View source for Catechol-O-methyltransferase

{{Primary sources|date=December 2016}}
{{DISPLAYTITLE:Catechol-''O''-methyltransferase}}
{{Infobox gene}}
{{enzyme
| Name = catechol-''O''-methyltransferase
| EC_number = 2.1.1.6
| CAS_number = 9012-25-3
| IUBMB_EC_number = 2/1/1/6
| GO_code = 0016206
| image = 
| width = {{Primary sources|section "Genetics in humans"|date=November 2016}}
| caption = 
}}
[[File:Noradrenaline breakdown.svg|thumb|350px|Norepinephrine degradation. Catechol-O-methyltransferase is shown in green boxes.<ref name="Rang&Dale6th-11-4">{{cite book |contribution=Figure 11-4 | first1 = Rod | last1 = Flower | first2 = Humphrey P. | last2 = Rang | first3 = Maureen M. | last3 = Dale | last4 = Ritter | first4 = James M. | name-list-format = vanc |title=Rang & Dale's pharmacology |edition=6th |publisher=Churchill Livingstone |location=Edinburgh |year=2007 |pages= |isbn=0-443-06911-5 }}</ref><ref>{{cite book | first1 = Humphrey P. | last1 = Rang | first2 = Maureen M. | last2 = Dale | first3 = James M. | last3 = Ritter | first4 = Rod J. | last4 = Flower | first5 = Graeme | last5 = Henderson | name-list-format = vanc | contribution = Figure 14.4 | contribution-url = https://books.google.com/books?id=s2R-ZYz_iBYC&pg=PT876 |title=Rang & Dale's Pharmacology | edition = 7th | date = 2011 | series = Student consult | publisher = Elsevier Health Sciences | isbn = 978-0-7020-4504-2 }}</ref>]]
'''Catechol-''O''-methyltransferase''' ('''COMT'''; {{EC number|2.1.1.6}}) is one of several [[enzyme]]s that degrade [[catecholamine]]s (such as [[dopamine]], [[epinephrine]], and [[norepinephrine]]), [[Catechol estrogen|catecholestrogens]], and various drugs and substances having a [[catechol]] structure.<ref>{{Cite web|url=http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/83301|title=Test ID: COMT: Catechol-O-Methyltransferase Genotype|last=|first=|date=|website=www.mayomedicallaboratories.com|publisher=Mayo Clinic: Mayo Medical Laboratories|access-date=November 16, 2016}}{{Dead link|date=November 2018 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> In humans, catechol-''O''-methyltransferase protein is encoded by the '''COMT''' [[gene]].<ref name="pmid1572656">{{cite journal | vauthors = Grossman MH, Emanuel BS, Budarf ML | title = Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1----q11.2 | journal = Genomics | volume = 12 | issue = 4 | pages = 822–5 | date = April 1992 | pmid = 1572656 | doi = 10.1016/0888-7543(92)90316-K }}</ref> 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.<ref name="pmid11873938">{{cite journal | vauthors = Tai CH, Wu RM | title = Catechol-O-methyltransferase and Parkinson's disease | journal = Acta Medica Okayama | volume = 56 | issue = 1 | pages = 1–6 | date = February 2002 | pmid = 11873938 | doi =  }}</ref> COMT was first discovered by the [[biochemist]] [[Julius Axelrod]] in 1957.<ref name="pmid13467217">{{cite journal | vauthors = Axelrod J | title = O-Methylation of Epinephrine and Other Catechols in vitro and in vivo | journal = Science | volume = 126 | issue = 3270 | pages = 400–1 | date = August 1957 | pmid = 13467217 | doi = 10.1126/science.126.3270.400 }}</ref>

== Function ==

Catechol-''O''-methyltransferase is involved in the inactivation of the [[catecholamine]] [[neurotransmitter]]s ([[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.<ref>{{cite journal | vauthors = Ruottinen HM, Rinne UK | title = COMT inhibition in the treatment of Parkinson's disease | journal = Journal of Neurology | volume = 245 | issue = 11 Suppl 3 | pages = P25–34 | date = November 1998 | pmid = 9808337 | doi = 10.1007/PL00007743 }}<br />{{in5}}{{cite journal | vauthors = Goetz CG | title = Influence of COMT inhibition on levodopa pharmacology and therapy | journal = Neurology | volume = 50 | issue = 5 Suppl 5 | pages = S26–30 | date = May 1998 | pmid = 9591519 | pmc =  | doi = 10.1212/WNL.50.5_Suppl_5.S26 }}</ref> 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]]
* [[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]].<ref>{{cite book | chapter-url = https://books.google.com/books?id=U4oDDAAAQBAJ&pg=PA75 | title = The Central Nervous System |vauthors=Brodal P| name-list-format = vanc | date = 2016 | publisher = Oxford University Press|year=|isbn=978-0-19-022896-5|location=|page=75 | chapter = Chapter 5: Neurotransmitters and their receptors }}</ref><ref>{{cite journal | vauthors = Scheggia D, Sannino S, Scattoni ML, Papaleo F | title = COMT as a drug target for cognitive functions and dysfunctions | journal = CNS & Neurological Disorders Drug Targets | volume = 11 | issue = 3 | pages = 209–21 | date = May 2012 | pmid = 22483296 | doi = 10.2174/187152712800672481 }}</ref><ref>{{cite journal | vauthors = Diaz-Asper CM, Weinberger DR, Goldberg TE | title = Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics | journal = NeuroRx | volume = 3 | issue = 1 | pages = 97–105 | date = January 2006 | pmid = 16490416 | pmc = 3593358 | doi = 10.1016/j.nurx.2005.12.010 }}</ref><ref name="Schacht-2016"/> (In the PFC, dopamine is also removed by presynaptic [[norepinephrine transporter]]<nowiki/>s (NET) and degraded by [[monoamine oxidase]].)<ref>{{cite journal | vauthors = Juarez B, Han MH | title = Diversity of Dopaminergic Neural Circuits in Response to Drug Exposure | journal = Neuropsychopharmacology | volume = 41 | issue = 10 | pages = 2424–46 | date = September 2016 | pmid = 26934955 | pmc = 4987841 | doi = 10.1038/npp.2016.32  }}</ref> Controversy exists about the predominance and orientation of membrane bound COMT in the CNS,<ref>{{cite book | url = https://books.google.com/books?id=bkUdEiPJ4EAC&pg=PA34 | title = Basic Aspects of Catechol-O-Methyltransferase and the Clinical Applications of its Inhibitors | date = 2010 | publisher = Academic Press | isbn = 978-0-12-381327-5 | veditors = Nissinen E | pages = 34 | via = Google books }}</ref><ref>{{cite journal | vauthors = Chen J, Song J, Yuan P, Tian Q, Ji Y, Ren-Patterson R, Liu G, Sei Y, Weinberger DR | title = Orientation and cellular distribution of membrane-bound catechol-O-methyltransferase in cortical neurons: implications for drug development | journal = The Journal of Biological Chemistry | volume = 286 | issue = 40 | pages = 34752–60 | date = October 2011 | pmid = 21846718 | doi = 10.1074/jbc.M111.262790 | pmc = 3186432 | quote = The cellular distribution of MB-COMT in cortical neurons remains unclear and the orientation of MB-COMT on the cellular membrane is controversial. | via =  }}</ref><!---previous ref documents controversy---><ref>{{cite journal | vauthors = Schott BH, Frischknecht R, Debska-Vielhaber G, John N, Behnisch G, Düzel E, Gundelfinger ED, Seidenbecher CI | title = Membrane-Bound Catechol-O-Methyl Transferase in Cortical Neurons and Glial Cells is Intracellularly Oriented | journal = Frontiers in Psychiatry | volume = 1 | pages = 142 | date = 2010 | pmid = 21423451 | pmc = 3059651 | doi = 10.3389/fpsyt.2010.00142 | quote = It has been a matter of debate whether in neural cells of the CNS the enzymatic domain of MB-COMT is oriented toward the cytoplasmic or the extracellular compartment.  }}</ref><!---previous ref documents controversy---> 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.<ref name=Golan2012>{{cite book | last = Golan | first = David E. | first2 = Armen H. | last2  =Tashjian | name-list-format = vanc | title = Principles of pharmacology|publisher=Wolters Kluwer Health|location=Philadelphia|isbn=1-60831-270-4|edition=3rd|oclc=705260923}}</ref>{{rp|210}} Despite its importance in neurons, COMT is actually primarily expressed in the liver.<ref name=Golan2012/>{{rp|135}}

==  Genetics in humans ==

The COMT protein is coded by the gene ''COMT''. 
The gene is associated with allelic variants.
The best-studied is [[Val158Met]].<ref name="Schacht-2016"/> 
Others are [[rs737865]] and [[rs165599]] that have been studied, e.g., for association with [[personality traits]],<ref name="Gold-2014">{{cite journal | vauthors = Gold MS, Blum K, Oscar-Berman M, Braverman ER | title = Low dopamine function in attention deficit/hyperactivity disorder: should genotyping signify early diagnosis in children? | journal = Postgraduate Medicine | volume = 126 | issue = 1 | pages = 153–77 | date = January 2014 | pmid = 24393762 | pmc = 4074363 | doi = 10.3810/pgm.2014.01.2735 }}</ref> response to [[antidepressant]] medications,<ref name="Porcelli-2011">{{cite journal | vauthors = Porcelli S, Drago A, Fabbri C, Gibiino S, Calati R, Serretti A | title = Pharmacogenetics of antidepressant response | journal = Journal of Psychiatry & Neuroscience | volume = 36 | issue = 2 | pages = 87–113 | date = March 2011 | pmid = 21172166 | pmc = 3044192 | doi = 10.1503/jpn.100059 }}</ref> and psychosis risk associated with [[Alzheimer's disease]].<ref name="DeMicheleSweet-2010">{{cite journal | vauthors = DeMichele-Sweet MA, Sweet RA | title = Genetics of psychosis in Alzheimer's disease: a review | journal = Journal of Alzheimer's Disease | volume = 19 | issue = 3 | pages = 761–80 | date = 2010 | pmid = 20157235 | pmc = 2942073 | doi = 10.3233/JAD-2010-1274 }}</ref> 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,<ref>{{cite journal | vauthors = Okochi T, Ikeda M, Kishi T, Kawashima K, Kinoshita Y, Kitajima T, Yamanouchi Y, Tomita M, Inada T, Ozaki N, Iwata N | title = Meta-analysis of association between genetic variants in COMT and schizophrenia: an update | journal = Schizophrenia Research | volume = 110 | issue = 1–3 | pages = 140–8 | date = May 2009 | pmid = 19329282 | doi = 10.1016/j.schres.2009.02.019 }}</ref> including Val158Met.<ref>{{cite journal | vauthors = Glatt SJ, Faraone SV, Tsuang MT | title = Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies | journal = The American Journal of Psychiatry | volume = 160 | issue = 3 | pages = 469–76 | date = March 2003 | pmid = 12611827 | doi = 10.1176/appi.ajp.160.3.469 }}</ref><ref>{{cite journal | vauthors = Munafò MR, Bowes L, Clark TG, Flint J | title = Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies | journal = Molecular Psychiatry | volume = 10 | issue = 8 | pages = 765–70 | date = August 2005 | pmid = 15824744 | doi = 10.1038/sj.mp.4001664 }}</ref><ref>{{cite journal | vauthors = Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, Feng GY, St Clair D, He L | title = Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis | journal = Biological Psychiatry | volume = 57 | issue = 2 | pages = 139–44 | date = January 2005 | pmid = 15652872 | doi = 10.1016/j.biopsych.2004.10.018 }}</ref>

=== ''Val158Met'' 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 (Val<sup>158</sup>Met) [[rs4680]].<ref name="Schacht-2016">{{cite journal |first=Joseph P. |last=Schacht |date=October 2016 |title=''COMT'' val158met moderation of dopaminergic drug effects on cognitive function: A critical review |journal=Pharmacogenomics Journal |volume=16 |issue=5 |pages=430–438 |pmid=27241058 |pmc=5028240 |doi=10.1038/tpj.2016.43 }}</ref> In vitro, the [[Zygosity#Homozygous|homozygous]] Val variant metabolizes dopamine at up to four times the rate of its methionine counterpart.<ref name="Porcelli-2011"/> However, in vivo the Met variant is [[Glossary of gene expression terms|overexpressed]] in the brain,<ref>{{cite journal | vauthors = Zhu G, Lipsky RH, Xu K, Ali S, Hyde T, Kleinman J, Akhtar LA, Mash DC, Goldman D | title = Differential expression of human COMT alleles in brain and lymphoblasts detected by RT-coupled 5' nuclease assay | journal = Psychopharmacology | volume = 177 | issue = 1–2 | pages = 178–84 | date = December 2004 | pmid = 15290009 | doi = 10.1007/s00213-004-1938-z }}</ref> resulting in a 40% decrease (rather than 75% decrease) in functional enzyme activity.<ref>{{cite journal | vauthors = Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR | title = Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain | journal = American Journal of Human Genetics | volume = 75 | issue = 5 | pages = 807–21 | date = November 2004 | pmid = 15457404 | pmc = 1182110 | doi = 10.1086/425589 }}</ref> The lower rates of catabolisis for the Met allele results in higher synaptic dopamine levels following neurotransmitter release, ultimately increasing dopaminergic stimulation of the post-synaptic neuron. Given the preferential role of COMT in prefrontal dopamine degradation, the Val158Met polymorphism is thought to exert its effects on cognition by modulating dopamine signaling in the [[frontal lobe]]s.

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.<ref>{{cite journal | vauthors = Bruder GE, Keilp JG, Xu H, Shikhman M, Schori E, Gorman JM, Gilliam TC | title = Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations | journal = Biological Psychiatry | volume = 58 | issue = 11 |pages = 901–7 | date = December 2005 | pmid = 16043133 | doi = 10.1016/j.biopsych.2005.05.010}}</ref>{{Unreliable medical source|sure=y|reason=Report on data collected by the authors (i.e., primary research). |date=December 2016}}<ref>{{cite journal |vauthors = Robinson S, Goddard L, Dritschel B, Wisley M, Howlin P | title = Executive functions in children with autism spectrum disorders | journal = Brain and Cognition | volume = 71 | issue = 3 | pages = 362–8 | date = December 2009 | pmid = 19628325 | doi = 10.1016/j.bandc.2009.06.007}}</ref>{{Unreliable medical source|sure=y|reason=Comparative study of data collected by the authors from a small sample (N=54). |date=December 2016}}<ref>{{cite journal | vauthors = Diamond A, Briand L, Fossella J, Gehlbach L |title = Genetic and neurochemical modulation of prefrontal cognitive functions in children | journal = The American Journal of Psychiatry |volume = 161 | issue = 1 | pages = 125–32 | date = January 2004 | pmid = 14702260 | doi = 10.1176/appi.ajp.161.1.125}}</ref>{{Unreliable medical source|sure=y|reason=Report on data collected by the authors (i.e., primary research). |date=December 2016}}

Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to [[schizophrenia]].<ref>NIH Record [https://nihrecord.nih.gov/newsletters/2005/10_07_2005/story04.htm [[Daniel R. Weinberger]] to Give Milder Lecture], October 7, 2005</ref><ref>The News and Editorial Staffs [http://science.sciencemag.org/content/302/5653/2039.full?_ga=2.180174176.513131095.1504024240-1632489804.1504024240#mentalillness Breakthrough of the Year: The Runner Up A Quest], Science Magazine, December 19, 2003.</ref> 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, naturally or due to adolescent-onset cannabis use.<ref name="pmid15866551">{{cite journal | vauthors = Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW | title = Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction | journal = Biological Psychiatry | volume = 57 | issue = 10 | pages = 1117–27 | date = May 2005 | pmid = 15866551 | doi = 10.1016/j.biopsych.2005.01.026 }}</ref>{{Unreliable medical source|sure=y|reason=Longitudinal study of data collected by the authors (i.e., primary research). |date=December 2016}}  However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on schizophrenia development.<ref name="pmid17978319">{{cite journal | vauthors = Zammit S, Spurlock G, Williams H, Norton N, Williams N, O'Donovan MC, Owen MJ | title = Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use | journal = The British Journal of Psychiatry | volume = 191 | issue = 5 | pages = 402–7 | date = November 2007 | pmid = 17978319 | doi = 10.1192/bjp.bp.107.036129 | laysummary = http://www.medwire-news.md/47/71003/Psychiatry/Cannabis_and_smoking_gene_links_to_schizophrenia_%E2%80%98unfounded%E2%80%99.html | laysource = MedWireNews }}</ref>{{Unreliable medical source|sure=y|reason=Comparative study of data collected by the authors (i.e., primary research). |date=December 2016}}

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 [[Sophia Frangou|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,<ref name=pmid20667170>{{cite journal | vauthors = Lelli-Chiesa G, Kempton MJ, Jogia J, Tatarelli R, Girardi P, Powell J, Collier DA, Frangou S | title = The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives | journal = Psychological Medicine | volume = 41 | issue = 4 | pages = 779–88 | date = April 2011 | pmid = 20667170 | doi = 10.1017/S0033291710001431 }}</ref>{{Unreliable medical source|sure=y|reason=Imaging data collected by the authors (i.e., primary research). |date=December 2016}} but these findings have not been replicated so far.

The COMT Val158Met polymorphism also has a [[pleiotropy|pleiotropic]] effect on emotional processing.<ref name=pmid20667170/>{{Unreliable medical source|sure=y|reason=Imaging data collected by the authors (i.e., primary research). |date=December 2016}}<ref name="pmid18796186">{{cite journal | vauthors = Kempton MJ, Haldane M, Jogia J, Christodoulou T, Powell J, Collier D, Williams SC, Frangou S | title = The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition: a fMRI study | journal = The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum | volume = 12 | issue = 3 | pages = 371–81 | date = April 2009 | pmid = 18796186 | doi = 10.1017/S1461145708009395 }}</ref>{{Unreliable medical source|sure=y|reason=Imaging data collected and analyzed by the authors (i.e., primary research). |date=December 2016}}
Furthermore, the polymorphism has been shown to affect ratings of [[Positive psychology#Subjective Well-being|subjective well-being]]. When 621 women were measured with [[Experience sampling method|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.<ref name="pmid17687265">{{cite journal | vauthors = Wichers M, Aguilera M, Kenis G, Krabbendam L, Myin-Germeys I, Jacobs N, Peeters F, Derom C, Vlietinck R, Mengelers R, Delespaul P, van Os J | title = The catechol-O-methyl transferase Val158Met polymorphism and experience of reward in the flow of daily life | journal = Neuropsychopharmacology | volume = 33 | issue = 13 | pages = 3030–6 | date = December 2008 | pmid = 17687265 | doi = 10.1038/sj.npp.1301520 }}</ref>{{Unreliable medical source|sure=y|reason=Data collected and analyzed by the authors (i.e., primary research). |date=December 2016}}  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.<ref name="pmid17687265"/> 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.<ref name="pmid17687265"/>{{Unreliable medical source|sure=y|reason=Data collected and analyzed by the authors (i.e., primary research). |date=December 2016}}

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<ref>{{cite journal | vauthors = Montag C, Jurkiewicz M, Reuter M | title = The role of the catechol-O-methyltransferase (COMT) gene in personality and related psychopathological disorders | journal = CNS & Neurological Disorders Drug Targets | volume = 11 | issue = 3 | pages = 236–50 | date = May 2012 | pmid = 22483293 | pmc = 4345409 | doi = 10.2174/187152712800672382 }}</ref>

=== 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.<ref>{{cite journal | vauthors = Cairns BE | title = Pathophysiology of TMD pain--basic mechanisms and their implications for pharmacotherapy | journal = Journal of Oral Rehabilitation | volume = 37 | issue = 6 | pages = 391–410 | date = May 2010 | pmid = 20337865 | doi = 10.1111/j.1365-2842.2010.02074.x }}</ref>

== Nomenclature ==

''COMT'' is the name given to the [[gene]] that codes for this enzyme. The '''''O''''' in the name stands for [[oxygen]], not for ''[[arene substitution patterns|ortho]]''.

== COMT inhibitors ==

[[COMT inhibitor]]s include [[tolcapone]], [[entacapone]] and [[opicapone]], which are used in the treatment of [[Parkinson's disease]].<ref name="pmid17894650">{{cite journal | vauthors = Bonifácio MJ, Palma PN, Almeida L, Soares-da-Silva P | title = Catechol-O-methyltransferase and its inhibitors in Parkinson's disease | journal = CNS Drug Reviews | volume = 13 | issue = 3 | pages = 352–79 | year = 2007 | pmid = 17894650 | doi = 10.1111/j.1527-3458.2007.00020.x }}</ref>  Risk of [[liver toxicity]] and related digestive disorders restricts the use of tolcapone.<ref>{{cite journal | vauthors = Jatana N, Apoorva N, Malik S, Sharma A, Latha N | title = Inhibitors of catechol-O-methyltransferase in the treatment of neurological disorders | journal = Central Nervous System Agents in Medicinal Chemistry | volume = 13 | issue = 3 | pages = 166–94 | date = January 2013 | pmid = 24450388 | url = https://www.researchgate.net/profile/Nidhi_Jatana/publication/259875125_Inhibitors_of_Catechol-O-Methyl_Transferase_in_the_Treatment_of_Neurological_Disorders/links/02e7e538c0634e19f9000000.pdf | via =  | quote = Two of the nitrocatechols, entacapone ... and tolcapone ... have been demonstrated to reduce the dose of L-DOPA required and also cause improvement in clinical symptoms, although tolcapone emerged to be more efficacious due to its greater bioavailability and a longer half-life when compared to entacapone. However, tolcapone is clinically restricted owning to its increased hepatotoxicity and other related digestive disorders. | archive-url = | doi=10.2174/1871524913666140109113341}}</ref>

== See also ==
* [[Dopamine]]
* [[Schizophrenia]]
* [[O-methyltransferase]]

==Additional images==
<gallery>
 Image:Dopamine degradation.svg
</gallery>

== References ==
{{Reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Trendelenburg U | title = The interaction of transport mechanisms and intracellular enzymes in metabolizing systems | journal = Journal of Neural Transmission. Supplementum | volume = 32 | issue =  | pages = 3–18 | year = 1991 | pmid = 2089098 | doi = 10.1007/978-3-7091-9113-2_1 | isbn = 978-3-211-82239-5 }}
* {{cite journal | vauthors = Zhu BT | title = On the mechanism of homocysteine pathophysiology and pathogenesis: a unifying hypothesis | journal = Histology and Histopathology | volume = 17 | issue = 4 | pages = 1283–91 | date = October 2002 | pmid = 12371153 | doi =  }}
* {{cite journal | vauthors = Oroszi G, Goldman D | title = Alcoholism: genes and mechanisms | journal = Pharmacogenomics | volume = 5 | issue = 8 | pages = 1037–48 | date = December 2004 | pmid = 15584875 | doi = 10.1517/14622416.5.8.1037 }}
* {{cite journal | vauthors = Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, Feng GY, St Clair D, He L | title = Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis | journal = Biological Psychiatry | volume = 57 | issue = 2 | pages = 139–44 | date = January 2005 | pmid = 15652872 | doi = 10.1016/j.biopsych.2004.10.018 }}
* {{cite journal | vauthors = Tunbridge EM, Harrison PJ, Weinberger DR | title = Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond | journal = Biological Psychiatry | volume = 60 | issue = 2 | pages = 141–51 | date = July 2006 | pmid = 16476412 | doi = 10.1016/j.biopsych.2005.10.024 }}
* {{cite journal | vauthors = Craddock N, Owen MJ, O'Donovan MC | title = The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons | journal = Molecular Psychiatry | volume = 11 | issue = 5 | pages = 446–58 | date = May 2006 | pmid = 16505837 | doi = 10.1038/sj.mp.4001808 }}
* {{cite journal | vauthors = Frank MJ, Moustafa AA, Haughey HM, Curran T, Hutchison KE | title = Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 41 | pages = 16311–6 | date = October 2007 | pmid = 17913879 | pmc = 2042203 | doi = 10.1073/pnas.0706111104 }}
{{refend}}
* {{cite journal |vauthors= Greenberg, Gary |title= What If the Placebo Effect Isn't a Trick? |journal= New York Times Magazine |date= November 7, 2018}}

== External links ==
{{Commons category|Catechol O-methyltransferase, COMT}}
* {{MeshName|Catechol+O-Methyltransferase}}

{{Neurotransmitter metabolism enzymes}}
{{One carbon transferases}}
{{Enzymes}}
{{Monoamine metabolism modulators}}
{{Portal bar|Molecular and Cellular Biology|border=no}}

{{DEFAULTSORT:Catechol-O-Methyltransferase}}
[[Category:EC 2.1.1]]
[[Category:O-Methylated natural phenols metabolism]]