Monoamine Oxidase A
Encyclopedia
Monoamine oxidase A, also known as MAO-A, is an enzyme
that in humans is encoded by the MAO-A gene
. 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
.
s, 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
.
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.
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. 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, depressed suicide in males, major depression and sleep disturbance in males and major depressive disorder in both males and females. Other studies failed to find a significant relationship between high-activity variants of the MAO-A gene and major depressive disorder.
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
, but this finding is not universal; it was shown in Caucasian but not non-white Americans.
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.
-A gene has been 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
). The allele associated with behavioural traits is shorter (30 bases
) and may produce less MAO-A enzyme. 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.
Statistical frequency of the MAO-A gene varies by ethnicity—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.
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
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the MAO-A gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Monoamine oxidase A is an isozyme
Isozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...
of monoamine oxidase
Monoamine oxidase
L-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...
. It preferentially deaminates norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(noradrenaline), epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
(adrenaline), serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
(dopamine is equally deaminated by MAO-A and MAO-B). It is inhibited by clorgiline and befloxatone
Befloxatone
Befloxatone is a selective monoamine oxidase inhibitor of type MAO-A....
.
Function
Monoamine oxidase A is an enzyme that degrades amine neurotransmitterNeurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s, such as dopamine, norepinephrine, and serotonin. The protein localizes to the outer mitochondrial membrane
Outer mitochondrial membrane
thumb|300px|Mitochondria structure :1) [[Inner membrane]]2) Outer membrane3) [[Crista]]4) [[Matrix |Matrix]]The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to the eukaryotic plasma 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
Brunner syndrome
Brunner syndrome is a rare genetic disorder caused by a mutation in the MAOA gene. It is characterized by mild mental retardation and problematic impulsive behavior...
.
Clinical significance
In humans, there is a 30-base region repeated different numbers of times in the promoter of the gene, There are 2R (two repeats), 3R, 3.5R, 4R, and 5R copies of the repeat sequence, the 3 and 4 repeats are most common in caucasians. Thus, people may have different versions of the gene. The 3.5R and 4R variants are more highly active than 3R or 5R .An association between a rare 2R repeat of the VNTR
Variable number tandem repeat
A Variable Number Tandem Repeat is a location in a genome where a short nucleotide sequence is organized as a tandem repeat. These can be found on many chromosomes, and often show variations in length between individuals. Each variant acts as an inherited allele, allowing them to be used for...
region of the gene and an increase in the likelihood of committing serious crime or violence has been found.
MAO-A levels in the brain as measured using positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
are elevated by an average of 34% in patients with major depressive disorder. 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, depressed suicide in males, major depression and sleep disturbance in males and major depressive disorder in both males and females. Other studies failed to find a significant relationship between high-activity variants of the MAO-A gene and major depressive disorder.
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
Psychopathy
Psychopathy is a mental disorder characterized primarily by a lack of empathy and remorse, shallow emotions, egocentricity, and deceptiveness. Psychopaths are highly prone to antisocial behavior and abusive treatment of others, and are very disproportionately responsible for violent crime...
, but this finding is not universal; it was shown in Caucasian but not non-white Americans.
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
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
response than those with other genotypes.
Warrior gene
A version of the primate monoamine oxidaseMonoamine oxidase
L-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...
-A gene has been 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
Brunner syndrome
Brunner syndrome is a rare genetic disorder caused by a mutation in the MAOA gene. It is characterized by mild mental retardation and problematic impulsive behavior...
). The allele associated with behavioural traits is shorter (30 bases
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
) and may produce less MAO-A enzyme. This gene variation is in a regulatory promoter region about 1000 bases
Bases
Bases may refer to:*Bases , a military style of dress adopted by the chivalry of the sixteenth century.*Business Association of Stanford Entrepreneurial Students...
from the start
Start codon
The start codon is generally defined as the point, sequence, at which a ribosome begins to translate a sequence of RNA into amino acids.When an RNA transcript is "read" from the 5' carbon to the 3' carbon by the ribosome the start codon is the first codon on which the tRNA bound to Met,...
of the region that encodes
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
the MAO-A enzyme. However, behaviour is dependent on both genes and the environment.
Statistical frequency of the MAO-A gene varies by ethnicity—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.
In a 2009 criminal trial in the United States, an argument based on a combination of "warrior gene" and history of child abuse
Child abuse
Child abuse is the physical, sexual, emotional mistreatment, or neglect of a child. In the United States, the Centers for Disease Control and Prevention and the Department of Children And Families define child maltreatment as any act or series of acts of commission or omission by a parent or...
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
Some MAO-A inhibitors
- Synthetic compounds
- BefloxatoneBefloxatoneBefloxatone is a selective monoamine oxidase inhibitor of type MAO-A....
(MD370503) - BrofaromineBrofaromineBrofaromine is a reversible inhibitor of monoamine oxidase A discovered by Ciba-Geigy. The drug is primarily useful in the treatment of depression and anxiety...
(Consonar) - CimoxatoneCimoxatoneCimoxatone is a reversible inhibitor of MAO-A .- References :...
- Clorgiline
- Methylene BlueMethylene blueMethylene blue is a heterocyclic aromatic chemical compound with the molecular formula C16H18N3SCl. It has many uses in a range of different fields, such as biology and chemistry. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in...
- MinaprineMinaprineMinaprine is an antidepressant used in France for the treatment of depression. It acts as a reversible inhibitor of MAO-A . It has also been found to inhibit acetylcholinesterase.- References :...
(Cantor) - MoclobemideMoclobemideMoclobemide is a monoamine oxidase inhibitor drug primarily used to treat depression and social anxiety. Although clinical trials with the medicine began in 1977, it is not approved for use in the United States...
(Aurox, Manerix) - PirlindolePirlindolePirlindole is a reversible inhibitor of monoamine oxidase A which is used in Russia as an antidepressant. It is structurally and pharmacologically related to metralindole.- References :...
(Pirazidol) - ToloxatoneToloxatoneToloxatone is an antidepressant launched in 1984 for the treatment of depression. It acts as a selective reversible inhibitor of MAO-A .- References :...
(Humoryl) - TyrimaTyrimaTyrima is a selective and reversible inhibitor of MAO-A . It is currently in phase II clinical trials for the treatment of depression.- References :...
(CX 157) - TranylcypromineTranylcypromineTranylcypromine is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor —it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase...
(non-selective)
- Befloxatone
- Herbal sources
- CurcuminCurcuminCurcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family . The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols and are responsible for the yellow color of turmeric...
(TurmericTurmericTurmeric is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae. It is native to tropical South Asia and needs temperatures between 20 °C and 30 °C and a considerable amount of annual rainfall to thrive...
) - CoptisineCoptisineCoptisine is an alkaloid found in Chinese goldthread . Famous for the bitter taste that it produces, it is used in Chinese herbal medicine along with the related compound berberine for treating digestive disorders caused by bacterial infections.Also found in Greater Celandine and has also been...
(Goldthread) - Harmala AlkaloidHarmala alkaloidSeveral alkaloids that function as monoamine oxidase inhibitors are found in the seeds of Peganum harmala , including harmine, harmaline, and harmalol, which are members of a group of substances with a similar chemical structure collectively known as harmala alkaloids...
s (TobaccoTobaccoTobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...
, Syrian Rue, Passion FlowerPassion flowerPassiflora, known also as the passion flowers or passion vines, is a genus of about 500 species of flowering plants, the namesakes of the family Passifloraceae. They are mostly vines, with some being shrubs, and a few species being herbaceous. For information about the fruit of the passiflora...
)- HarmineHarmineHarmine is a fluorescent harmala alkaloid belonging to the beta-carboline family of compounds. It occurs in a number of different plants, most notably the Middle Eastern plant harmal or Syrian rue and the South American vine Banisteriopsis caapi...
- HarmalineHarmalineHarmaline is a fluorescent psychoactive indole alkaloid from the group of harmala alkaloids and beta-carbolines. It is the reduced hydrogenated form of harmine.-Occurrence in nature:...
- Tetrahydroharmaline
- Harmine
- Curcumin