Catechol-O-methyl transferase (COMT; ) is one of several enzymes that degrade catecholamines such as dopamine, epinephrine, and norepinephrine. 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 biochemist Julius Axelrod.

Function

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

Levodopa, a precursor of catecholamines, is an important substrate of COMT. COMT inhibitors, like 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 Parkinson's disease.

Specific reactions catalyzed by COMT include:

• Norepinephrine -> Normetanephrine
• Epinephrine -> Metanephrine
• Dihydroxyphenylethylene glycol (DOPEG) -> Methoxyhydroxyphenylglycol (MOPEG)
• 3,4-Dihydroxymandelic acid (DOMA) -> Vanillyl mandelic acid (VMA)

Genetics

The COMT protein is coded by the gene COMT. The gene is associated with allelic variants. The most well-studied is Val158Met. Others are rs737865 and rs165599 that have been studied, e.g., for association with personality traits.

The val158met polymorphism

Val158Met (rs4680), a functional single nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyl transferase, has been shown to affect cognitive tasks broadly related to executive function, such as set shifting, response inhibition, abstract thought, and the acquisition of rules or task structure. This polymorphism in the COMT gene results in the substitution of the amino acid valine for methionine at codon 158, thus the name Val158Met for the polymorphism. It has been shown that this valine variant catabolizes dopamine at up to four times the rate of its methionine counterpart, resulting in a significant reduction of synaptic dopamine following neurotransmitter release, ultimately reducing dopaminergic stimulation of the post-synaptic neuron. As a consequence, neurons with valine-variant COMT show higher levels of activation during certain cognitive tasks, as they require higher levels of neuron firing to achieve the same level of post-synaptic stimulation.

The link between impairments in these sorts of cognitive tasks and the COMT gene is thought to be mediated by an effect on dopamine signaling in the frontal lobes.

Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to schizophrenia. It is not surprising, then, that an inherited variant of COMT is thought to be one of the genetic factors that may predispose someone to developing schizophrenia later in life, naturally or due to adolescent-onset cannabis use.

Nomenclature

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

COMT inhibitors

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

See also

• Dopamine
• Schizophrenia
• Methyltransferase

Additional images

References

Further reading

• Frank MJ, Moustafa AA, Haughey H, Curran T, Hutchison KE (2007). "Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning". Proc Natl Acad Sci U S A 104 (41): 16311–6.

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