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COMT
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4XUE, 3A7E, 3BWM, 3BWY, 4PYI, 4PYJ, 4PYK, 4XUC, 4XUD
Identifiers
Aliases	COMT, HEL-S-98n, catechol-O-methyltransferase
External IDs	OMIM: 116790; MGI: 88470; HomoloGene: 30982; GeneCards: COMT; OMA:COMT - orthologs
Gene location (Human) Chr. Chromosome 22 (human) Band 22q11.21 Start 19,941,371 bp End 19,969,975 bp
Gene location (Mouse) Chr. Chromosome 16 (mouse) Band 16 A3|16 11.4 cM Start 18,225,636 bp End 18,245,602 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right adrenal cortex stromal cell of endometrium left adrenal gland olfactory bulb left adrenal cortex C1 segment mucosa of pharynx right lobe of liver corpus callosum mucosa of esophagus Top expressed in white adipose tissue right kidney proximal tubule liver human kidney adrenal gland urinary bladder heart striatum of neuraxis duodenum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity O-methyltransferase activity metal ion binding protein binding magnesium ion binding catechol O-methyltransferase activity methyltransferase activity L-dopa O-methyltransferase activity orcinol O-methyltransferase activity Cellular component cytoplasm integral component of membrane cell body cytosol postsynaptic membrane membrane plasma membrane dendritic spine axon dendrite mitochondrion extracellular exosome intracellular membrane-bounded organelle Biological process multicellular organismal reproductive process negative regulation of smooth muscle cell proliferation response to organic cyclic compound regulation of sensory perception of pain estrogen metabolic process cellular response to phosphate starvation catechol-containing compound metabolic process female pregnancy negative regulation of dopamine metabolic process developmental process learning catecholamine metabolic process neurotransmitter catabolic process response to lipopolysaccharide methylation dopamine metabolic process response to pain short-term memory negative regulation of renal sodium excretion dopamine catabolic process positive regulation of homocysteine metabolic process catecholamine catabolic process response to estrogen Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1312 12846 Ensembl ENSG00000093010 ENSMUSG00000000326 UniProt P21964 O88587 RefSeq (mRNA) NM_000754 NM_001135161 NM_001135162 NM_007310 NM_001362828 NM_001111062 NM_001111063 NM_007744 RefSeq (protein) NP_000745 NP_001128633 NP_001128634 NP_009294 NP_001349757 NP_001104532 NP_001104533 NP_031770 Location (UCSC) Chr 22: 19.94 – 19.97 Mb Chr 16: 18.23 – 18.25 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Catechol-O-methyltransferase (COMT; EC 2.1.1.6) is one of several enzymes that degrade catecholamines (neurotransmitters such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol structure. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene. Two isoforms of COMT are produced: the soluble short form (S-COMT) and the membrane bound long form (MB-COMT). 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 in 1957.

Function

Catechol-O-methyltransferase 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). 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:

• L-DOPA (levodopa) → 3-O-methyldopa
• Dopamine → 3-methoxytyramine
• DOPAC → HVA (homovanillic acid)
• Norepinephrine → normetanephrine
• Epinephrine → metanephrine
• Dihydroxyphenylethylene glycol (DOPEG) → methoxyhydroxyphenylglycol (MOPEG)
• 3,4-Dihydroxymandelic acid (DOMA) → vanillylmandelic acid (VMA)

In the brain, COMT-dependent dopamine degradation is of particular importance in brain regions with low expression of the presynaptic dopamine transporter (DAT), such as the prefrontal cortex (In the PFC, dopamine is also removed by presynaptic norepinephrine transporters (NET) and degraded by monoamine oxidase.). Controversy exists about the predominance and orientation of membrane bound COMT in the CNS, that is, whether this COMT process is active intracellularly in postsynaptic neurons and glia, or oriented outward on the membrane, acting extracellularly on synaptic and extrasynaptic dopamine.

Soluble 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 ValMet. Others are rs737865 and rs165599 that have been studied, e.g., for association with personality traits, response to antidepressant medications, and psychosis risk associated with Alzheimer's disease. COMT has been studied as a potential gene in the pathogenesis of schizophrenia; however meta-analyses find no association between the risk of schizophrenia and a number of polymorphisms, including ValMet.

ValMet polymorphism

A functional single-nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyltransferase results in a valine to methionine mutation at position 158 (ValMet) rs4680. In vitro, the homozygous Val variant metabolizes dopamine at up to four times the rate of its methionine counterpart. However, in vivo the Met variant is overexpressed in the brain, resulting in a 40% decrease (rather than 75% decrease) in functional enzyme activity. The lower rates of catabolism for the Met allele results in higher synaptic dopamine levels following neurotransmitter release, ultimately increasing dopaminergic stimulation of the postsynaptic neuron. Given the preferential role of COMT in prefrontal dopamine degradation, the ValMet polymorphism is thought to exert its effects on cognition by modulating dopamine signaling in the frontal lobes.

The gene variant 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.

Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to 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. A more recent study cast doubt on the proposed connection between this gene and any alleged casual effect of cannabis on schizophrenia development.

A non-synonymous single-nucleotide polymorphism rs4680 was found to be associated with depressed factor of Positive and Negative Syndrome Scale(PANSS) and efficiency of emotion in schizophrenia subjects. 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 ValMet 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 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.

One review found that those with Val/Val tended to be more extroverted, more novelty-seeking, and less neurotic than those with the Met/Met allele

Temporomandibular joint dysfunction

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

COMT inhibitors

COMT inhibitors include entacapone, tolcapone, opicapone, and nitecapone. All except nitecapone are used in the treatment of Parkinson's disease. Risk of liver toxicity and related digestive disorders restricts the use of tolcapone.

See also

• Dopamine
• Schizophrenia
• O-methyltransferase

Additional images

References

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Further reading

• Trendelenburg U (1991). "The interaction of transport mechanisms and intracellular enzymes in metabolizing systems". In Riederer P, Moussa Youdim MB (eds.). Amine Oxidases and Their Impact on Neurobiology. Proceedings of the 4th International Amine Oxidases Workshop, Würzburg, Federal Republic of Germany, July 7–10, 1990. Journal of Neural Transmission. Supplementum. Vol. 32. pp. 3–18. doi:10.1007/978-3-7091-9113-2_1. ISBN 978-3-211-82239-5. PMID 2089098.
• Zhu BT (October 2002). "On the mechanism of homocysteine pathophysiology and pathogenesis: a unifying hypothesis". Histology and Histopathology. 17 (4): 1283–1291. doi:10.14670/HH-17.1283. PMID 12371153.
• Oroszi G, Goldman D (December 2004). "Alcoholism: genes and mechanisms". Pharmacogenomics. 5 (8): 1037–1048. doi:10.1517/14622416.5.8.1037. PMID 15584875.
• Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, et al. (January 2005). "catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis". Biological Psychiatry. 57 (2): 139–144. doi:10.1016/j.biopsych.2004.10.018. PMID 15652872. S2CID 23416733.
• Tunbridge EM, Harrison PJ, Weinberger DR (July 2006). "Catechol-O-methyltransferase, cognition, and psychosis: ValMet and beyond". Biological Psychiatry. 60 (2): 141–151. doi:10.1016/j.biopsych.2005.10.024. PMID 16476412. S2CID 45705154.
• Craddock N, Owen MJ, O'Donovan MC (May 2006). "The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons". Molecular Psychiatry. 11 (5): 446–458. doi:10.1038/sj.mp.4001808. PMID 16505837.
• Frank MJ, Moustafa AA, Haughey HM, Curran T, Hutchison KE (October 2007). "Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning". Proceedings of the National Academy of Sciences of the United States of America. 104 (41): 16311–16316. Bibcode:2007PNAS..10416311F. doi:10.1073/pnas.0706111104. PMC 2042203. PMID 17913879.
• Greenberg, Gary (November 7, 2018). "What If the Placebo Effect Isn't a Trick?". New York Times Magazine.

External links

• Catechol+O-Methyltransferase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P21964 (Human Catechol O-methyltransferase) at the PDBe-KB.

• Biology

• Genes on human chromosome 22
• EC 2.1.1
• O-methylated natural phenols metabolism
• O-methylation