DEFINITION
Catechol-O-methyltransferase - COMT is one of several enzymes (EC=2.1.1.6) that degrade catecholamines 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 may play an important role in the pathophysiology of different human disorders including estrogen-induced cancers, Parkinson’s disease, depression, and hypertension, because the substrates of COMT are catechol estrogens (e.g., carcinogenic 4-hydroxyestradiol), indolic intermediates in melanin metabolism, xenobiotic catechols (e.g., carcinogenic flavonoids), catechol neurotransmitters (e.g., dopamine and noradrenaline), and drugs (e.g., levodopa)
Characterization and Implications of Estrogenic Down-Regulation of Human Catechol-O-Methyltransferase Gene Transcription1, 1999
TOMT (Transmembrane O-methyltransferase, Catechol O-methyltransferase 2 is a different gene that encodes a protein with the same enzymatic activity of COMT (EC=2.1.1.6)
THE GENES
Polymorphism
The gene COMT is associated with allelic variants. The best-studied is Val158Met.
Two codominant alleles (G and A) in exon 4 of the COMT gene influence the amino acid structure (Val or Met) at codon 158. The COMT enzyme activity is genetically polymorphic with a trimodal distribution (high activity in Val/Val genotype, intermediate activity in Val/Met genotype, and low activity in Met/Met genotype). The difference in COMT activity is three to four-fold (Val/Val vs Met/Met). The COMT enzyme is thermostable in Val/Val genotype and thermolabile in Met/Met homozygotes.
The Val158Met polymorphism of the COMT gene is functional, easily detectable, and significantly related to metabolism of catecholamines, which underlie pathogenesis of many mental disorders.
The lower rates of catabolisis for the Met allele results in higher synaptic dopamine levels following neurotransmitter release, ultimately increasing 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 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.
Role of the COMT gene Val158Met polymorphism in mental disorders: a review. 2007
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
COMT_HUMAN
- MB-COMT n= 271
- S-COMT (lacks the first 50 N-terminal aminoacids) n= 221
!-50 = L 36%
"TOMT_HUMAN":
- Primary structure
- Secondary structure
- Tertiary structure
!!http://upload.wikimedia.org/wikipedia/commons/thumb/4/4b/Catechol-O-methyl_transferase_3bwm.png/250px-Catechol-O-methyl_transferase_3bwm.png!
!
** PDB
* Quaternary structure
Protein Aminoacids Percentage (Width 700 px)
SYNTHESIS AND TURNOVER
mRNA synthesis
Estrogens inhibit mRNA COMT transcription
Another reason why the COMT polymorphism is particularly interesting in anorexia nervosa is that it allows us to explore its effects in women in various conditions of exposure to estrogens. There is a role for estrogen in cognitive functioning and an influence on dopaminergic function in striatum. Estradiol is synthesized in the brain via steroidogenic enzymes localized in the brain. Estrogen functions as a multipurpose brain messenger that can interact with neurotransmitter systems at critical brain nuclei and facilitate neuronal function via gene expression and transmitter-gated ion channels. Estrogen action is mediated through estrogen receptors α and β, which are widely distributed throughout the brain and located in regions associated with cognitive functions. Receptors for estrogen have been localized in the prefrontal cortex, and have been considered to this region of the brain as the site of estrogen's effect on cognition. There are two estrogen response elements in the COMT promoter and that estrogen at physiological concentrations inhibits COMT mRNA expression in cells expressing estrogen receptors.
Since estrogen levels decrease greatly in starvation, underweight patients with anorexia nervosa represent a unique opportunity to analyze the convergence between estrogen levels and the COMT genotype.
Low levels of estrogens, like those observed in underweight women with anorexia nervosa, fail to exert their well-known inhibitory effects on COMT.
Executive functions and selective attention are favored in middle-aged healthy women carriers of the Val/Val genotype of the catechol-o-methyltransferase gene: a behavioral genetic study
2010
protein synthesis
post-translational modifications
degradation
CELLULAR FUNCTIONS
cellular localization,
There is one single gene for COMT, which codes for both soluble COMT (S-COMT) and membrane-bound COMT (MB-COMT). When S-COMT and MB-COMT polypeptides of various rat and human tissues were quantified through Western blot analysis, S-COMT was usually dominant by a factor of 3 or higher. The only exception was the human brain, where 70% of the total COMT polypeptides was MB-COMT and 30% was S-COMT. Although S-COMT and MB-COMT have identical kinetic mechanisms S-COMT and MB-COMT are certainly different enzymes, and MB-COMT is not a precursor of S-COMT.
biological function
Function
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.
Specific reactions catalyzed by COMT include:
* Dopamine → 3-Methoxytyramine
* DOPAC→ HVA (homovanillic acid)
* Norepinephrine → Normetanephrine
* Epinephrine → Metanephrine
* Dihydroxyphenylethylene glycol (DOPEG) → 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. This process is supposed to take place in postsynaptic neurons, as, in general, COMT is 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.
Source
- Cell signaling and Ligand transport
- Structural proteins
REGULATION
DIAGNOSTIC USE
