Disease relevance of Comt

• We have previously reported that methylation of catecholamines by catechol-O-methyltransferase (COMT) was attenuated in spontaneously hypertensive rats (SHR) with acute hypotension as compared with that of Wistar-Kyoto (WKY) rats [1].
• Sensitization to the generalized Shwartzman reaction by catechol-O-methyltransferase inhibitors [2].
• The amounts of monoamine oxidase, catechol-O-methyltransferase, and S-100 were also determined in surface cultures of fetal mouse brain cells, as well as glioma and neuroblastoma cell lines [3].
• Monoamine oxidase and catechol-O-methyltransferase activity in hamster and rat insulinomas [4].
• Inhibition of catechol-O-methyltransferase (COMT; EC 2.1.1.6) is a new therapeutic strategy in the treatment of Parkinson's disease [5].

Psychiatry related information on Comt

• Repeated administration of tolcapone, an inhibitor of catechol-O-methyltransferase, was able to partially restore the memory deficits caused by bilateral cholinotoxin (AF64A) lesions in the basal magnocellular nuclei of Meynert [6].
• Co-administration of catechol-O-methyltransferase inhibitors and L-DOPA/carbidopa increased the performance of rats in both tests without increasing locomotor activity [7].
• The administration of catechol-O-methyltransferase inhibitors alone changed neither the behavior of the rats in two animal models of depression, the forced swimming test (entacapone and tolcapone) or in the learned helplessness paradigm (tolcapone), nor the locomotor activity [7].
• 4. When the tissues were kept in KCl-Triton-X-100 (0.9%-0.2%) for longer periods to study time related responses, brain COMT showed progressive increases in activity up to 4 hours of treatment and the increase persisted till 24 hours [8].

High impact information on Comt

• Dexamethasone did not alter ventricular epinephrine levels but increased levels of both PNMT and catechol-O-methyltransferase, the major catabolic enzyme for epinephrine [9].
• The higher concentrations of [3H]normetanephrine and deaminated catechols indicated a faster metabolic rate of norepinephrine metabolism in hearts from diabetic rats; both monoamine oxidase and catechol-O-methyltransferase activities were also increased [10].
• Here we describe a sensitive radiochemical assay for dihydrodiol dehydrogenase in which the oxidation of benzenedihydrodiol to pyrocatechol is coupled to O-methylation catalyzed by catechol-O-methyltransferase (EC 2.1.1.6) [11].
• The data presented here indicate that use of catechol-O-methyltransferase inhibitors with L-dopa may be of value in the treatment of parkinsonian patients [12].
• In contrast, the mutagenic properties of 2-aminofluorene were not affected by COMT/SAM [13].

Chemical compound and disease context of Comt

• The generalized Shwartzman reaction (GSR) was produced by a single injection of endotoxin in male rats pretreated with catechol-o-methyltransferase (COMT) inhibitors (tropolone, pyrogallol) [2].
• Catechol-O-methyltransferase inhibition attenuates levodopa toxicity in mesencephalic dopamine neurons [5].
• Methylation by catechol-O-methyltransferase did not appear to play a major role in the inactivation of tissue catecholamines since there were no noticeable increases of normetanephrine or 3-methoxytyramine in the tissues of the rats with pheochromocytoma [14].
• Inhibition of catechol-O-methyltransferase (COMT) has protective effects on levodopa (L-DOPA), but not D-DOPA toxicity towards dopamine (DA) neurons in rat primary mesencephalic cultures [Mol. Pharmacol. 57 (2000) 589] [15].
• The accumulation of ISO when catechol-O-methyltransferase (COMT) (EC 2.1.1.6) was inhibited by 3',4'-dihydroxy-2-methylpropiophenone (U-0521) was decreased by ischemia to about 50% of the control value [16].

Biological context of Comt

• However, in the case of Comt, the Dahl-S genotype correlated with low BP [17].
• Kinetics and crystal structure of catechol-o-methyltransferase complex with co-substrate and a novel inhibitor with potential therapeutic application [18].
• One of the designed molecules was found to be a bisubstrate inhibitor of COMT with an IC50 = 2 microM [19].
• The compounds were tested for in vitro inhibitory activity against COMT obtained from rat liver, and the inhibition kinetics were examined with regard to the binding sites of cofactor and substrate [19].
• Useful structure-activity relationships were established which provide important guidelines for the design of future generations of bisubstrate inhibitors of COMT [19].

Anatomical context of Comt

• The synthesis of dopamine in tissues incubated with 500 microM L-dopa for 20 min in conditions of catechol-O-methyltransferase (Comt) inhibition was found to be in the duodenum, jejunum and ileum 2-fold that in the proximal colon, 6-fold that in the glandular stomach and 120-fold that in the non-glandular stomach and distal colon [20].
• Expression experiments in COS-7 cells using full-length COMT cDNAs showed that this alteration affected the initiation of the translation of the MB-AUG and consequently changed the relative amounts of MB- and S-COMT polypeptides produced [21].
• We examined the expression profile of catechol O-methyltransferase (COMT) mRNA and its protein in the neonatal rat hypothalamus by in situ hybridization and immunohistochemistry to clarify the sites of dopamine degradation [22].
• Neuronal expression of catechol O-methyltransferase mRNA in neonatal rat suprachiasmatic nucleus [22].
• Both the activities and the amounts of MB-COMT in the liver were lower in SHR than in WKY rats, but no such trend was found in the kidney or erythrocytes [1].

Associations of Comt with chemical compounds

• Catechol-O-methyltransferase (COMT; E.C. 2.1.1.6) is a ubiquitous enzyme in nature that plays an important role in the metabolism of catechol neurotransmitters and xenobiotics [18].
• In tests for specificity, COMT/SAM was found to react with catechols, but not with dihydrodiols, quinones, a phenol, an epoxide, or 1,4-hydroquinone [13].
• After several weeks these reaggregated brain cell cultures show markedly increased specific activities of monoamine oxidase, lactate dehydrogenase, and the brain-specific protein S-100, while catechol-O-methyltransferase activity increases slightly [3].
• The crystallographic structure of rat liver catechol O-methyltransferase was used as a template to construct a homology model for tobacco caffeoyl-coenzyme A O-methyltransferase [23].
• We administered Ro 40-7592, an inhibitor of the enzyme catechol-O-methyltransferase (COMT) that crosses the blood-brain barrier, to rats and monitored extracellular catecholamine levels in the corpus striatum before and after the intraperitoneal administration of a bolus of l-dopa [24].

Regulatory relationships of Comt

• Rat soluble catechol-O-methyltransferase cDNA was cloned into the pCAL-n-FLAG vector and expressed in Escherichia coli as a fusion protein with a calmodulin-binding peptide tag [25].

Other interactions of Comt

• The correlation analysis between genotypes of differentially expressed genes and BP in F2 rats indicated that pyridoxine 5'-phosphate oxidase (Pnpo) and catecholamine-O-methyltransferease (Comt) showed a highly significant association with BP [17].
• Effect of monoamine oxidase A and B and of catechol-O-methyltransferase inhibition on L-DOPA-induced circling behavior [26].
• In the ACI strain, a mismatch repair gene, Msh2, was preferentially expressed, at approximately 20-fold the F344 level, along with a gene encoding a detoxification enzyme, catechol-O-methyltransferase [27].
• Tyrosine hydroxylase and catechol O-methyltransferase activities were also diminished, whereas tyrosine transaminase, acid phosphatase, and monoamine oxidase activities were not affected by addition of epinephrine to the medium [28].
• A series of base- and amino acid modified analogues of S-aristeromycinyl-L-homocysteine, a carbocyclic nucleoside, were synthesized and evaluated as inhibitors of S-adenosyl-L-methionine-dependent methyltransferases, including catechol O-methyltransferase, phenylethanolamine N-methyltransferase, and histamine N-methyltransferase [29].

Analytical, diagnostic and therapeutic context of Comt

• Molecular cloning and characterization of rat liver catechol-O-methyltransferase [30].
• The presence of both membrane-bound and soluble COMT was confirmed by immunoblotting [31].
• Inhibition of catechol-O-methyltransferase by 6,7-dihydroxy-3,4-dihydroisoquinolines related to dopamine: demonstration using liquid chromatography and a novel substrate for O-methylation [32].
• The activity of hepatic COMT (substrate: catechol [5 mM] was not affected by transplantation or denervation [33].
• Catechol-O-methyltransferase (COMT) was visualized in homogenates and subcellular fractions of rat tissues, including liver and brain, by gel electrophoresis, electrophoretic transfer of proteins to nitrocellulose (Western blotting), and immune fixation with antiserum to highly purified soluble rat liver COMT [34].

References