Monoamine oxidase A
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]
Structures[edit]
Gene[edit]
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[edit]
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]
Clinical significance[edit]
Cancer[edit]
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[edit]
MAOA activity is linked to apoptosis and cardiac damage during cardiac injury following ischemic-reperfusion.[8]
Behavioral and neurological disorders[edit]
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]
Animal studies[edit]
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[edit]
Transcription factors[edit]
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[edit]
Synthetic compounds that up-regulate the expression of MAO-A include Valproic acid (Depakote)[65]