Catechol-o-methyl-transferase

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. 

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

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. 

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. 

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...

Degradation of catecholamines The catecholamines are inacti vated by oxidative deamination catalyzed by monoamine oxidase (MAO), and by O-methylation carried out by catechol-O-methyl-transferase (COMT, Figure 21.15). The two reactions can occur in either order. The aldehyde products of the MAO reaction are axi dized to the corresponding acids. The metabolic products of these reactions are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine. 

Not only is NE created by enzymes, but it can also be destroyed by enzymes (Fig. 5 — 18). Two principal destructive enzymes act on NE to turn it into inactive metabolites. The first is MAO, which is located in mitochondria in the presynaptic neuron and elsewhere. The second is catechol-O-methyl transferase (COMT), which is thought to be located laigely outside of the presynaptic nerve terminal (Fig. 5—18). 

FIGURE 5—32. Dopamine (DA) is destroyed by the same enzymes that destroy norepinephrine (see Fig. 5 — 18), namely monoamine oxidase (MAO) and catechol-O-methyl-transferase (COMT). The DA neuron has a presynaptic transporter (reuptake pump), which is unique to the DA neuron but works analogously to the NE transporter (Fig. 5-18). 

Figure 6.2 Immunocytochemical detection of catechol-O-methyl transferase (COMT) in human umbilical vein endothelial cells (HUVEC). Polyclonal COMT antibody from Chemicon Millipore, USA. (From Kravets E. [2008].)...

---