edit Catechol-O-methyltransferase Cartoon diagram of human COMT in complex with 3,5-dinitrocatechol (dark blue) and S-adenosyl methionine (yellow). From PDB 3BWM. Identifiers Symbols COMT; External IDs OMIM: 116790 MGI: 88470 HomoloGene: 30982 GeneCards: COMT Gene EC number 2.1.1.6 Gene Ontology Molecular function • magnesium ion binding • protein binding • O-methyltransferase activity • catechol O-methyltransferase activity • transferase activity Cellular component • soluble fraction • microsome • membrane • integral to membrane Biological process • catecholamine metabolic process • dopamine catabolic process Sources: Amigo / EGO RNA expression pattern More reference expression data Orthologs Species Human Mouse Entrez 1312 12846 Ensembl ENSG00000093010 ENSMUSG00000000326 UniProt P21964 Q91XH4 RefSeq (mRNA) NM_000754 NM_007744 RefSeq (protein) NP_000745 NP_031770 Location (UCSC) Chr 22: 18.31 - 18.34 Mb Chr 16: 18.32 - 18.33 Mb PubMed search [1] [2]

catechol O-methyltransferase Identifiers EC number 2.1.1.6 CAS number 9012-25-3 IntEnz IntEnz view BRENDA BRENDA entry ExPASy NiceZyme view KEGG KEGG entry MetaCyc metabolic pathway PRIAM profile PDB structures Gene Ontology AmiGO / EGO Search PMC articles PubMed articles

Catechol O-methyl transferase (COMT; EC 2.1.1.6) is one of several enzymes that degrade catecholamines such as dopamine, epinephrine, and norepinephrine. In humans, catechol O-methyl transferase protein is encoded by the COMT gene.^[1] 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.^[2] COMT was first discovered by the biochemist Julius Axelrod in 1957.^[3]

[edit] 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:

• Dopamine ? 3-Methoxytyramine
• Norepinephrine ? Normetanephrine
• Epinephrine ? Metanephrine
• Dihydroxyphenylethylene glycol (DOPEG) ? Methoxyhydroxyphenylglycol (MOPEG)
• 3,4-Dihydroxymandelic acid (DOMA) ? Vanillylmandelic acid (VMA)

[edit] 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.^[4]

[edit] The met/met polymorphism

A functional single-nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyl transferase resulting in a valine to methionine mutation at position 158 (Val¹⁵⁸Met), has been shown to affect ratings of subjective well being. When 621 women were measured 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.^[5] 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.^[5] Persons with the met/met phenotype describe events as very pleasant or pleasant with twice the numeric amplitude of those absent the met/met genetic polymorphism.^[5]

[edit] 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,^[6]

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.^{[citation needed]} 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.^[7]

[edit] 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.

[edit] COMT inhibitors

COMT inhibitors include tolcapone and entacapone, which are commonly used in the treatment of Parkinson disease.^[8]

[edit] See also

• Dopamine
• Schizophrenia
• Methyltransferase

[edit] Additional images

[edit] References

[edit] Further reading

[edit] External links

• MeSH Catechol+O-Methyltransferase

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Catechol-O-methyl transferase".