Monoamine oxidase A

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

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 (MAO-B) on the opposite strand of chromosome X. Mutation in this gene results in monoamine oxidase deficiency, or Brunner syndrome.^[4]

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 MAOA. 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.^[5]

An association between a rare 2R repeat of the VNTR region of the gene and an increase in the likelihood of committing serious crime or violence has been found.^[6][5]

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 MAO-A 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 MAO-A gene and major depressive disorder.^[12][13]

The version of the gene that a person carries may determine or at least significantly influence whether a traumatic childhood experience of violence leads to psychopathy,^[14] but this finding is not universal; it was shown in Caucasian but not non-white Americans.^[15]

In patients with major depressive disorder, those with MAO-A 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.^[16]

Warrior gene

A version of the primate monoamine oxidase-A gene has been popularly referred to as the warrior gene. 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).^[17] The allele associated with behavioural traits is shorter (30 bases) and may produce less MAO-A enzyme.^[18] This gene variation is in a regulatory promoter region about 1000 bases from the start of the region that encodes the MAO-A enzyme. However, behaviour is dependent on both genes and the environment.^[14]

The frequency distribution of variants of the MAO-A gene differs between ethnic groups^[18][19]—as is the case for many genotypes. Due to the sensitive political nature of the findings, and the standard peer review process, the research has been heavily scrutinised. Several objections have been raised, such as the small sample size, and the extrapolation of non-Maori studies to the Maori population. In addition, ideological objections were raised, as well as concerns about announcing such findings in the early stages of research.^{[15][20][21][22]}

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 jail ^[23][24]

Some MAO-A inhibitors

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

• Herbal sources
  • Curcumin (Turmeric)
  • Coptisine (Goldthread)
  • Harmala Alkaloids (Tobacco, Syrian Rue, Passion Flower)
    • Harmine
    • Harmaline
    • Tetrahydroharmaline

References

Further reading