Catechol-O-methyltransferase
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| Location (UCSC) | Chr 22: 19.94 – 19.97 Mb | Chr 16: 18.23 – 18.25 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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| catechol-O-methyltransferase | |||||||||
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ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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Catechol-O-methyltransferase (COMT;
Function
Catechol-O-methyltransferase is involved in the inactivation of the
Specific reactions catalyzed by COMT include:
- 3-methoxytyramine
- DOPAC → HVA (homovanillic acid)
- Norepinephrine → normetanephrine
- Epinephrine → metanephrine
- 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.[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 polymorphism
A functional
The gene variant has been shown to affect
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
COMT inhibitors
See also
Additional images
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000093010 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000326 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ISBN 978-0-443-06911-6.
- ISBN 978-0-7020-4504-2.
- ^ "Test ID: COMT: Catechol-O-Methyltransferase Genotype". mayomedicallaboratories.com. Mayo Clinic: Mayo Medical Laboratories. Archived from the original on September 18, 2008. Retrieved November 16, 2016.
- PMID 1572656.
- PMID 11873938.
- PMID 13467217.
- S2CID 32448444.
- ISBN 978-0-19-022896-5.
- PMID 22483296.
- PMID 16490416.
- ^ PMID 27241058.
- PMID 26934955.
- ISBN 978-0-12-381327-5– via Google books.
- 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.
- 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.
- ^ OCLC 705260923.
- PMID 24393762.
- ^ PMID 21172166.
- PMID 20157235.
- S2CID 22875066.
- S2CID 25352000.
- PMID 15824744.
- S2CID 23416733.
- S2CID 33013401.
- PMID 15457404.
- S2CID 17902043.
- S2CID 14587250.
- S2CID 2341627.
- ^ "Daniel R. Weinberger to Give Milder Lecture". NIH Record. LVII (20): 3. 7 October 2005. Archived from the original on 22 May 2015.
- S2CID 220088635.
- S2CID 39405111.
- PMID 17978319.
- Davenport L (16 November 2007). "Cannabis and smoking gene links to schizophrenia 'unfounded'". MedWireNews. Archived from the original on 5 November 2012. Retrieved 5 July 2010.
- S2CID 221718209.
- ^ S2CID 206251638.
- PMID 18796186.
- ^ PMID 17687265.
- PMID 22483293.
- PMID 20337865.
- PMID 17894650.
- 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
- Trendelenburg U (1991). "The interaction of transport mechanisms and intracellular enzymes in metabolizing systems". Amine Oxidases and Their Impact on Neurobiology. Vol. 32. pp. 3–18. )
- Zhu BT (October 2002). "On the mechanism of homocysteine pathophysiology and pathogenesis: a unifying hypothesis". Histology and Histopathology. 17 (4): 1283–1291. PMID 12371153.
- Oroszi G, Goldman D (December 2004). "Alcoholism: genes and mechanisms". Pharmacogenomics. 5 (8): 1037–1048. PMID 15584875.
- 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. S2CID 23416733.
- Tunbridge EM, Harrison PJ, Weinberger DR (July 2006). "Catechol-O-methyltransferase, cognition, and psychosis: Val158Met and beyond". Biological Psychiatry. 60 (2): 141–151. S2CID 45705154.
- Craddock N, Owen MJ, O'Donovan MC (May 2006). "The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons". Molecular Psychiatry. 11 (5): 446–458. PMID 16505837.
- Frank MJ, Moustafa AA, Haughey HM, Curran T, Hutchison KE (October 2007). "Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning". Proceedings of the National Academy of Sciences of the United States of America. 104 (41): 16311–16316. PMID 17913879.
- Greenberg, Gary (November 7, 2018). "What If the Placebo Effect Isn't a Trick?". New York Times Magazine.
External links
- Catechol+O-Methyltransferase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P21964 (Human Catechol O-methyltransferase) at the PDBe-KB.
