Cartoon diagram of human COMT in complex with 3,5-dinitrocatechol (dark blue) and S-adenosyl methionine (yellow). From PDB 3BWM.
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
Catechol-O-methyltransferase (COMT; EC 220.127.116.11) 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. 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.
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:
- 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. This process is supposed to take place in postsynaptic neurons, as, in general, COMT is located intracellularly in the CNS.
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 Val158Met. Others are rs737865 and rs165599 that have been studied, e.g., for association with personality traits.
The 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 (Val158Met) rs4680. The Val variant catabolizes dopamine at up to four times the rate of its methionine counterpart. However, the Met variant is overexpressed in the brain, resulting in a 40% decrease in functional enzyme activity. 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.
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. However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on schizophrenia development.
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 Val158Met 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.
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.
- Figure 11-4 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.
- 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.
- Tai CH, Wu RM (February 2002). "Catechol-O-methyltransferase and Parkinson's disease". Acta Med. Okayama 56 (1): 1–6. PMID 11873938.
- 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.
- Matsumoto, M; Weickert, C.Shannon; Akil, M.; Lipska, B.K.; Hyde, T.M.; Herman, M.M.; Kleinman, J.E.; Weinberger, D.R. (2003). "Catechol O-methyltransferase mRNA expression in human and rat brain: Evidence for a role in cortical neuronal function". Neuroscience 116: 127. doi:10.1016/S0306-4522(02)00556-0.
- Karoum, Farouk; Chrapusta, Stanislaw J.; Egan, Michael F. (2002). "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 T". Journal of Neurochemistry 63 (3): 972–9. doi:10.1046/j.1471-4159.1994.63030972.x. PMID 7914228.
- Ulmanen, Ismo; Peranen, Johan; Tenhunen, Jukka; Tilgmann, Carola; Karhunen, Tuula; Panula, Pertti; Bernasconi, Lilia; Aubry, Jean-Piere; Lundstrom, Kenneth (1997). "Expression and Intracellular Localization of Catechol O-methyltransferase in Transfected Mammalian Cells". European Journal of Biochemistry 243 (1–2): 452–9. doi:10.1111/j.1432-1033.1997.0452a.x. PMID 9030772.
- Schott et al., 2010 http://www.frontiersin.org/molecular_psychiatry/10.3389/fpsyt.2010.00142/abstract
- Golan, David E.; Armen H. Tashjian Jr. Principles of pharmacology (3rd ed.). Philadelphia: Wolters Kluwer Health. p. 210. ISBN 1-60831-270-4.
- Golan, David E.; Armen H. Tashjian Jr. Principles of pharmacology (3rd ed.). Philadelphia: Wolters Kluwer Health. p. 135. ISBN 1-60831-270-4.
- 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.
- Lotta T, Vidgren J, Tilgmann C, et al. (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.
- Lachman HM, Morrow B, Shprintzen R, et al. (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 (inactive 2014-03-24). PMID 8886163.
- Zhu G, Lipsky RH, Xu K, et al.; Lipsky; Xu; Ali; Hyde; Kleinman; Akhtar; Mash; Goldman (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.
- Chen J, Lipska BK, Halim N, et al.; Lipska; Halim; Ma; Matsumoto; Melhem; Kolachana; Hyde; Herman; Apud; Egan; Kleinman; Weinberger (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 1182110. PMID 15457404.
- 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". Biol. Psychiatry 58 (11): 901–7. doi:10.1016/j.biopsych.2005.05.010. PMID 16043133.
- Robinson S, Goddard L, Dritschel B, Wisley M, Howlin P (2009). "Executive functions in children with autism spectrum disorders". Brain Cogn. 71 (3): 362–368. doi:10.1016/j.bandc.2009.06.007. PMC 3481002. PMID 19628325.
- Diamond et al. (2004). Genetic and neurochemical modulation of prefrontal cognitive functions in children" The American Journal of Psychiatry 161, no. 1: 125-132
- 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". Biol. Psychiatry 57 (10): 1117–27. doi:10.1016/j.biopsych.2005.01.026. PMID 15866551.
- 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". Br J Psychiatry 191 (5): 402–7. doi:10.1192/bjp.bp.107.036129. PMID 17978319. Lay summary – MedWireNews.
- Lelli-Chiesa G, Kempton MJ, Jogia J, et al. (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". Psychol Med 41 (4): 779–88. doi:10.1017/S0033291710001431. PMID 20667170.
- Lelli-Chiesa G, Kempton MJ, Jogia J, Tatarelli R, Girardi P, Powell J, Collier DA, Frangou S (July 2010). "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". Psychol Med 41 (4): 1–10. doi:10.1017/S0033291710001431. PMID 20667170.
- 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". Int. J. Neuropsychopharmacol. 12 (3): 371–81. doi:10.1017/S1461145708009395. PMID 18796186.
- 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.
- 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.
- Bonifácio MJ, Palma PN, Almeida L, Soares-da-Silva P (2007). "Catechol-O-methyltransferase and its inhibitors in Parkinson's disease". CNS Drug Rev 13 (3): 352–79. doi:10.1111/j.1527-3458.2007.00020.x. PMID 17894650.
- Wichers, M.; Aguilera, M; Kenis, G; Krabbendam, L; Myin-Germeys, I; Jacobs, N; Peeters, F; Derom, C et al. (2008). "The Catechol-O-Methyl Transferase Val158Met Polymorphism and Experience of Reward in the Flow of Daily Life". Neuropsychopharmacology 33 ((2008) 33, 3030–3036): 3030–6. doi:10.1038/sj.npp.1301520. PMID 17687265.http://www.nature.com/npp/journal/v33/n13/full/1301520a.html
- Trendelenburg U (1991). "The interaction of transport mechanisms and intracellular enzymes in metabolizing systems". J. Neural Transm. Suppl. 32: 3–18. doi:10.1007/978-3-7091-9113-2_1. PMID 2089098.
- Tai CH, Wu RM (2002). "Catechol-O-methyltransferase and Parkinson's disease". Acta Med. Okayama 56 (1): 1–6. PMID 11873938.
- Zhu BT (2003). "On the mechanism of homocysteine pathophysiology and pathogenesis: a unifying hypothesis". Histol. Histopathol. 17 (4): 1283–91. PMID 12371153.
- Oroszi G, Goldman D (2005). "Alcoholism: genes and mechanisms". Pharmacogenomics 5 (8): 1037–48. doi:10.1517/14622418.104.22.1687. PMID 15584875.
- Fan JB, Zhang CS, Gu NF, et al. (2005). "Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis". Biol. Psychiatry 57 (2): 139–44. doi:10.1016/j.biopsych.2004.10.018. PMID 15652872.
- Tunbridge EM, Harrison PJ, Weinberger DR (2006). "Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond". Biol. Psychiatry 60 (2): 141–51. doi:10.1016/j.biopsych.2005.10.024. PMID 16476412.
- Diaz-Asper CM, Weinberger DR, Goldberg TE (2006). "Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics". NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics 3 (1): 97–105. doi:10.1016/j.nurx.2005.12.010. PMID 16490416.
- Craddock N, Owen MJ, O'Donovan MC (2006). "The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons". Mol. Psychiatry 11 (5): 446–58. doi:10.1038/sj.mp.4001808. PMID 16505837.
- Frank MJ, Moustafa AA, Haughey H, Curran T, Hutchison KE (2007). "Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning". Proc Natl Acad Sci USA 104 (41): 16311–6. doi:10.1073/pnas.0706111104. PMC 2042203. PMID 17913879.
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