Catechol-O-methyl transferase

From Wikipedia, the free encyclopedia
  (Redirected from COMT (gene))
Jump to: navigation, search
Catechol-O-methyl transferase 3bwm.png
Available structures
PDB Ortholog search: PDBe RCSB
Aliases COMT, HEL-S-98n, catechol-O-methyltransferase
External IDs OMIM: 116790 MGI: 88470 HomoloGene: 30982 GeneCards: 1312
Targeted by Drug
entacapone, tolcapone[1]
RNA expression pattern
PBB GE COMT 208817 at tn.png

PBB GE COMT 208818 s at tn.png

PBB GE COMT 213981 at tn.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 22: 19.94 – 19.97 Mb Chr 16: 18.41 – 18.43 Mb
PubMed search [2] [3]
View/Edit Human View/Edit Mouse
EC number
CAS number 9012-25-3
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Norepinephrine degradation. Catechol-O-methyltransferase is shown in green boxes.[4]

Catechol-O-methyltransferase (COMT; EC is one of several enzymes that degrade catecholamines such as dopamine, epinephrine, and norepinephrine. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene.[5] 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.[6] COMT was first discovered by the biochemist Julius Axelrod in 1957.[7]


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.[8][9] 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:

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.[10][11] This process is supposed to take place in postsynaptic neurons, as, in general, COMT is located intracellularly in the central nervous system (CNS).[12][13]

COMT can also be found extracellularly, although extracellular COMT plays a less significant role in the CNS than it does peripherally.[14] Despite its importance in neurons, COMT is actually primarily expressed in the liver.[15]

Genetics in humans[edit]

The COMT protein is coded by the gene COMT. The gene is associated with allelic variants. The best-studied is Val158Met. Others are rs737865 and rs165599 that have been studied, e.g., for association with personality traits.[16]

Val158Met polymorphism[edit]

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 (Val158Met) rs4680.[17] The Val variant catabolizes dopamine at up to four times the rate of its methionine counterpart.[18] However, the Met variant is overexpressed in the brain,[19] resulting in a 40% decrease in functional enzyme activity.[20] 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 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.[21][22][23]

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, naturally or due to adolescent-onset cannabis use.[24] However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on schizophrenia development.[25]

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,[26] but these findings have not been replicated so far.

The COMT Val158Met polymorphism also has a pleiotropic effect on emotional processing.[27][28] 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.[29] 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.[29] 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.[29]

Temporomandibular joint dysfunction[edit]

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.[30]


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[edit]

COMT inhibitors include tolcapone and entacapone, which are commonly used in the treatment of Parkinson's disease.[31]

See also[edit]

Additional images[edit]


  1. ^ "Drugs that physically interact with Catechol O-methyltransferase view/edit references on wikidata". 
  2. ^ "Human PubMed Reference:". 
  3. ^ "Mouse PubMed Reference:". 
  4. ^ Figure 11-4 in: Flower R, Rang HP, Dale MM, Ritter JM (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5. 
  5. ^ Grossman MH, Emanuel BS, Budarf ML (April 1992). "Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1----q11.2". Genomics. 12 (4): 822–5. doi:10.1016/0888-7543(92)90316-K. PMID 1572656. 
  6. ^ Tai CH, Wu RM (February 2002). "Catechol-O-methyltransferase and Parkinson's disease". Acta Medica Okayama. 56 (1): 1–6. PMID 11873938. 
  7. ^ Axelrod J (August 1957). "O-Methylation of Epinephrine and Other Catechols in vitro and in vivo". Science. 126 (3270): 400–1. doi:10.1126/science.126.3270.400. PMID 13467217. 
  8. ^ Ruottinen HM, Rinne UK (November 1998). "COMT inhibition in the treatment of Parkinson's disease". Journal of Neurology. 245 (11 Suppl 3): P25–34. PMID 9808337. 
  9. ^ Goetz CG (May 1998). "Influence of COMT inhibition on levodopa pharmacology and therapy". Neurology. 50 (5 Suppl 5): S26–30. PMID 9591519. 
  10. ^ Matsumoto M, Weickert CS, Akil M, Lipska BK, Hyde TM, Herman MM, Kleinman JE, Weinberger DR (2003). "Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function". Neuroscience. 116 (1): 127–37. doi:10.1016/S0306-4522(02)00556-0. PMID 12535946. 
  11. ^ Karoum F, Chrapusta SJ, Egan MF (September 1994). "3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model". Journal of Neurochemistry. 63 (3): 972–9. doi:10.1046/j.1471-4159.1994.63030972.x. PMID 7914228. 
  12. ^ Ulmanen I, Peränen J, Tenhunen J, Tilgmann C, Karhunen T, Panula P, Bernasconi L, Aubry JP, Lundström K (January 1997). "Expression and intracellular localization of catechol O-methyltransferase in transfected mammalian cells". European Journal of Biochemistry / FEBS. 243 (1–2): 452–9. doi:10.1111/j.1432-1033.1997.0452a.x. PMID 9030772. 
  13. ^ Schott et al., 2010
  14. ^ Golan DE, Armen H. Tashjian Jr. Principles of pharmacology (3rd ed.). Philadelphia: Wolters Kluwer Health. p. 210. ISBN 1-60831-270-4. 
  15. ^ Golan DE, Tashjian AH. Principles of pharmacology (3rd ed.). Philadelphia: Wolters Kluwer Health. p. 135. ISBN 1-60831-270-4. 
  16. ^ Stein MB, Fallin MD, Schork NJ, Gelernter J (November 2005). "COMT polymorphisms and anxiety-related personality traits". Neuropsychopharmacology. 30 (11): 2092–102. doi:10.1038/sj.npp.1300787. PMID 15956988. 
  17. ^ Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melén K, Julkunen I, Taskinen J (April 1995). "Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme". Biochemistry. 34 (13): 4202–10. doi:10.1021/bi00013a008. PMID 7703232. 
  18. ^ Lachman HM, Morrow B, Shprintzen R, Veit S, Parsia SS, Faedda G, Goldberg R, Kucherlapati R, Papolos DF (September 1996). "Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome". American Journal of Medical Genetics. 67 (5): 468–72. doi:10.1002/(SICI)1096-8628(19960920)67:5<468::AID-AJMG5>3.0.CO;2-G. PMID 8886163. 
  19. ^ Zhu G, Lipsky RH, Xu K, Ali S, Hyde T, Kleinman J, Akhtar LA, Mash DC, Goldman D (December 2004). "Differential expression of human COMT alleles in brain and lymphoblasts detected by RT-coupled 5' nuclease assay". Psychopharmacology. 177 (1–2): 178–84. doi:10.1007/s00213-004-1938-z. PMID 15290009. 
  20. ^ 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 (November 2004). "Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain". American Journal of Human Genetics. 75 (5): 807–21. doi:10.1086/425589. PMC 1182110free to read. PMID 15457404. 
  21. ^ Bruder GE, Keilp JG, Xu H, Shikhman M, Schori E, Gorman JM, Gilliam TC (December 2005). "Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations". Biological Psychiatry. 58 (11): 901–7. doi:10.1016/j.biopsych.2005.05.010. PMID 16043133. 
  22. ^ Robinson S, Goddard L, Dritschel B, Wisley M, Howlin P (December 2009). "Executive functions in children with autism spectrum disorders". Brain and Cognition. 71 (3): 362–8. doi:10.1016/j.bandc.2009.06.007. PMID 19628325. 
  23. ^ Diamond et al. (2004). Genetic and neurochemical modulation of prefrontal cognitive functions in children" The American Journal of Psychiatry 161, no. 1: 125-132
  24. ^ Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW (May 2005). "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". Biological Psychiatry. 57 (10): 1117–27. doi:10.1016/j.biopsych.2005.01.026. PMID 15866551. 
  25. ^ Zammit S, Spurlock G, Williams H, Norton N, Williams N, O'Donovan MC, Owen MJ (November 2007). "Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use". The British Journal of Psychiatry. 191 (5): 402–7. doi:10.1192/bjp.bp.107.036129. PMID 17978319. Lay summaryMedWireNews. 
  26. ^ Lelli-Chiesa G, Kempton MJ, Jogia J, Tatarelli R, Girardi P, Powell J, Collier DA, Frangou S (April 2011). "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". Psychological Medicine. 41 (4): 779–88. doi:10.1017/S0033291710001431. PMID 20667170. 
  27. ^ Lelli-Chiesa G, Kempton MJ, Jogia J, Tatarelli R, Girardi P, Powell J, Collier DA, Frangou S (April 2011). "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". Psychological Medicine. 41 (4): 779–88. doi:10.1017/S0033291710001431. PMID 20667170. 
  28. ^ Kempton MJ, Haldane M, Jogia J, Christodoulou T, Powell J, Collier D, Williams SC, Frangou S (April 2009). "The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition: a fMRI study". The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum. 12 (3): 371–81. doi:10.1017/S1461145708009395. PMID 18796186. 
  29. ^ a b c 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 (December 2008). "The catechol-O-methyl transferase Val158Met polymorphism and experience of reward in the flow of daily life". Neuropsychopharmacology. 33 (13): 3030–6. doi:10.1038/sj.npp.1301520. PMID 17687265. 
  30. ^ Cairns BE (May 2010). "Pathophysiology of TMD pain--basic mechanisms and their implications for pharmacotherapy". Journal of Oral Rehabilitation. 37 (6): 391–410. doi:10.1111/j.1365-2842.2010.02074.x. PMID 20337865. 
  31. ^ Bonifácio MJ, Palma PN, Almeida L, Soares-da-Silva P (2007). "Catechol-O-methyltransferase and its inhibitors in Parkinson's disease". CNS Drug Reviews. 13 (3): 352–79. doi:10.1111/j.1527-3458.2007.00020.x. PMID 17894650. 

Further reading[edit]

External links[edit]