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Catechol-O-methyltransferase

Cartoon diagram of human COMT in complex with 3,5-dinitrocatechol (dark blue) and S-adenosyl methionine (yellow). From PDB 3BWM.
Identifiers
Symbols COMT;
External IDs OMIM116790 MGI88470 HomoloGene30982 GeneCards: COMT Gene
RNA expression pattern
PBB GE COMT 208818 s at tn.png
PBB GE COMT 208817 at tn.png
PBB GE COMT 213981 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1312 12846
Ensembl ENSG00000093010 ENSMUSG00000000326
UniProt P21964 Q91XH4
RefSeq (mRNA) NM_000754 NM_007744
RefSeq (protein) NP_000745 NP_031770
Location (UCSC) Chr 22:
18.31 - 18.34 Mb
Chr 16:
18.32 - 18.33 Mb
PubMed search [1] [2]

Catechol-O-methyl transferase (COMT; EC 2.1.1.6) is one of several enzymes that degrade catecholamines such as dopamine, epinephrine, and norepinephrine. 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.

Contents

Function

Catechol-O-methyl transferase 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). COMT is an intracellular enzyme located in the postsynaptic neuron. 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:

Genetics

The COMT protein is coded by the gene COMT. The gene is associated with allelic variants. The most well-studied is Val158Met. Others are rs737865 and rs165599 that have been studied, e.g., for association with personality traits.[1]

The val158met polymorphism

Val158Met (rs4680), a functional single nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyl transferase, has been shown to affect cognitive tasks broadly related to executive function,[2] such as set shifting, response inhibition, abstract thought, and the acquisition of rules or task structure. This polymorphism in the COMT gene results in the substitution of the amino acid valine for methionine at codon 158, thus the name Val158Met for the polymorphism. It has been shown that this valine variant catabolizes dopamine at up to four times the rate of its methionine counterpart, resulting in a significant reduction of synaptic dopamine following neurotransmitter release, ultimately reducing dopaminergic stimulation of the post-synaptic neuron. As a consequence, neurons with valine-variant COMT show higher levels of activation during certain cognitive tasks, as they require higher levels of neuron firing to achieve the same level of post-synaptic stimulation.

The link between impairments in these sorts of cognitive tasks and the COMT gene is thought to be mediated by an effect on dopamine signaling in the frontal lobes.

Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to schizophrenia. It is not surprising, then, that an inherited variant of COMT is thought to be one of the genetic factors that may predispose someone to developing schizophrenia later in life, naturally or due to adolescent-onset cannabis use.[3]

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 tolcapone and entacapone, which are commonly used in the treatment of Parkinson disease.

See also

Additional images

References

  1. ^ 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.  
  2. ^ 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.  
  3. ^ 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.  

Further reading

  • Trendelenburg U (1991). "The interaction of transport mechanisms and intracellular enzymes in metabolizing systems". J. Neural Transm. Suppl. 32: 3–18. 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:10.1517/14622416.5.8.1037. 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. PMID 17913879.  

External links


edit
Catechol-O-methyltransferase

Cartoon diagram of human COMT in complex with 3,5-dinitrocatechol (dark blue) and S-adenosyl methionine (yellow). From PDB 3BWM.
Identifiers
SymbolsCOMT;
External IDsOMIM116790 MGI88470 HomoloGene30982 GeneCards: COMT Gene
EC number2.1.1.6
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez131212846
EnsemblENSG00000093010ENSMUSG00000000326
UniProtP21964Q91XH4
RefSeq (mRNA)NM_000754NM_007744
RefSeq (protein)NP_000745NP_031770
Location (UCSC)Chr 22:
18.31 - 18.34 Mb
Chr 16:
18.32 - 18.33 Mb
PubMed search[1][2]
catechol-O-methyltransferase
Identifiers
EC number 2.1.1.6
CAS number 9012-25-3
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures
Gene Ontology AmiGO / EGO
File:Noradrenaline
Norepinephrine degradation. Catechol-O-methyltransferase is shown in green boxes. [1]

Catechol-O-methyltransferase (COMT; EC 2.1.1.6) 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.[2] 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.[3] COMT was first discovered by the biochemist Julius Axelrod in 1957.[4]

Contents

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). COMT is an intracellular enzyme located in the postsynaptic neuron. 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:

Genetics

The COMT protein is coded by the gene COMT. The gene is associated with allelic variants. The most well-studied is Val158Met. Others are rs737865 and rs165599 that have been studied, e.g., for association with personality traits.[5]

The met/met polymorphism

A functional single-nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyltransferase resulting in a valine to methionine mutation at position 158 (Val158Met), 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.[6] 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.[6] Persons with the met/met phenotype describe events as very pleasant or pleasant with twice the numeric amplitude of those absent the met/met genetic polymorphism.[6]

The Val158Met polymorphism

a functional single nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyltransferase, has been shown to affect cognitive tasks broadly related to executive function,[7]

Val158Met (rs4680), a functional single nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyltransferase, 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.[citation needed] This polymorphism in the COMT gene results in the substitution of the amino acid valine for methionine at codon 158, thus the name Val158Met for the polymorphism. It has been shown that this valine variant catabolizes dopamine at up to four times the rate of its methionine counterpart, resulting in a significant reduction of synaptic dopamine following neurotransmitter release, ultimately reducing dopaminergic stimulation of the post-synaptic neuron. As a consequence, neurons with valine-variant COMT show higher levels of activation during certain cognitive tasks, as they require higher levels of neuron firing to achieve the same level of post-synaptic stimulation.

The link between impairments in these sorts of cognitive tasks and the COMT gene is thought to be mediated by an effect on dopamine signaling in the frontal lobes.

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.[8] However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on schizophrenia development.[9]

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 tolcapone and entacapone, which are commonly used in the treatment of Parkinson disease.[10]

See also

Additional images

References

Further reading

  • M. Wichers; Aguilera, M; Kenis, G; Krabbendam, L; Myin-Germeys, I; Jacobs, N; Peeters, F; Derom, C et al. (2008). [Expression error: Unexpected < operator "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). [Expression error: Unexpected < operator "The interaction of transport mechanisms and intracellular enzymes in metabolizing systems"]. J. Neural Transm. Suppl. 32: 3–18. PMID 2089098. 
  • Tai CH, Wu RM (2002). [Expression error: Unexpected < operator "Catechol-O-methyltransferase and Parkinson's disease"]. Acta Med. Okayama 56 (1): 1–6. PMID 11873938. 
  • Zhu BT (2003). [Expression error: Unexpected < operator "On the mechanism of homocysteine pathophysiology and pathogenesis: a unifying hypothesis"]. Histol. Histopathol. 17 (4): 1283–91. PMID 12371153. 
  • Oroszi G, Goldman D (2005). [Expression error: Unexpected < operator "Alcoholism: genes and mechanisms"]. Pharmacogenomics 5 (8): 1037–48. doi:10.1517/14622416.5.8.1037. PMID 15584875. 
  • Fan JB, Zhang CS, Gu NF, et al. (2005). [Expression error: Unexpected < operator "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). [Expression error: Unexpected < operator "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). [Expression error: Unexpected < operator "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). [Expression error: Unexpected < operator "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). [Expression error: Unexpected < operator "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. PMID 17913879. 

External links








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