Monoamine oxidase

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Monoamine oxidase
Identifiers
EC number 1.4.3.4
CAS number Template:CAS
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
monoamine oxidase A
Monoamine oxidase A 2BXS.png
Ribbon diagram of a monomer of human MAO-A, with FAD and clorgiline bound, oriented as if attached to the outer membrane of a mitochondrion. From PDB: 2BXS​.
Identifiers
Symbol MAOA
Entrez 4128
HUGO 6833
OMIM 309850
RefSeq NM_000240
UniProt P21397
Other data
Locus Chr. X p11.4-p11.3
monoamine oxidase B
MonoamineOxidase-1GOS.png
Ribbon diagram of human MAO-B. From PDB: 1GOS​.
Identifiers
Symbol MAOB
Entrez 4129
HUGO 6834
OMIM 309860
RefSeq NM_000898
UniProt P27338
Other data
Locus Chr. X p11.4-p11.3

L-Monoamine oxidases (MAO) (EC 1.4.3.4) are a family of enzymes that catalyze the oxidation of monoamines.[1][2] 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.[3][4] They belong to the protein family of flavin-containing amine oxidoreductases.

Subtypes and tissue distribution

In humans there are two types of MAO: MAO-A and MAO-B.[5]

Function

Norepinephrine degradation. Monoamine oxidase is shown left in the blue box.[6]

Monoamine oxidases catalyze the oxidative deamination of monoamines. Oxygen is used to remove an amine group from a molecule, resulting in the corresponding aldehyde and ammonia.

Monoamine oxidases contain the covalently bound cofactor FAD and are, thus, classified as flavoproteins.

Substrate specificities

They are well known enzymes in pharmacology, 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 neurotransmitters, for which they display different specificities.

Specific reactions catalyzed by MAO include:

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 schizophrenia,[8][9] depression,[10] attention deficit disorder,[citation needed] substance abuse,[citation needed] migraines,[citation needed] and irregular sexual maturation.[citation needed] Monoamine oxidase inhibitors 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 catecholamines (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.[11]

PET research has shown that MAO-B is also heavily depleted by use of tobacco cigarettes.[12]

Animal models

Mice unable to produce either MAO-A or MAO-B display autistic-like traits.[13] These knockout mice display an increased response to stress.[14]

Genetics

The genes 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.[15] 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 argued to provide direct support for the idea that genetic susceptibility to disease is not determined at birth, but varies with exposure to environmental influences. However, most individuals 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.[16]

A possible link between predisposition to novelty seeking and a genotype of the MAO-A gene has been found.[17]

A particular variant (or genotype), dubbed "warrior gene" in the popular press, was over-represented in Māori. 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.[18]

See also

References

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External links