Catechol-O-methyl transferase
Encyclopedia
Catechol-O-methyltransferase (COMT; ) is one of several enzyme
s that degrade catecholamine
s such as dopamine
, epinephrine
, and norepinephrine
. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene
. 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.
neurotransmitter
s (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. 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
. This process is supposed to take place in postsynaptic neurons as COMT is generally located intracellularly in the CNS .
COMT can also be found extracellularly, although extracellular COMT plays a less significant role in the CNS than it does peripherally. Despite its importance in neurons, COMT is actually primarily expressed in the liver.
The gene is associated with allelic variants.
The best-studied is Val158Met.
Others are rs737865 and rs165599 that have been studied, e.g., for association with personality traits.
to methionine
mutation at position 158 (Val158Met) rs4680
The Val variant catabolizes dopamine at up to four times the rate of its methionine counterpart, resulting in significant lower synaptic dopamine levels following neurotransmitter release, ultimately reducing dopaminergic stimulation of the post-synaptic 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 lobe
s.
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.
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. However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on schizophrenia development.
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 (Lelli-Chiesa et al., 2010)
The COMT Val158Met polymorphism also has a pleiotropic
effect on emotional processing.
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. 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. 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.
that codes for this enzyme. The O in the name stands for oxygen
, not for ortho
.
s include tolcapone
and entacapone
, which are commonly used in the treatment of Parkinson disease.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s that degrade catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
s such as dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
, and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. 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
Biochemist
Biochemists are scientists who are trained in biochemistry. Typical biochemists study chemical processes and chemical transformations in living organisms. The prefix of "bio" in "biochemist" can be understood as a fusion of "biological chemist."-Role:...
Julius Axelrod
Julius Axelrod
Julius Axelrod was an American biochemist. He won a share of the Nobel Prize in Physiology or Medicine in 1970 along with Bernard Katz and Ulf von Euler...
in 1957.
Function
Catechol-O-methyltransferase is involved in the inactivation of the catecholamineCatecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s (dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
, and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
). The enzyme introduces a methyl group to the catecholamine, which is donated by S-adenosyl methionine
S-Adenosyl methionine
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate and methionine by methionine adenosyltransferase . Transmethylation, transsulfuration, and aminopropylation are the...
(SAM). Any compound having a catechol structure, like catecholestrogens and catechol-containing flavonoids, are substrates of COMT.
Levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
, a precursor of catecholamines, is an important substrate of COMT. COMT inhibitors, like entacapone
Entacapone
Entacapone is a drug that functions as a catechol-O-methyl transferase inhibitor. It is used in the treatment of Parkinson's disease....
, 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
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
Specific reactions catalyzed by COMT include:
- DopamineDopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
→ 3-Methoxytyramine3-Methoxytyramine3-Methoxytyramine , also known as 3-methoxy-4-hydroxyphenethylamine, is a metabolite of the neurotransmitter dopamine formed by the introduction of a methyl group to dopamine by the enzyme catechol-O-methyl transferase... - DOPACDopac3,4-Dihydroxyphenylacetic acid is a metabolite of the neurotransmitter dopamine.Dopamine can be metabolized into one of three substances. One such substance is DOPAC. Another is 3-methoxytyramine . Both of these substances are degraded to form homovanillic acid...
→ HVA (homovanillic acidHomovanillic acidHomovanillic acid is a major catecholamine metabolite...
) - NorepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
→ NormetanephrineNormetanephrineNormetanephrine is a metabolite of norepinephrine created by action of catechol-O-methyl transferase on norepinephrine. It is excreted in the urine and found in certain tissues. It is a marker for catecholamine-secreting tumors such as pheochromocytoma.... - EpinephrineEpinephrineEpinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
→ MetanephrineMetanephrineMetanephrine is a metabolite of epinephrine created by action of catechol-O-methyl transferase on epinephrine. An article in the Journal of the American Medical Association, 2002, indicated that the measurement of plasma free metanephrines is the best tool in the diagnosis of pheochromocytoma, an... - Dihydroxyphenylethylene glycolDihydroxyphenylethylene glycolDihydroxyphenylethylene glycol is a metabolite of norepinephrine....
(DOPEG) → Methoxyhydroxyphenylglycol (MOPEG) - 3,4-Dihydroxymandelic acid3,4-Dihydroxymandelic acid3,4-Dihydroxymandelic acid is a metabolite of norepinephrine.-References:...
(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
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
(DAT), such as the prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
. This process is supposed to take place in postsynaptic neurons as COMT is generally located intracellularly in the CNS .
COMT can also be found extracellularly, although extracellular COMT plays a less significant role in the CNS than it does peripherally. Despite its importance in neurons, COMT is actually primarily expressed in the liver.
Genetics
The COMT protein is coded by the gene COMT.The gene is associated with allelic variants.
The best-studied is Val158Met.
Others are rs737865 and rs165599 that have been studied, e.g., for association with personality traits.
The Val158Met polymorphism
A functional single-nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyltransferase results in a valineValine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
to methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
mutation at position 158 (Val158Met) rs4680
Rs4680
In genetics, rs4680 is a genetic variant.It is a single nucleotide polymorphism in the COMT gene that codes catechol-O-Methyltransferase....
The Val variant catabolizes dopamine at up to four times the rate of its methionine counterpart, resulting in significant lower synaptic dopamine levels following neurotransmitter release, ultimately reducing dopaminergic stimulation of the post-synaptic 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 lobe
Frontal lobe
The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...
s.
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.
Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. 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. However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on schizophrenia development.
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
Sophia Frangou
Sophia Frangou is Reader in Psychiatry at the Institute of Psychiatry, King's College London where she heads the Neurobiology of Psychosis section. She is a Fellow of the Royal College of Psychiatrists and of the European Psychiatric Association and Vice-President for Research of the...
, Institute of Psychiatry, King's College London has demonstrated an effect of COMT both in patients with bipolar disorder and in their relatives (Lelli-Chiesa et al., 2010)
The COMT Val158Met polymorphism also has a pleiotropic
Pleiotropy
Pleiotropy occurs when one gene influences multiple phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously...
effect on emotional processing.
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. 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. 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.
Nomenclature
COMT is the name given to the geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that codes for this enzyme. The O in the name stands for oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
, not for ortho
Arene substitution patterns
Arene substitution patterns are part of organic chemistry IUPAC nomenclature and pinpoint the position of substituents other than hydrogen in relation to each other on an aromatic hydrocarbon.- Ortho, meta, and para substitution :...
.
COMT inhibitors
COMT inhibitorCOMT inhibitor
A COMT inhibitor is a drug that inhibits the action of catechol-O-methyl transferase. This enzyme is involved in degrading neurotransmitters. COMT inhibitors are used in the treatment of Parkinson's disease....
s include tolcapone
Tolcapone
Tolcapone is a drug that inhibits the enzyme catechol-O-methyl transferase . - Uses :Tolcapone is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa medication.- Chemistry :...
and entacapone
Entacapone
Entacapone is a drug that functions as a catechol-O-methyl transferase inhibitor. It is used in the treatment of Parkinson's disease....
, which are commonly used in the treatment of Parkinson disease.