; ) is one of several enzymes
that degrade catecholamines
such as dopamine
, 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
-methyl transferase is involved in the inactivation of the catecholamine neurotransmitters
, 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:
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
that have been studied, e.g., for association with personality traits
The val158met polymorphism
), 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
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.
is the name given to the gene
that codes for this enzyme. The O
in the name stands for oxygen
, not for ortho
, which are commonly used in the treatment of Parkinson disease
- 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.