Monoamine oxidase
Encyclopedia
L-Monoamine oxidases (MAO) are a family of enzyme
s 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. They belong to the protein family
of flavin-containing amine oxidoreductases.
and MAO-B.
of monoamines. Oxygen
is used to remove an amine
group from a molecule, resulting in the corresponding aldehyde
and ammonia
. The general form of the catalyzed reaction (with R denoting an arbitrary group) is:
Monoamine oxidase
s contain the covalently bound cofactor
FAD
and are, thus, classified as flavoprotein
s.
, since they are the substrate for the action of a number of monoamine oxidase inhibitor
drugs
. MAO-A is particularly important in the catabolism
of monoamines ingested in food. Both MAOs are also vital to the inactivation of monoaminergic neurotransmitter
s, for which they display different specificities.
Specific reactions catalyzed by MAO include:
,schizophrenia
, substance abuse
, attention deficit disorder, migraines, and irregular sexual maturation. Monoamine oxidase inhibitor
s are one of the major classes of drug prescribed for the treatment of depression, although they are often last-line treatment due to risk of the drug's interaction with diet or other drugs. Excessive levels of catecholamine
s (epinephrine
, norepinephrine
, and dopamine
) may lead to a hypertensive crisis
, and excessive levels of serotonin
may lead to serotonin syndrome
.
In fact, MAO-A inhibitors act as antidepressant and antianxiety agents, whereas MAO-B inhibitors are used alone or in combination to treat Alzheimer’s and Parkinson’s diseases .
PET
research has shown that MAO is also heavily depleted by use of tobacco
cigarettes.
s encoding MAO-A and MAO-B are located side-by-side on the short arm of the X chromosome
, and have about 70% sequence similarity. Rare mutations in the gene are associated with Brunner syndrome
.
A study based on the Dunedin cohort concluded that maltreated children with a low-activity polymorphism in the promoter region of the MAO-A gene were more likely to develop antisocial conduct disorders
than maltreated children with the high-activity variant. Out of the 442 total males in the study (maltreated or not), 37% had the low activity variant. Of the 13 maltreated males with low MAO-A activity, 11 had been assessed as exhibiting adolescent conduct disorder
and 4 were convicted for violent offenses. The suggested mechanism for this effect is the decreased ability of those with low MAO-A activity to quickly degrade norepinephrine, the synaptic neurotransmitter involved in sympathetic
arousal and rage. This is alleged to provide direct support for the idea that genetic susceptibility to disease is not determined at birth, but varies with exposure to environmental influences. Note however that most of those with conduct disorder or convictions did not have low activity of MAO-A; maltreatment was found to have caused stronger predisposition for antisocial behavior than differences in MAO-A activity.
The claim that an interaction between low MAO-A activity and maltreatment would cause anti-social behavior has been criticized since the predisposition towards anti-social behavior could equally well have been caused by other genes inherited from abusive parents.
A possible link between predisposition to novelty seeking and a genotype
of the MAO-A gene has been found.
A particular variant (or genotype
) was over-represented in Māori, a Warrior gene. This supported earlier studies finding different proportions of variants in different ethnic groups. This is the case for many genetic variants, with 33% White/Non-Hispanic, 61% Asian/Pacific Islanders having the low-activity MAO-A promoter variant.
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...
s that catalyze
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
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
Mary Bernheim
Mary Bernheim was a British biochemist who obtained her doctorate at Cambridge University. While a graduate student, she discovered the enzyme tyramine oxidase that was later renamed monoamine oxidase ....
in the liver and was named tyramine oxidase. They belong to the protein family
Protein family
A protein family is a group of evolutionarily-related proteins, and is often nearly synonymous with gene family. The term protein family should not be confused with family as it is used in taxonomy....
of flavin-containing amine oxidoreductases.
Subtypes and tissue distribution
In humans there are two types of MAO: MAO-AMonoamine Oxidase A
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 , epinephrine , serotonin, and dopamine...
and MAO-B.
- Both are found in neuronNeuronA neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s and astroglia. - Outside the central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
:- MAO-A is also found in the liverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, gastrointestinal tractGastrointestinal tractThe human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
, and placentaPlacentaThe placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
. - MAO-B is mostly found in bloodBloodBlood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
plateletPlateletPlatelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s.
- MAO-A is also found in the liver
Function
Monoamine oxidases catalyze the oxidative deaminationOxidative deamination
Oxidative deamination is a form of deamination that generates oxoacids in the liver.The presence of nitrous acid can cause transition mutations, by converting cytosine to uracil. Primarily occurs in the liver and kidneys.-In Urea cycle:...
of monoamines. Oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
is used to remove an amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
group from a molecule, resulting in the corresponding aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
and ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
. The general form of the catalyzed reaction (with R denoting an arbitrary group) is:
Monoamine oxidase
Oxidase
An oxidase is any enzyme that catalyzes an oxidation-reduction reaction involving molecular oxygen as the electron acceptor. In these reactions, oxygen is reduced to water or hydrogen peroxide ....
s contain the covalently bound cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
FAD
FAD
In biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states, which it converts between by accepting or donating electrons. The molecule consists of a riboflavin moiety bound to the phosphate...
and are, thus, classified as flavoprotein
Flavoprotein
Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin: the flavin adenine dinucleotide or flavin mononucleotide ....
s.
Substrate specificities
They are well known enzymes in pharmacologyPharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
, since they are the substrate for the action of a number of monoamine oxidase inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
drugs
DRUGS
Destroy Rebuild Until God Shows are an American post-hardcore band formed in 2010. They released their debut self-titled album on February 22, 2011.- Formation :...
. MAO-A is particularly important in the catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
of monoamines ingested in food. Both MAOs are also vital to the inactivation of monoaminergic neurotransmitter
Monoamine neurotransmitter
thumb|right|350px| A phylogenetic tree showing how a number of monoamine receptors are related to each other.Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain...
s, for which they display different specificities.
- SerotoninSerotoninSerotonin 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...
, melatoninMelatoninMelatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
, norepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, and epinephrineEpinephrineEpinephrine 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...
are mainly broken down by MAO-A. - PhenethylaminePhenethylaminePhenylethylamine or phenethylamine is a natural monoamine alkaloid, trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects. Studies suggest that phenylethylamine functions as a neuromodulator or neurotransmitter in the...
and benzylamineBenzylamineBenzylamine is the chemical compound with the formula C6H5CH2NH2. It consists of a benzyl group, C6H5CH2, attached to an amine functional group...
are mainly broken down by MAO-B. - Both forms break down dopamineDopamineDopamine 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...
, tyramineTyramineTyramine is a naturally occurring monoamine compound and trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent...
, and tryptamineTryptamineTryptamine is a monoamine alkaloid found in plants, fungi, and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived...
equally.
Specific reactions catalyzed by MAO include:
- EpinephrineEpinephrineEpinephrine 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...
or norepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
to 3,4-Dihydroxymandelic acid3,4-Dihydroxymandelic acid3,4-Dihydroxymandelic acid is a metabolite of norepinephrine.-References:... - MetanephrineMetanephrineMetanephrine is a metabolite of epinephrine created by action of catechol-O-methyl transferase on epinephrine. An article in the Journal of the American Medical Association, 2002, indicated that the measurement of plasma free metanephrines is the best tool in the diagnosis of pheochromocytoma, an...
or normetanephrineNormetanephrineNormetanephrine is a metabolite of norepinephrine created by action of catechol-O-methyl transferase on norepinephrine. It is excreted in the urine and found in certain tissues. It is a marker for catecholamine-secreting tumors such as pheochromocytoma....
to vanillylmandelic acid (VMA) - DopamineDopamineDopamine 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...
to dihydroxyphenylacetic acid - 3-Methoxytyramine3-Methoxytyramine3-Methoxytyramine , also known as 3-methoxy-4-hydroxyphenethylamine, is a metabolite of the neurotransmitter dopamine formed by the introduction of a methyl group to dopamine by the enzyme catechol-O-methyl transferase...
to homovanillic acidHomovanillic acidHomovanillic acid is a major catecholamine metabolite...
Clinical significance
Because of the vital role that MAOs play in the inactivation of neurotransmitters, MAO dysfunction (too much or too little MAO activity) is thought to be responsible for a number of psychiatric and neurological disorders. For example, unusually high or low levels of MAOs in the body have been associated with depressionClinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
,schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, substance abuse
Substance abuse
A substance-related disorder is an umbrella term used to describe several different conditions associated with several different substances .A substance related disorder is a condition in which an individual uses or abuses a...
, attention deficit disorder, migraines, and irregular sexual maturation. Monoamine oxidase inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s are one of the major classes of drug prescribed for the treatment of depression, although they are often last-line treatment due to risk of the drug's interaction with diet or other drugs. Excessive levels of catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
s (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...
, norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, 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...
) may lead to a hypertensive crisis
Hypertensive emergency
Malignant hypertension or hypertensive emergency is severe hypertension with acute impairment of an organ system and the possibility of irreversible organ-damage...
, and excessive levels of 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...
may lead to serotonin syndrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
.
In fact, MAO-A inhibitors act as antidepressant and antianxiety agents, whereas MAO-B inhibitors are used alone or in combination to treat Alzheimer’s and Parkinson’s diseases .
PET
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...
research has shown that MAO is also heavily depleted by use of tobacco
Tobacco
Tobacco 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...
cigarettes.
Genetics
The geneGene
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...
s encoding MAO-A and MAO-B are located side-by-side on the short arm of the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
, and have about 70% sequence similarity. Rare mutations in the gene are associated 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...
.
A study based on the Dunedin cohort concluded that maltreated children with a low-activity polymorphism in the promoter region of the MAO-A gene were more likely to develop antisocial conduct disorders
Conduct disorder
Conduct disorder is psychological disorder diagnosed in childhood that presents itself through a repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate norms are violated...
than maltreated children with the high-activity variant. Out of the 442 total males in the study (maltreated or not), 37% had the low activity variant. Of the 13 maltreated males with low MAO-A activity, 11 had been assessed as exhibiting adolescent conduct disorder
Conduct disorder
Conduct disorder is psychological disorder diagnosed in childhood that presents itself through a repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate norms are violated...
and 4 were convicted for violent offenses. The suggested mechanism for this effect is the decreased ability of those with low MAO-A activity to quickly degrade norepinephrine, the synaptic neurotransmitter involved in sympathetic
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
arousal and rage. This is alleged to provide direct support for the idea that genetic susceptibility to disease is not determined at birth, but varies with exposure to environmental influences. Note however that most of those with conduct disorder or convictions did not have low activity of MAO-A; maltreatment was found to have caused stronger predisposition for antisocial behavior than differences in MAO-A activity.
The claim that an interaction between low MAO-A activity and maltreatment would cause anti-social behavior has been criticized since the predisposition towards anti-social behavior could equally well have been caused by other genes inherited from abusive parents.
A possible link between predisposition to novelty seeking and a genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
of the MAO-A gene has been found.
A particular variant (or genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
) was over-represented in Māori, a Warrior gene. This supported earlier studies finding different proportions of variants in different ethnic groups. This is the case for many genetic variants, with 33% White/Non-Hispanic, 61% Asian/Pacific Islanders having the low-activity MAO-A promoter variant.
External links
- MAO-B Structure at eurekalert.org
- Calculated orientations of Monoamine oxidases in membrane
- Monoamine oxidase (MAO) at bmc.uu.se
- Slides showing the effects of tobacco smoking on MAO at nida.nih.gov
- Foods to avoid when taking MAO inhibitors at lycaeum.org
- Information Hyperlinked Over Proteins -- MAO-A