Catechol-O-methyl transferase

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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
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
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	1312	12846
Ensembl	ENSG00000093010	ENSMUSG00000000326
Uniprot	P21964	Q91XH4
Refseq	NM_000754 (mRNA) NP_000745 (protein)	NM_007744 (mRNA) NP_031770 (protein)
Location	Chr 22: 18.31 - 18.34 Mb	Chr 16: 18.32 - 18.33 Mb
Pubmed search	[1]	[2]

Catechol-O-methyl transferase (COMT; EC 2.1.1.6) 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.

Contents 1 Function 2 Genetics 2.1 The val158met polymorphism 3 Nomenclature 4 COMT inhibitors 5 See also 6 Additional images 7 References 8 Further reading 9 External links

[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:

• 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.^[1]

[edit] 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,^[2] 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.^[3]

[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.

[edit] See also

• Dopamine
• Schizophrenia
• Methyltransferase

[edit] Additional images

[edit] References

[edit] Further reading

[edit] External links

• MeSH Catechol+O-Methyltransferase

v • d • e Transferase: one carbon transferases (EC 2.1) 2.1.1: Methyl- N- Histamine N-methyltransferase - Phenylethanolamine N-methyltransferase - Tryptamine N-methyltransferase - Phosphatidylethanolamine N-methyltransferase O- 5-hydroxyindole-O-methyltransferase/Acetylserotonin O-methyltransferase - Catechol-O-methyl transferase Homocysteine Betaine-homocysteine methyltransferase - Homocysteine methyltransferase - 5-Methyltetrahydrofolate-homocysteine methyltransferase Other Phosphatidyl ethanolamine methyltransferase - DNMT3B - Histone methyltransferase - Thymidylate synthase - DNA methyltransferase - Thiopurine methyltransferase 2.1.2: Hydroxymethyl-, Formyl- and Related Hydroxymethyltransferase Serine hydroxymethyltransferase - 3-methyl-2-oxobutanoate hydroxymethyltransferase Formyltransferase Phosphoribosylglycinamide formyltransferase - Inosine monophosphate synthase - Glutamate formimidoyltransferase Other Aminomethyltransferase 2.1.3: Carboxy- and Carbamoyl Carboxy methylmalonyl-CoA carboxytransferase Carbamoyl Aspartate carbamoyltransferase - Ornithine carbamoyltransferase - Oxamate carbamoyltransferase - Putrescine carbamoyltransferase - 3-hydroxymethylcephem carbamoyltransferase - Lysine carbamoyltransferase - N-acetylornithine carbamoyltransferase 2.1.4: Amidino Arginine:glycine amidinotransferase

v • d • e Metabolism: amino acid metabolism - neurotransmitter enzymes monoamine histidine→histamine anabolism: Histidine decarboxylase catabolism: Histamine N-methyltransferase - Amine oxidase tyrosine→dopamine→epinephrine anabolism: Tyrosine hydroxylase - Aromatic L-amino acid decarboxylase - Dopamine beta hydroxylase - Phenylethanolamine N-methyltransferase catabolism: Catechol-O-methyl transferase - Monoamine oxidase glutamate→GABA anabolism: Glutamate decarboxylase catabolism: 4-aminobutyrate aminotransferase - 4-aminobutyrate transaminase tryptophan→serotonin→melatonin Tryptophan hydroxylase - Aromatic L-amino acid decarboxylase - Acetylserotonin O-methyltransferase arginine→NO Nitric oxide synthase (NOS1, NOS2A, NOS3) choline→Acetylcholine anabolism: Choline acetyltransferase catabolism: Cholinesterase (Acetylcholinesterase, Butyrylcholinesterase) see also intermediates