Biology:Catechol-O-methyltransferase

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Short description: Class of enzymes


catechol-O-methyltransferase
Identifiers
EC number2.1.1.6
CAS number9012-25-3
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Norepinephrine degradation. Catechol-O-methyltransferase is shown in green boxes.[1][2]

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.[3] In humans, catechol-O-methyltransferase protein is encoded by the COMT gene.[4] 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.[5] COMT was first discovered by the biochemist Julius Axelrod in 1957.[6]

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.[7] 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.[8][9][10][11] (In the PFC, dopamine is also removed by presynaptic norepinephrine transporters (NET) and degraded by monoamine oxidase.)[12] Controversy exists about the predominance and orientation of membrane bound COMT in the CNS,[13][14][15] 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.[16]:210 Despite its importance in neurons, COMT is actually primarily expressed in the liver.[16]: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.[11] Others are rs737865 and rs165599 that have been studied, e.g., for association with personality traits,[17] response to antidepressant medications,[18] and psychosis risk associated with Alzheimer's disease.[19] 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,[20] including Val158Met.[21][22][23]

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.[11] In vitro, the homozygous Val variant metabolizes dopamine at up to four times the rate of its methionine counterpart.[18] However, in vivo the Met variant is overexpressed in the brain,[24] resulting in a 40% decrease (rather than 75% decrease) in functional enzyme activity.[25] 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.[26][27][28]

Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to schizophrenia.[29][30] 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.[31] A more recent study cast doubt on the proposed connection between this gene and any alleged casual effect of cannabis on schizophrenia development.[32]

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.[33] 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,[34] but these findings have not been replicated so far.

The COMT Val158Met polymorphism also has a pleiotropic effect on emotional processing.[34][35] 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.[36] 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.[36] 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.[36]

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[37]

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.[38]

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.[39] Risk of liver toxicity and related digestive disorders restricts the use of tolcapone.[40]

See also

Additional images

  • Dopamine degradation.svg

References

  1. ↑ "Figure 11-4". Rang & Dale's pharmacology (6th ed.). Edinburgh: Churchill Livingstone. 2007. ISBN 978-0-443-06911-6. 
  2. ↑ "Figure 14.4". Rang & Dale's Pharmacology. Student consult (7th ed.). Elsevier Health Sciences. 2011. ISBN 978-0-7020-4504-2. https://books.google.com/books?id=s2R-ZYz_iBYC&pg=PT876. 
  3. ↑ "Test ID: COMT: Catechol-O-Methyltransferase Genotype". Mayo Clinic: Mayo Medical Laboratories. http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/83301. 
  4. ↑ "Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1----q11.2". Genomics 12 (4): 822–825. April 1992. doi:10.1016/0888-7543(92)90316-K. PMID 1572656. 
  5. ↑ "catechol-O-methyltransferase and Parkinson's disease". Acta Medica Okayama 56 (1): 1–6. February 2002. doi:10.18926/AMO/31725. PMID 11873938. 
  6. ↑ "O-methylation of epinephrine and other catechols in vitro and in vivo". Science 126 (3270): 400–401. August 1957. doi:10.1126/science.126.3270.400. PMID 13467217. Bibcode: 1957Sci...126..400A. 
  7. ↑ "COMT inhibition in the treatment of Parkinson's disease". Journal of Neurology 245 (11 Suppl 3): P25–P34. November 1998. doi:10.1007/PL00007743. PMID 9808337. 
    Script error: No such module "in5"."Influence of COMT inhibition on levodopa pharmacology and therapy". Neurology 50 (5 Suppl 5): S26–S30. May 1998. doi:10.1212/WNL.50.5_Suppl_5.S26. PMID 9591519. 
  8. ↑ "Chapter 5: Neurotransmitters and their receptors". The Central Nervous System. Oxford University Press. 2016. p. 75. ISBN 978-0-19-022896-5. https://books.google.com/books?id=U4oDDAAAQBAJ&pg=PA75. 
  9. ↑ "COMT as a drug target for cognitive functions and dysfunctions". CNS & Neurological Disorders Drug Targets 11 (3): 209–221. May 2012. doi:10.2174/187152712800672481. PMID 22483296. 
  10. ↑ "catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics". NeuroRx 3 (1): 97–105. January 2006. doi:10.1016/j.nurx.2005.12.010. PMID 16490416. 
  11. ↑ 11.0 11.1 11.2 "COMT val158met moderation of dopaminergic drug effects on cognitive function: a critical review". The Pharmacogenomics Journal 16 (5): 430–438. October 2016. doi:10.1038/tpj.2016.43. PMID 27241058. 
  12. ↑ "Diversity of Dopaminergic Neural Circuits in Response to Drug Exposure". Neuropsychopharmacology 41 (10): 2424–2446. September 2016. doi:10.1038/npp.2016.32. PMID 26934955. 
  13. ↑ Basic Aspects of Catechol-O-Methyltransferase and the Clinical Applications of its Inhibitors. Academic Press. 2010. pp. 34. ISBN 978-0-12-381327-5. https://books.google.com/books?id=bkUdEiPJ4EAC&pg=PA34. 
  14. ↑ "Orientation and cellular distribution of membrane-bound catechol-O-methyltransferase in cortical neurons: implications for drug development". The Journal of Biological Chemistry 286 (40): 34752–34760. October 2011. doi:10.1074/jbc.M111.262790. PMID 21846718. "The cellular distribution of MB-COMT in cortical neurons remains unclear and the orientation of MB-COMT on the cellular membrane is controversial.". 
  15. ↑ "Membrane-Bound Catechol-O-Methyl Transferase in Cortical Neurons and Glial Cells is Intracellularly Oriented". Frontiers in Psychiatry 1: 142. 2010. doi:10.3389/fpsyt.2010.00142. PMID 21423451. "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.". 
  16. ↑ 16.0 16.1 Principles of pharmacology (3rd ed.). Philadelphia: Wolters Kluwer Health. 2011-12-15. ISBN 978-1-60831-270-2. OCLC 705260923. 
  17. ↑ "Low dopamine function in attention deficit/hyperactivity disorder: should genotyping signify early diagnosis in children?". Postgraduate Medicine 126 (1): 153–177. January 2014. doi:10.3810/pgm.2014.01.2735. PMID 24393762. 
  18. ↑ 18.0 18.1 "Pharmacogenetics of antidepressant response". Journal of Psychiatry & Neuroscience 36 (2): 87–113. March 2011. doi:10.1503/jpn.100059. PMID 21172166. 
  19. ↑ "Genetics of psychosis in Alzheimer's disease: a review". Journal of Alzheimer's Disease 19 (3): 761–780. 2010. doi:10.3233/JAD-2010-1274. PMID 20157235. 
  20. ↑ "Meta-analysis of association between genetic variants in COMT and schizophrenia: an update". Schizophrenia Research 110 (1–3): 140–148. May 2009. doi:10.1016/j.schres.2009.02.019. PMID 19329282. 
  21. ↑ "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. March 2003. doi:10.1176/appi.ajp.160.3.469. PMID 12611827. 
  22. ↑ "Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies". Molecular Psychiatry 10 (8): 765–770. August 2005. doi:10.1038/sj.mp.4001664. PMID 15824744. 
  23. ↑ "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. January 2005. doi:10.1016/j.biopsych.2004.10.018. PMID 15652872. 
  24. ↑ "Differential expression of human COMT alleles in brain and lymphoblasts detected by RT-coupled 5' nuclease assay". Psychopharmacology 177 (1–2): 178–184. December 2004. doi:10.1007/s00213-004-1938-z. PMID 15290009. https://zenodo.org/record/1232621. 
  25. ↑ "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): 807–821. November 2004. doi:10.1086/425589. PMID 15457404. 
  26. ↑ "catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations". Biological Psychiatry 58 (11): 901–907. December 2005. doi:10.1016/j.biopsych.2005.05.010. PMID 16043133. 
  27. ↑ "Executive functions in children with autism spectrum disorders". Brain and Cognition 71 (3): 362–368. December 2009. doi:10.1016/j.bandc.2009.06.007. PMID 19628325. 
  28. ↑ "Genetic and neurochemical modulation of prefrontal cognitive functions in children". The American Journal of Psychiatry 161 (1): 125–132. January 2004. doi:10.1176/appi.ajp.161.1.125. PMID 14702260. 
  29. ↑ "Daniel R. Weinberger to Give Milder Lecture". NIH Record LVII (20): 3. 7 October 2005. https://nihrecord.nih.gov/newsletters/2005/10_07_2005/story04.htm. 
  30. ↑ "The Runners-Up". Science 302 (5653): 2039–2045. 2003. doi:10.1126/science.302.5653.2039. 
  31. ↑ "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. May 2005. doi:10.1016/j.biopsych.2005.01.026. PMID 15866551. 
  32. ↑ "Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use". The British Journal of Psychiatry 191 (5): 402–407. November 2007. doi:10.1192/bjp.bp.107.036129. PMID 17978319. 
  33. ↑ "The effect of rs1076560 (DRD2) and rs4680 (COMT) on tardive dyskinesia and cognition in schizophrenia subjects". Psychiatric Genetics 30 (5): 125–135. October 2020. doi:10.1097/YPG.0000000000000258. PMID 32931693. 
  34. ↑ 34.0 34.1 "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): 779–788. April 2011. doi:10.1017/S0033291710001431. PMID 20667170. https://publications.aston.ac.uk/id/eprint/20428/1/Impact_of_the_Val158Met_catechol_O_methyltransferase_genotype_on_neural_correlates_of_sad_facial_affect_processing.pdf. 
  35. ↑ "The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition: a fMRI study". The International Journal of Neuropsychopharmacology 12 (3): 371–381. April 2009. doi:10.1017/S1461145708009395. PMID 18796186. 
  36. ↑ 36.0 36.1 36.2 "The catechol-O-methyl transferase Val158Met polymorphism and experience of reward in the flow of daily life". Neuropsychopharmacology 33 (13): 3030–3036. December 2008. doi:10.1038/sj.npp.1301520. PMID 17687265. 
  37. ↑ "The role of the catechol-O-methyltransferase (COMT) gene in personality and related psychopathological disorders". CNS & Neurological Disorders Drug Targets 11 (3): 236–250. May 2012. doi:10.2174/187152712800672382. PMID 22483293. 
  38. ↑ "Pathophysiology of TMD pain--basic mechanisms and their implications for pharmacotherapy". Journal of Oral Rehabilitation 37 (6): 391–410. May 2010. doi:10.1111/j.1365-2842.2010.02074.x. PMID 20337865. 
  39. ↑ "catechol-O-methyltransferase and its inhibitors in Parkinson's disease". CNS Drug Reviews 13 (3): 352–379. 2007. doi:10.1111/j.1527-3458.2007.00020.x. PMID 17894650. 
  40. ↑ "Inhibitors of catechol-O-methyltransferase in the treatment of neurological disorders". Central Nervous System Agents in Medicinal Chemistry 13 (3): 166–194. January 2013. doi:10.2174/1871524913666140109113341. PMID 24450388. "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

External links



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