O-methylation of catechol

Nagai, M., Conney, A.H., and Zhu, B.T., Strong inhibitory effects of common tea catechins and bioflavonoids on the O-methylation of catechol estrogens catalyzed by human Ever cytosolic catechol-O-methyltransferase, Drug Metab. Dispos., 32,497, 2004. 

Table 3. Influence of samarium phosphate calcination temperature on selectivity in O-methylation of catechol...

Catechol-O-Methyltransferase. Figure. 1 The basic function of COMT. Enzymatic O-methylation of the catechol substrate to 3-methoxy (major route) or 4-methoxy (minor route) products in the presence of Mg2+ and S-adenosyl-methionine (AdoMet). 

Brossi, A. 1991. Mammalian alkaloids Conversion of tetrahydroisoquinoline-1-carboxylic acids derived from Dopamine. Planta Medica, 57 S93-S100 and, Xe, X. S., Tadic, D Brzostowska, M Brossi, A., Bell, M. and Creveling, C. 1991. Mammalian alkaloids - Synthesis and O-methylation of (S)-3 -hydroxycoclaurine and R-3 -hydroxycoclaurine and their N-methylated analogs with S-adenosyl-L-[methyl-C-14]methionine in presence of mammalian catechol O-methyltransferase. Helvetica Chimica Acta, 74 1399-1411. 

Axelrod, Julius, and Robert Tomchick. 1958. "Enzymatic O-Methylation of Epinephrine and Other Catechols." Journal of Biological Chemistry 233 702-5. 

Further details of the pathways for the degradation of PAFIs are described in Chapter 6, Section 6.2.1 and in a review (Neilson and Allard 1998). It seems that most of the degradative enzymes are inducible, and this is consistent with the fact that most strains have been isolated after specific enrichment with the xenobiotic. The case of the partially constitutive synthesis of catechol 1,2-dioxygenase in the yeast Trichosporon cutaneum (Shoda and Udaka 1980) has been noted (Section 4.5.2). In the case of biotransformation, however, there are sporadic examples of the constitutive synthesis of enzymes. For example, the system carrying out the O-methylation of halogenated phenolic compounds was apparently constitutive (Neilson et al. 1988) this observation is consistent with the isolation of the strains by enrichment with Q compounds structurally unrelated to the halogenated substrates. The O-methylation reaction may function primarily as a detoxification system, so that in this case constitutive synthesis of the enzyme would clearly be advantageous to the survival of the cells. 

A number of methyltransferases are able tc methylate small molecules (46,47). Thus, re. actions of methylation fulfill only two of the three criteria defined above, because the methyl group is small compared with the substrate. The main enzyme responsible for O-methylation is catechol 0-methyltransferas (EC 2.1.1.6 COMT), which is mainly cytosolic but also exists in membrane-bound form. Several enzymes catalyze reactions of xenobiotic N-methylation with different substrate specificities, e.g., nicotinamide iV-methyltrans-ferase (EC 2.1.1.1), histamine methyltrans-ferase (EC 2.1.1.8), phenylethanolamine N-methy 1 transferase (noradrenal ine A-meth-yltransferase EC 2.1.1.28), and nonspecific amine N-methyltransferase (arylamine N-methyltransferase, tryptamine JV-methyl-transferase EC 2.1.1.49) of which some isozymes have been characterized. Reactions of xenobiotic S-methylation are mediated by the membrane-bound thiol methyltransferase (EC 2.1.1.9) and the cytosolic thiopurine methyltransferase (EC 2.1.1.67) (3). 

The study of O-methylation of phenol as well as 1,4-dihydroxybenzene in anisole and 4-methoxyphenol respectively and the condensation of catechol with ethylene glycol demonstrates that the use of LaP04, Cs2HP04 as a catalyst is a powerfull methodology to selectively access numerous alkylarylethers. Results are presented in Table 5. 

Zhu, B. T., Ezell, E. L., and Liehr, J. G. 1994. Catechol-O-methyltransferase-catalyzed rapid O-methylation of mutagenic flavonoids—Metabolic inactivation as a possible reason for their lack of carcinogenicity in-vivo. J. Biol. Chem. 269 292-99. 

A20. Axelrod, J., O-methylation of epinephrine and other catechols in vitro and in vivo. Science 126, 400 (1957). 

S-methyl group to one of the two hydroxyl groups of a catechol to give a methylated catechol and 5-adenosyl-L-homocysteine, Figure 8. Catechol 0-methyltransferase is a monomeric enzyme that catalyzes the O-methylation of a variety of catecholamine neurotransmitters such as dopamine. It requires magnesium ions [42], and the rate-determining step appears to be transfer of the methyl group [43, 44],... 

FIGURE 20-7 Pharmacological preservation of L-DOPA and striatal dopamine. The principal site of action of inhibitors of catechol-O-methyltransferase (COMT) (such as tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of levodopa (l-DOPA) and increase the fraction of the drug available for delivery to the brain. Tolcapone also has effects in the CNS. Inhibitors of MAO-B, such as low-dose selegiline and rasagiline, will act within the CNS to reduce oxidative deamination of DA, thereby enhancing vesicular stores. AAD, aromatic L-amino acid decarboxylase DA, dopamine DOPAC, 3,4-dihydroxyphenylacetic acid MAO, monoamine oxidase 3MT, 3-methoxyl-tyramine 3-O-MD, 3-O-methyl DOPA. 

O-Methylation of xenobiotic catechols occurs preferentially at the meta position, L-dopa and isoproterenol being classical examples. Frequently 0-methylation is a late event in the metabolism of aryl groups, after they have been oxidized to catechols. Thus the anti-inflammatory drug diclofenac yields in humans 3 -hydroxy-4 -methoxy-diclo-fenac as the major metabolite with a very long plasmatic half-life. Noncatechol diphenols are not subject to methylation, e.g. terbutaUne. A few monophenols can also undergo methylation to a limited extent. 

Axelrod, J. and Tomchick, R., Enzymatic O-methylation of epinephrine and other catechols, J. Biol. Chem. 233, 702 (1958). 

The action of catechol O-methyl transferase might be a central metabolic event after the absorption of free caffeic acid or some of its metabolites with a still intact catechol moiety, such as dihydrocaffeic acid or protocatechuic acid. In most studies administering chlorogenic acid or preparations rich in caffeic acid derivatives (i.e., coffee), only 0-methylated metabolites but no metabolites with an intact catechol group were detected in urine, supporting the central role of 0-methylation of caffeic acid post absorption [6,17,18]. Studying the O-methylation of caffeic acid in vitro by using rat or rabbit liver slices or preparations of liver, both possible O-methylation products, ferulic and iso-femlic acids, were formed, and a meta/para ratio of 2.8 1 was recorded [13]. In addition, the ability to reduce the residual double bond was also observed in vitro with rat or rabbit liver slices [10]. 

However, the O-methylation of the catechol group seems to influence the rate of absorption of ferulic acid compared to that of caffeic acid. In rats 10.5 2.5% of an oral administered dose of 50 mg/kg was recovered in urine, approximately 50% as the free acid and the other 50% conjugated with... 

Dopamine is formed within the brain from both L-dopa and l-3-O-methyldopa, but the latter is probably demethylated first. Administration of either amino acid to man or to animals [487, 494,499] enhances brain levels of dopamine and noradrenaline, and of their O-methylated metabolites, the former effect being further enhanced by monoamine oxidase inhibitors and inhibitors of catechol 0-methyl transferase. Cerebral 3-O-methyldopamine arises by methylation of dopamine rather than by decarboxylation of L-3-O-methyldopa, while the increases in cerebral and urinary homovanillic acid levels after L-dopa arise by oxidative deamination and 3-O-methylation of dopamine formed at the periphery and the neuron. The accumulation of the long-lived amino acid, L-3-O-methyldopa, in the brain, and its slow conversion to dopamine, may well explain why the therapeutic effects of L-dopa in Parkinsonism disappear only slowly upon discontinuation of treatment. Indeed, preliminary studies in man [494] indicate that l-3-O-methyldopa exerts a therapeutic action in Parkinsonism without the com-comitant side effects normally associated with L-dopa therapy. The relevant information regarding the fate and mode of action of L-dopa in the central nervous system is summarised in Figure 5.8. 

COMT catalyses the O-methylation of a wide variety of catechol compounds, even those with long or bulky side chains. At neutral pH in vitro the en me preferentially O-methylates catecholamines in the meta- position, because of the nucleophilic nature of that hydroxyl group. At higher pH values, howevn, O-methylation also occurs on the para- position. The extent of pora-O-methylation of any particular catechol substrate depends upon the nucleophilic character of the hydroxyl groups. For example, at pH 8-2. 3.4-dihydroxyacetophenone, which possesses a strongly nucleophilic para- hydroxyl, yields about 56% of the p-O-methylated derivative, whereas DA at this pH yields only about 10% of the p-O-methylated metabolite. In vivo almost all of the catabolites derived from the action of COMT on catecholamines are m-O-methylated. COMT will not catalyse the formation of 3,4-dimethoxy metabolites from catecholamines or from their p- or m-O-methylated derivatives. 

O-methylation. Substrates for O-methylation are catechols, iodophenols. and hydroxyindoles. The enzymes are found in the soluble fraction of liver and other tissues and utilize S-adenosylmethionine as a methyl donor (see also p. 278) ... 

COMT O-methylates catecholamines and other compounds having a catechol structure including catecholoestrogens (Fig. 2). The two isoforms of... 

Second generation COMT inhibitors were developed by three laboratories in the late 1980s. Apart from CGP 28014, nitrocatechol is the key structure of the majority of these molecules (Fig. 3). The current COMT inhibitors can be classified as follows (i) mainly peripherally acting nitrocatechol-type compounds (entacapone, nitecapone, BIA 3-202), (ii) broad-spectrum nitrocatechols having activity both in peripheral tissues and the brain (tolcapone, Ro 41-0960, dinitrocatechol, vinylphenylk-etone), and (iii) atypical compounds, pyridine derivatives (CGP 28014,3-hydroxy-4-pyridone and its derivatives), some of which are not COMT inhibitors in vitro but inhibit catechol O-methylation by some other mechanism. The common features of the most new compounds are excellent potency, low toxicity and activity through oral administration. Their biochemical properties have been fairly well characterized. Most of these compounds have an excellent selectivity in that they do not affect any other enzymes studied [2,3]. 

Catechol-O-Methyltransferase. Figure 3 Chemical structures of some inhibitors of catechol O-methylation. 

Mannisto PT, Kaakkola S (1999) Catechol-O-methyl-transferase (COMT). Biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 51 593-628... 

Just as the synthesis of DA and NA is similar so is their metabolism. They are both substrates for monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). In the brain MAO is found in, or attached to, the membrane of the intraneuronal mitochondria. Thus it is only able to deaminate DA which has been taken up into nerve endings and blockade of DA uptake leads to a marked reduction in the level of its deaminated metabolites and in particular DOPAC. The final metabolite, homovanillic... 

After reuptake into the cytosol, some noradrenaline may be taken up into the storage vesicles by the vesicular transporter and stored in the vesicles for subsequent release (see above). However, it is thought that the majority is broken down within the cytosol of the nerve terminal by monoamine oxidase (MAO ECl.4.3.4). A second degradative enzyme, catechol-O-methyl transferase (COMT EC2.1.1.6), is found mostly in nonneuronal tissues, such as smooth muscle, endothelial cells or glia. The metabolic pathway for noradrenaline follows a complex sequence of alternatives because the metabolic product of each of these enzymes can act as a substrate for the other (Fig 8.8). This could enable one of these enzymes to compensate for a deficiency in the other to some extent. 

The deamination of DA to DOPAC can be prevented by MAOb inhibitors such as selegiline while COMT inhibitors stop its further o-methylation to HVA and the conversion of dopa to OMD. COMT inhibitors can act just peripherally (entacapone) or in the CNS as well (tolcapone). DD — dopa decarboxylase MAO—monoamine oxidase COMT—catechol-o-methyl transferase... 

Catechol-O-methyltransferase (COMT EC 2.1.1.6) is located in many tissues and catalyzes the methylation of polyphenols. The methylation is a well-established pathway in the metabolism of flavonoids such as those that undergo 3, 4 -dihydrox-ylation of ring B excreted as 3 -0-methyl ether metabohtes in rat bile. " Recently, the apparent methylation of both cyanidin-3-glucoside and cyanidin-3-sambubioside (cyanidin is an anthocyanin with a 3, 4 -dihydroxylation of ring B) to peonidin-3-glucoside and peonidin-3-sambubioside was reported in humans. In rats, this transformation occurred mainly in the liver and was catalyzed by COMT."°... 

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