Catechol-O-methyl transferase

Catechol-O-methyltransferase (COMT; ) is one of several is_associated_with::enzymes that degrade is_associated_with::catecholamines such as is_associated_with::dopamine, is_associated_with::epinephrine, and is_associated_with::norepinephrine. In humans, catechol-O-methyltransferase protein is encoded by the COMT is_associated_with::gene. As the regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines. COMT was first discovered by the is_associated_with::biochemist is_associated_with::Julius Axelrod in 1957.

Function
Catechol-O-methyltransferase is involved in the inactivation of the is_associated_with::catecholamine is_associated_with::neurotransmitters (is_associated_with::dopamine, is_associated_with::epinephrine, and is_associated_with::norepinephrine). The enzyme introduces a is_associated_with::methyl group to the catecholamine, which is donated by is_associated_with::S-adenosyl methionine (SAM). Any compound having a catechol structure, like catecholestrogens and catechol-containing flavonoids, are substrates of COMT.

is_associated_with::Levodopa, a precursor of catecholamines, is an important substrate of COMT. COMT inhibitors, like is_associated_with::entacapone, save levodopa from COMT and prolong the action of levodopa. Entacapone is a widely used adjunct drug of levodopa therapy. When given with an inhibitor of dopa decarboxylase (carbidopa or benserazide), levodopa is optimally saved. This "triple therapy" is becoming a standard in the treatment of is_associated_with::Parkinson's disease.

Specific reactions catalyzed by COMT include:
 * is_associated_with::Dopamine → is_associated_with::3-Methoxytyramine
 * is_associated_with::DOPAC → HVA (is_associated_with::homovanillic acid)
 * is_associated_with::Norepinephrine → is_associated_with::Normetanephrine
 * is_associated_with::Epinephrine → is_associated_with::Metanephrine
 * is_associated_with::Dihydroxyphenylethylene glycol (DOPEG) → is_associated_with::Methoxyhydroxyphenylglycol (MOPEG)
 * is_associated_with::3,4-Dihydroxymandelic acid (DOMA) → is_associated_with::Vanillylmandelic acid (VMA)

In the brain, COMT-dependent dopamine degradation is of particular importance in brain regions with low expression of the presynaptic is_associated_with::dopamine transporter (DAT), such as the is_associated_with::prefrontal cortex. This process is supposed to take place in postsynaptic neurons, as, in general, COMT is located intracellularly in the central nervous system (CNS).

COMT can also be found extracellularly, although extracellular COMT plays a less significant role in the CNS than it does peripherally. Despite its importance in neurons, COMT is actually primarily expressed in the liver.

Genetics in humans
The COMT protein is coded by the gene COMT. The gene is associated with allelic variants. The best-studied is is_associated_with::Val158Met. Others are is_associated_with::rs737865 and is_associated_with::rs165599 that have been studied, e.g., for association with is_associated_with::personality traits.

Val158Met polymorphism
A functional is_associated_with::single-nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyltransferase results in a is_associated_with::valine to is_associated_with::methionine mutation at position 158 (Val158Met) is_associated_with::rs4680. The Val variant catabolizes dopamine at up to four times the rate of its methionine counterpart. However, the Met variant is overexpressed in the brain, resulting in a 40% decrease in functional enzyme activity. The lower rates of catabolisis for the Met allele results in higher synaptic dopamine levels following neurotransmitter release, ultimately increasing dopaminergic stimulation of the post-synaptic neuron. Given the preferential role of COMT in prefrontal dopamine degradation, the Val158Met polymorphism is thought to exert its effects on cognition by modulating dopamine signaling in the is_associated_with::frontal lobes.

The gene variant has been shown to affect is_associated_with::cognitive tasks broadly related to is_associated_with::executive function, such as set shifting, response inhibition, abstract thought, and the acquisition of rules or task structure.

Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to is_associated_with::schizophrenia. It has been proposed that an inherited variant of COMT is one of the genetic factors that may predispose someone to developing schizophrenia later in life, naturally or due to adolescent-onset cannabis use. However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on schizophrenia development.

It is increasingly recognised that allelic variation at the COMT gene are also relevant for emotional processing, as they seem to influence the interaction between prefrontal and limbic regions. Research conducted at the Section of Neurobiology of Psychosis, Institute of Psychiatry, King's College London has demonstrated an effect of COMT both in patients with bipolar disorder and in their relatives, but these findings have not been replicated so far.

The COMT Val158Met polymorphism also has a pleiotropic effect on emotional processing. Furthermore, the polymorphism has been shown to affect ratings of subjective well-being. When 621 women were measured with is_associated_with::experience sample monitoring, which is similar to mood assessment as response to beeping watch, the met/met form confers double the subjective mental sensation of well-being from a wide variety of daily events. The ability to experience reward increased with the number of ‘Met’ alleles. Also, the effect of different genotype was greater for events that were felt as more pleasant. The effect size of genotypic moderation was quite large: Subjects with the val/val genotype generated almost similar amounts of subjective well-being from a ‘very pleasant event’ as met/met subjects did from a ‘bit pleasant event’. Genetic variation with functional impact on cortical dopamine tone has a strong influence on reward experience in the flow of daily life. In one study participants with the met/met phenotype described an increase of positive affect twice as high in amplitude as participants with the val/val phenotype following very pleasant or pleasant events.

Temporomandibular joint dysfunction
is_associated_with::Temporomandibular joint dysfunction (TMD) does not appear to be a classic genetic disorder, however variations in the gene that codes for COMT have been suggested to be responsible for inheritance of a predisposition to develop TMD during life.

Nomenclature
COMT is the name given to the is_associated_with::gene that codes for this enzyme. The O in the name stands for is_associated_with::oxygen, not for ortho.

COMT inhibitors
is_associated_with::COMT inhibitors include is_associated_with::tolcapone and is_associated_with::entacapone, which are commonly used in the treatment of is_associated_with::Parkinson's disease.