
  • Moclobemide (Aurorix, Manerix)
  • Pirlindole (Pirazidol)
  • Toloxatone (Humoryl)
  • Tyrima (CX 157)
  • Tranylcypromine (non-selective&irreversable)

• Herbal sources
  • Curcumin (Turmeric)
  • Harmala Alkaloids (Syrian Rue, Passion Flower, Ayahuasca)
    • Harmine
    • Harmaline

MAO-A inducers

• Synthetic compounds
  • Valproic Acid (Depakote)^[49]

References

Further reading

PDB gallery 2bxr: HUMAN MONOAMINE OXIDASE A IN COMPLEX WITH CLORGYLINE, CRYSTAL FORM A  2bxs: HUMAN MONOAMINE OXIDASE A IN COMPLEX WITH CLORGYLINE, CRYSTAL FORM B

CH-NH2 oxidoreductases (EC 1.4) - primarily amino acid oxidoreductases 1.4.1: NAD/NADP acceptor Glutamate dehydrogenase GLUD1 GLUD2 Glutamate synthase (NADPH) 1.4.3: oxygen acceptor D-amino acid oxidase Amine oxidase Lysyl oxidase Monoamine oxidase 1.4.4: disulfide acceptor Glycine decarboxylase complex 1.4.99: other acceptors D-amino acid dehydrogenase Amine dehydrogenase Biochemistry overview Enzymes overview By EC number: 1.1 2 3 4 5 6 7 8 10 11 13 14 15-18 2.1 2 3 4 5 6 7 2.7.10 11-12 8 3.1 3.1.3.48 2 3 4 3.4.21 22 23 24 5 6 7 4.1 2 3 4 5 6 5.1 2 3 4 99 6.1-3 4 5-6

Mitochondrial proteins Outer membrane fatty acid degradation Carnitine palmitoyltransferase I Long-chain-fatty-acid—CoA ligase tryptophan metabolism Kynureninase monoamine neurotransmitter metabolism Monoamine oxidase Intermembrane space Adenylate kinase Creatine kinase Inner membrane oxidative phosphorylation Coenzyme Q – cytochrome c reductase Cytochrome c NADH dehydrogenase Succinate dehydrogenase pyrimidine metabolism Dihydroorotate dehydrogenase mitochondrial shuttle Malate-aspartate shuttle Glycerol phosphate shuttle other Glutamate aspartate transporter Glycerol-3-phosphate dehydrogenase ATP synthase Carnitine palmitoyltransferase II Uncoupling protein Matrix citric acid cycle Citrate synthase Aconitase Isocitrate dehydrogenase Oxoglutarate dehydrogenase complex Succinyl coenzyme A synthetase Fumarase Malate dehydrogenase anaplerotic reactions Aspartate transaminase Glutamate dehydrogenase Pyruvate dehydrogenase complex urea cycle Carbamoyl phosphate synthetase I Ornithine transcarbamylase N-Acetylglutamate synthase alcohol metabolism ALDH2 PMPCB Other/to be sorted steroidogenesis Cholesterol side-chain cleavage enzyme Steroid 11-beta-hydroxylase Aldosterone synthase Frataxin Mitochondrial membrane transport protein Mitochondrial permeability transition pore Mitochondrial carrier Mitochondrial DNA Complex I MT-ND1 MT-ND2 MT-ND3 MT-ND4 MT-ND4L MT-ND5 MT-ND6 Complex III MT-CYB Complex IV MT-CO1 MT-CO2 MT-CO3 ATP synthase MT-ATP6 MT-ATP8 tRNA MT-TA MT-TC MT-TD MT-TE MT-TF MT-TG MT-TH MT-TI MT-TK MT-TL1 MT-TL2 MT-TM MT-TN MT-TP MT-TQ MT-TR MT-TS1 MT-TS2 MT-TT MT-TV MT-TW MT-TY see also mitochondrial diseases Index of cells Description Structure nucleus chromosome genetics Organelles peroxisome cytoskeleton centrosome epithelia cilia mitochondria Membranes proteins cell adhesions Membrane transport ion channels vesicular transport solute carrier ABC transporters ATPase oxidoreduction-driven Disease Structural peroxisome cytoskeleton cilia mitochondria nucleus scleroprotein Membrane channelopathy solute carrier ATPase ABC transporters other extracellular ligands cell surface receptors intracellular signalling Vesicular transport Pore-forming toxins

Enzymes involved in neutrotransmission monoamine histidine → histamine anabolism: Histidine decarboxylase catabolism: Histamine N-methyltransferase Amine oxidase tyrosine→dopamine→epinephrine anabolism: Tyrosine hydroxylase Aromatic L-amino acid decarboxylase Dopamine beta hydroxylase Phenylethanolamine N-methyltransferase catabolism: Catechol-O-methyl transferase Monoamine oxidase glutamate→GABA anabolism: Glutamate decarboxylase catabolism: 4-aminobutyrate transaminase tryptophan→serotonin→melatonin Tryptophan hydroxylase Aromatic L-amino acid decarboxylase Acetylserotonin O-methyltransferase arginine→NO Nitric oxide synthase (NOS1, NOS2, NOS3) choline→Acetylcholine anabolism: Choline acetyltransferase catabolism: Cholinesterase (Acetylcholinesterase, Butyrylcholinesterase) Index of the central nervous system Description Anatomy meninges cortex association fibers commissural fibers lateral ventricles basal ganglia diencephalon mesencephalon pons cerebellum medulla spinal cord tracts Physiology neutrotransmission enzymes intermediates Development Disease Cerebral palsy Meningitis Demyelinating diseases Seizures and epilepsy Headache Stroke Sleep Congenital Injury Neoplasms and cancer Other paralytic syndromes ALS Symptoms and signs head and neck eponymous lesions Tests CSF Treatment Procedures Drugs general anesthetics analgesics addiction epilepsy cholinergics migraine Parkinson's vertigo other