Norepinephrine degradation. Catechol-O-methyltransferase is shown in green boxes.[5][6]
Catechol-O-methyltransferase (COMT; EC2.1.1.6) 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.[7] In humans, catechol-O-methyltransferase protein is encoded by the COMTgene.[8] 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.[9] COMT was first discovered by the biochemistJulius Axelrod in 1957.[10]
Function
Catechol-O-methyltransferase is involved in the inactivation of the catecholamineneurotransmitters (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.[11] 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.
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[12][13][14][15] (In the PFC, dopamine is also removed by presynaptic norepinephrine transporters (NET) and degraded by monoamine oxidase.).[16] Controversy exists about the predominance and orientation of membrane bound COMT in the CNS,[17][18][19] 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.[20]: 210 Despite its importance in neurons, COMT is actually primarily expressed in the liver.[20]: 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.[15]
Others are rs737865 and rs165599 that have been studied, e.g., for association with personality traits,[21] response to antidepressant medications,[22] and psychosis risk associated with Alzheimer's disease.[23] 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,[24] including Val158Met.[25][26][27]
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.[15] In vitro, the homozygous Val variant metabolizes dopamine at up to four times the rate of its methionine counterpart.[22] However, in vivo the Met variant is overexpressed in the brain,[28] resulting in a 40% decrease (rather than 75% decrease) in functional enzyme activity.[29] 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 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.[30][31][32]
Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to schizophrenia.[33][34] 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.[35] A more recent study cast doubt on the proposed connection between this gene and any alleged casual effect of cannabis on schizophrenia development.[36]
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.[37] 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,[38] but these findings have not been replicated so far.
The COMT Val158Met polymorphism also has a pleiotropic effect on emotional processing.[38][39]
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.[40] 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.[40] 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.[40]
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[41]
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.[42]
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.
^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): 822–825. doi:10.1016/0888-7543(92)90316-K. PMID1572656.
^Scheggia D, Sannino S, Scattoni ML, Papaleo F (May 2012). "COMT as a drug target for cognitive functions and dysfunctions". CNS & Neurological Disorders Drug Targets. 11 (3): 209–221. doi:10.2174/187152712800672481. PMID22483296.
^Okochi T, Ikeda M, Kishi T, Kawashima K, Kinoshita Y, Kitajima T, et al. (May 2009). "Meta-analysis of association between genetic variants in COMT and schizophrenia: an update". Schizophrenia Research. 110 (1–3): 140–148. doi:10.1016/j.schres.2009.02.019. PMID19329282. S2CID22875066.
^Glatt SJ, Faraone SV, Tsuang MT (March 2003). "Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies". The American Journal of Psychiatry. 160 (3): 469–476. doi:10.1176/appi.ajp.160.3.469. PMID12611827. S2CID25352000.
^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. PMID15652872. S2CID23416733.
^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): 901–907. doi:10.1016/j.biopsych.2005.05.010. PMID16043133. S2CID17902043.
^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): 362–368. doi:10.1016/j.bandc.2009.06.007. PMID19628325. S2CID14587250.
^Diamond A, Briand L, Fossella J, Gehlbach L (January 2004). "Genetic and neurochemical modulation of prefrontal cognitive functions in children". The American Journal of Psychiatry. 161 (1): 125–132. doi:10.1176/appi.ajp.161.1.125. PMID14702260. S2CID2341627.
^Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, et al. (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): 1117–1127. doi:10.1016/j.biopsych.2005.01.026. PMID15866551. S2CID39405111.
^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. PMID20337865.
^Jatana N, Apoorva N, Malik S, Sharma A, Latha N (January 2013). "Inhibitors of catechol-O-methyltransferase in the treatment of neurological disorders". Central Nervous System Agents in Medicinal Chemistry. 13 (3): 166–194. doi:10.2174/1871524913666140109113341. PMID24450388. 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 owing to its increased hepatotoxicity and other related digestive disorders.
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. ISBN978-3-211-82239-5. PMID2089098.
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. PMID12371153.
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. PMID15652872. S2CID23416733.
Tunbridge EM, Harrison PJ, Weinberger DR (July 2006). "Catechol-O-methyltransferase, cognition, and psychosis: Val158Met and beyond". Biological Psychiatry. 60 (2): 141–151. doi:10.1016/j.biopsych.2005.10.024. PMID16476412. S2CID45705154.
