Catechol-O-methyltransferase

Last updated
COMT
Catechol-O-methyl transferase 3bwm.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases COMT , HEL-S-98n, catechol-O-methyltransferase
External IDs OMIM: 116790 MGI: 88470 HomoloGene: 30982 GeneCards: COMT
Orthologs
SpeciesHumanMouse
Entrez

1312

12846

Ensembl

ENSG00000093010

ENSMUSG00000000326

UniProt

P21964

O88587

RefSeq (mRNA)

NM_000754
NM_001135161
NM_001135162
NM_007310
NM_001362828

NM_001111062
NM_001111063
NM_007744

RefSeq (protein)

NP_000745
NP_001128633
NP_001128634
NP_009294
NP_001349757

NP_001104532
NP_001104533
NP_031770

Location (UCSC) Chr 22: 19.94 – 19.97 Mb Chr 16: 18.23 – 18.25 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
catechol-O-methyltransferase
Identifiers
EC no. 2.1.1.6
CAS no. 9012-25-3
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins
Norepinephrine degradation. Catechol-O-methyltransferase is shown in green boxes. Noradrenaline breakdown.svg
Norepinephrine degradation. Catechol-O-methyltransferase is shown in green boxes.

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. [7] In humans, catechol-O-methyltransferase protein is encoded by the COMT gene. [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 biochemist Julius Axelrod in 1957. [10]

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. [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.

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. [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 .

COMT inhibitors

COMT inhibitors include entacapone, tolcapone, opicapone, and nitecapone. All except nitecapone are used in the treatment of Parkinson's disease. [43] Risk of liver toxicity and related digestive disorders restricts the use of tolcapone. [44]

See also

Additional images

Related Research Articles

<span class="mw-page-title-main">Dopamine</span> Organic chemical that functions both as a hormone and a neurotransmitter

Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

Schizotypal personality disorder, also known as schizotypal disorder, is a cluster A personality disorder. The Diagnostic and Statistical Manual of Mental Disorders (DSM) classification describes the disorder specifically as a personality disorder characterized by thought disorder, paranoia, a characteristic form of social anxiety, derealization, transient psychosis, and unconventional beliefs. People with this disorder feel pronounced discomfort in forming and maintaining social connections with other people, primarily due to the belief that other people harbor negative thoughts and views about them. Peculiar speech mannerisms and socially unexpected modes of dress are also characteristic. Schizotypal people may react oddly in conversations, not respond, or talk to themselves. They frequently interpret situations as being strange or having unusual meanings for them; paranormal and superstitious beliefs are common. Schizotypal people usually disagree with the suggestion that their thoughts and behaviors are a 'disorder' and seek medical attention for depression or anxiety instead. Schizotypal personality disorder occurs in approximately 3% of the general population and is more commonly diagnosed in males.

The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model that attributes the positive symptoms of schizophrenia to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the observation that a large number of antipsychotics have dopamine-receptor antagonistic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia. Rather, the overactivation of D2 receptors, specifically, is one effect of the global chemical synaptic dysregulation observed in this disorder.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.

<span class="mw-page-title-main">Norepinephrine transporter</span> Protein-coding gene in the species Homo sapiens

The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.

<span class="mw-page-title-main">Entacapone</span> Chemical compound

Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of Parkinson's disease. Entacapone together with levodopa and carbidopa allows levodopa to have a longer effect in the brain and reduces Parkinson's disease signs and symptoms for a greater length of time than levodopa and carbidopa therapy alone.

<span class="mw-page-title-main">Tolcapone</span> Chemical compound

Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.

Catechol-<i>O</i>-methyltransferase inhibitor

A catechol-O-methyltransferase(COMT) inhibitor is a drug that inhibits the enzyme catechol-O-methyltransferase. This enzyme methylates catecholamines such as dopamine, norepinephrine and epinephrine. It also methylates levodopa. COMT inhibitors are indicated for the treatment of Parkinson's disease in combination with levodopa and an aromatic L-amino acid decarboxylase inhibitor. The therapeutic benefit of using a COMT inhibitor is based on its ability to prevent the methylation of levodopa to 3-O-methyldopa, thus increasing the bioavailability of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.

In genetics, rs6311 is a gene variation—a single nucleotide polymorphism (SNP)—in the human HTR2A gene that codes for the 5-HT2A receptor. 5-HT2A is a neuroreceptor, and several scientific studies have investigated the effect of the genetic variation on personality, e.g., personality traits measured with the Temperament and Character Inventory or with a psychological task measuring impulsive behavior. The SNP has also been investigated in rheumatology studies.

Rs6265, also called Val66Met or G196A, is a gene variation, a single nucleotide polymorphism (SNP) in the BDNF gene that codes for brain-derived neurotrophic factor.

<span class="mw-page-title-main">Carbidopa/levodopa/entacapone</span> Anti Parkinson medicine

Carbidopa/levodopa/entacapone, sold under the brand name Stalevo among others, is a dopaminergic fixed-dose combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease.

In genetics, rs4680 (Val158Met) is a genetic variant. It is a single nucleotide polymorphism (SNP) in the COMT gene that codes catechol-O-Methyltransferase. The single nucleotide substitution between G--> A results in an amino acid change from valine to methionine at codon 158.

Sophia Frangou is a professor of psychiatry at the Icahn School of Medicine at Mount Sinai where she heads the Psychosis Research Program. She is a Fellow of the Royal College of Psychiatrists and vice-chair of the RCPsych Panamerican Division. She is a Fellow of the European Psychiatric Association (EPA) and of the American Psychiatric Association (APA). She served as vice-president for Research of the International Society for Bipolar Disorders from 2010 to 2014. She has also served on the Council of the British Association for Psychopharmacology. She is founding member of the EPA NeuroImaging section and founding chair of the Brain Imaging Network of the European College of Neuropsychopharmacology. She is one of the two Editors of European Psychiatry, the official Journal of the European Psychiatric Association.

The causes of schizophrenia that underlie the development of schizophrenia, a psychiatric disorder, are complex and not clearly understood. A number of hypotheses including the dopamine hypothesis, and the glutamate hypothesis have been put forward in an attempt to explain the link between altered brain function and the symptoms and development of schizophrenia.

The C957T gene polymorphism is a synonymous mutation located within the 957th base pair of the DRD2 gene. This base pair is located in exon 7. Most synonymous mutations are silent. However, the C957T mutation is an exception to this rule. While the 957C allele codes for the same polypeptide as the 957T allele, the conformation of 957T messenger RNA differs from the conformation of 957C messenger RNA. 957T messenger RNA is less stable and more prone to degradation. Dopamine D2 receptor expression is increased among individuals who carry the 957T allele compared to individuals who carry the 957C allele.

3-<i>O</i>-Methyldopa Chemical compound

3-O-Methyldopa (3-OMD) is one of the most important metabolites of L-DOPA, a drug used in the treatment of the Parkinson's disease.

The genetic influences of post-traumatic stress disorder (PTSD) are not understood well due to the limitations of any genetic study of mental illness; in that, it cannot be ethically induced in selected groups. Because of this, all studies must use naturally occurring groups with genetic similarities and differences, thus the amount of data is limited. Still, genetics play some role in the development of PTSD.

<span class="mw-page-title-main">Catechol estrogen</span>

A catechol estrogen is a steroidal estrogen that contains catechol (1,2-dihydroxybenzene) within its structure. The catechol estrogens are endogenous metabolites of estradiol and estrone and include the following compounds:

<span class="mw-page-title-main">Opicapone</span> Chemical compound

Opicapone, sold under the brand name Ongentys, is a medication which is administered together with levodopa in people with Parkinson's disease. Opicapone is a catechol-O-methyltransferase (COMT) inhibitor.

References

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  44. ↑ 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. 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.

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