Catechol-0-methyl transferase

Catechol methyl transferases require the catechol function to be present to bind to the Mg ion. In the search for p2-adrenoceptor selectivity to produce potent bron-chodilators with low cardiovascular effects, changing the 3,4-hydroxy grouping of the catechol to 3,5- or 3-hydroxyl, 4-methyl-hydroxy, proved to be important (Figure 7.25). These compounds now have much improved bioavailability and pharmacokinetics due to their resistance to catechol methyl transferases. 

Dopamine. Dopamine (DA) (2) is an intermediate in the synthesis of NE and Epi from tyrosine. DA is localized to the basal ganglia of the brain and is involved in the regulation of motor activity and pituitary hormone release. The actions of DA are terminated by conversion to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase-A and -B (MAO-A and -B) in the neuron following reuptake, or conversion to homovanillic acid (HVA) through the sequential actions of catechol-0-methyl transferase (COMT) and MAO-A and -B in the synaptic cleft. 

Guldberg HC, Marsden CA (1975) Catechol-O-methyl transferase Pharmacological aspects and physiological role. Pharmacol Rev 27 135-206... 

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... 

The principal mechanism for terminating dopamine signaling is reuptake by the presynaptic neuron via the dopamine transporter (DAT). Dopamine that is not taken up is metabolized by the enzymes monoamine oxidase (MAO) and catechol-O-methyl transferase... 

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... 

McLeod HL, Syvanen A-C, Githang a J, Indalo A, Ismai D, Dewar K et al. Ethnic differences in catechol O-methyl-transferase pharmacogenetics frequency of the codon 108/158 low activity allele is lower in Kenyan than Caucasian or South-west Asian individuals. Pharmacogenetics 1998 8 195-199. 

Gogos, J. A., Morgan, M.,Luine, V. etal. Catechol-O-methyl-transferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc. Natl Acad. Sci. U.S.A. 95 9991-9996,1998. 

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

COMT = Catechol-O-Methyl transferase MAO = Monoamine Oxidase HMMA = Hydroxy Methoxy Mandelic Acid... 

Biochemical changes in animal central nervous sterns have been reported by Skillen et who noted a decrease in brain 5-hydroxytiypt-amine (serotonin) in rats exposed to ozone at 6 ppm for 4 h, and by Trams et who observed decreases in catecholamines and catechol-O-methyl-transferase in dogs chronically exposed to ozone at 1,2, or 3 ppm. Electro-encephalographic (eeg) measurements in the same dogs were recently presented by Johnson et who noted alterations in eeg patterns at 9 months of ozone exposure, but not after 18 months of exposure. Previously, Xintaras et o/. had observed alterations in the visual evoked electric response in rats acutely exposed to 0.5-1.0 ppm. As pointed out by Johnson et it is not clear whether these findings indicate a direct neurotoxic action of ozone or are secondary to damage in other organs. 

Some biologically important o-quinones can react with the superoxide ion giving catechol derivatives, which may play a role in many diseases. For example, compounds bearing a nitro-catechol moiety have been claimed to be efficient catechol-0-methyl transferase inhibitors (Suzuki et al. 1992, Perez et al. 1992). The transferase is the first enzyme in the metabolism of catecholamine a hyperactivity of this enzyme leads to Parkinson s disease. Therefore, prediction of biological activity and antioxidant properties of quinones is an important challenge for researchers. 

Fig. 7.25 Design of beta-2 selective adrenoceptor agonists resistant to catechol O-methyl transferase (COMT).

Inhibition of the enzymes involved in dopamine degradation, catechol-amine-oxygen-methyl-transferase Lullmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

The methyl transferases (MTs) catalyze the methyl conjugation of a number of small molecules, such as drugs, hormones, and neurotransmitters, but they are also responsible for the methylation of such macromolecules as proteins, RNA, and DNA. A representative reaction of this type is shown in Figure 4.1. Most of the MTs use S-adenosyl-L-methionine (SAM) as the methyl donor, and this compound is now being used as a dietary supplement for the treatment of various conditions. Methylations typically occur at oxygen, nitrogen, or sulfur atoms on a molecule. For example, catechol-O-methyltransferase (COMT) is responsible for the biotransformation of catecholamine neurotransmitters such as dopamine and norepinephrine. A-methylation is a well established pathway for the metabolism of neurotransmitters, such as conversion of norepinephrine to epinephrine and methylation of nicotinamide and histamine. Possibly the most clinically relevant example of MT activity involves 5-methylation by the enzyme thiopurine me thy Itransf erase (TPMT). Patients who are low or lacking in TPMT (i.e., are polymorphic) are at... 

Compared to NE, the metabolism of the false neurotransmitter metaramind (MR), mediated by catechol-O-methyl transferase (COMT) and MAO, is reduced because of the absence of the catechol function and the presence of an a-methyl group, respectively (Fig. 24) [161],... 

Norepinephrine is removed from the synapse by means of two mechanisms. In the hrst, catechol-O-methyl-transferase (COMT) degrades intrasynaptic NE. In the second, the norepinephrine transporter (NET), a Na /CH-dependent neurotransmitter transporter, is the primary way of removing NE from the synapse [(4) in Fig. 2.7]. The NET is blocked selectively by desipramine and nortriptyline. Once internalized. 

FIGURE 2.7 Noradrenergic synapse. The release of norepinephrine (1) can be enhanced by compounds such as amphetamine. Once released, norepinephrine binds to a2 receptors (2a), al receptors (2b), and pi receptors (3). Norepinephrine is removed from the synapse via cleavage by catechol-O-methyl-transferase (COMT) or via reuptake by the norepinephrine transporter (4). 

Another approach to the therapy of Parkinson s disease involves the use of enzyme inhibitors. For example, inhibition of the enzyme monoamine oxidase B (MAO-B) by selegiline (4.105) improves the duration of L-DOPA therapy because it inhibits the breakdown of dopamine but not of NE. Likewise, inhibitors of catechol-O-methyl-transferase (COMT) can also be exploited as agents for the treatment of Parkinson s disease. L-DOPA and dopamine become inactivated by methylation the COMT enzyme responsible for this metabolic transformation can be clocked by agents such as entacapone (4.106) or tolcapone (4.107), allowing higher levels of L-DOPA and dopamine to be achieved in the corpus striamm of the brain. 

This reaction is catalysed by enzyme methyl-transferases (catechol-o-methyl-transferase) and generally uses S-adenosylmethionine as a methyl donor. Examples are conversion of norepi-nephrine into normetanephrine, which has less than one percent of the vasoconstrictor activity of the parent compound. 

Adrenaline is synthesised in the adrenal medulla and at sympathetic nerve endings from phenylalanine and metabolised by oxidation (monoamine oxidase MAO) or conjugation (catechol 0-methyl transferase COMT). It is excreted in the urine as vanillylmandelic acid. Its main physiological effects are at pi and a adrenoceptors, with less marked effects at (P2... 

Aksoy,., J. Klener, and Richard M. Weinshilboum. 1993. "Catechol-O-Methyl-transferase Pharmacogenetics Photoaffinity Labelling and Western Blot Analysis of Human Liver Samples." Pharmacogenetics 3 116-22. 

Scanlon, Paul D., Fredrick A. Raymond, and Richard A. Weinshilboum. 1979. "Catechol- -Methyl Transferase Thermolabile Enzyme in Erythrocytes of Subjects Homozygous for the Allele for Low Activity." Science 203 63-65. 

Weinshitboum, Richard M., and Fredrick A. Raymond. 1977. "Inheritance of Low Erythrocyte Catechol-O-Methyl Transferase Activity in Man." American Journal of Human Genetics 29 125-35. 

Fig. (15). Metabolism of dietary flavonoids. GlcA = glucuronic acid UGT - uridine 5 -diphospoglucuronosyl transferase Met = methyl Sulf = sulfate COMT = catechol-O-methyl transferase PST = phenol sulfo transferase...

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