Catecholamines O-methylated

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

It is generally aeeepted that COMT is an extraeellular enzyme in the CNS that catalyses the transfer of methyl groups from S-adenylmethionine to the meta-hydroxy group of the eateehol nueleus. Until recently the only inhibitors of this enzyme were pyragallol and eateehol whieh were too toxic for clinical use. Now other inhibitors have been developed, e.g. entaeapone and tolcapone, but these are used mainly to protect dopa (also a catecholamine) from O-methylation, in the treatment of Parkinson s disease (Chapter 15). 

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. 

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. 

Changes in catecholamines and 3-O-methyl metabolite concentrations in human plasma Erythropoietin in pharmaceutical products 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, amphetamine, and methamphetamine in rat urine Azoxystrobin, kresoxim-methyl, and trifloxystrobin fungiddes ... 

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. 

Most hormones have a half-life in the blood of only a few minutes because they are cleared or metabolized very rapidly. The rapid degradation of hormones allows target cells to respond transiently. Polypeptide hormones are removed from the circulation by serum and cell surface proteases, by endocytosis followed by lysosomal degradation, and by glomerular filtration in the kidney. Steroid hormones are taken up by the liver and metabolized to inactive forms, which are excreted into the bile duct or back into the blood for removal by the kidneys. Catecholamines are metaboli-cally inactivated by O-methylation, by deamination, and by conjugation with sulfate or glucuronic acid. 

Two important pathways for catecholamine metabolism are O-methylation by COMT, which is cytoplasmically localized, and oxidative deamination by the mitochondrial localized enzyme MAO. There are large amounts of MAO in tissues such as the liver and the heart which are responsible for the removal of most of the circulating monoamine, including some taken in from the diet. Tyramine is found in bigb concentrations in certain foods such as cheese, and in wine. Normally, this tyramine is deaminated in the liver. However, if MAO is inhibited, the tyramine may then be converted into octopamine [104-14-57] which may indirecdy cause release of NE from nerve terminals to cause hypertensive crisis. Thus MAO, which is rdatively nonspecific, plays an important role in the detoxification of pharmacologically active amines ingested from the diet. 

Nakamura, H. and Pisano, J.J., Specific detection of primary catecholamines and their 3-O-methyl derivatives on thin-layer plates using a fluorigenic reaction with fluorescamine, J. Chromatogr., 154, 51, 1978 Chem. Abs., 89, 117958x, 1978. 

Dihydroxyphenylalanine (DOPA) (99) is produced by tyrosine hydroxylase-catalyzed hydroxylation of Tyr. Recent interest in the use of [18F]-6-F-DOPA (100) as a PET scanning agent for regional dopaminergic brain function is based on its conversion, in the brain, to [,8F]-6-F-dopamine (101)161. The fact that fluorine in the 6-position of DOPA, dopamine and other catecholamines retards methylation by catechol-O-methyl transferase presumably increases the biological half-life of the tracer. In contrast, fluorine in the 5-position increases the rate of methylation162. 

Catecholamines can be variously oxidized or methylated. Extracellular epinephrine is O-methylated [via liver catechol-O-methyltransferase (COMT)] to 3-methoxyepinephrine (metanephrine) which can thence be oxidized [via monoamine oxidase (MAO)] to 3-methoxy-4-hydroxy-mandelic aldehyde and thence to 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxy-mandelic. acid (VMA). Similarly, extracellular norepinephrine is O-methylated [via liver COMT] to 3-methoxynorepinephrine (normetanephrine) which can be oxidized [via MAO] to 3-methoxy-4-hydroxy-mandelic... 

Methylation is a common feature of the metabolism of phenols and A-heterocyclic compounds. Thus, phenolic steroids, adrenaline, and some other catecholamines undergo O-methylation, while pyridine, nicotinic acid, and normorphine undergo N-methylation. The reaction occurs under the influence of 5-adenosylmethionine and a non-specific methyl transf erase. 

Norepinephrine (NE), a catecholamine, was first identified as a neurotransmitter in 1946. In the peripheral nervous system, it is found as a neuro transmitter in the sympathetic postganglionic synapse. NE is synthesized by the enzyme dopamine-p-hydroxylase (DbH) from the precursor dopamine (which is derived from tyrosine via DOPA). The rate-limiting step is the production of DOPA by tyrosine hydroxylase, which can be activated through phosphorylation. NE is removed from the synapse by two mechanisms (1) catechol-O-methyl-transferase (COMT), which degrades intrasynaptic NE, and (2) the norepinephrine transporter (NET), the primary way of removing NE from the synapse. Once internalized, NE can be degraded by the intracellular enzyme monoamine oxidase (MAO). 

Methionine, USP. An adequate diet should provide the methionine ncccs.sary for normal metabolism in the human.. Viethionine is considered an essential amino acid in humans. It is the precursor in the biosynthesis of -adcnosylnie(hio-niiic, which is an important methylating coenzyme involved In a variety of methylations (e.g.. N-me(hyla(ion of norepinephrine to form epinephrine and O-methylation of catecholamines catalyzed by ca(cchul-CI-mcthyl(iansfcra.ses). Adenosylmcthionine also participates in the methylation of pho.sphatidylcthanolaininc to form phosphatidylcholine, but this pathway is not efficient enough to provide all of the choline required hy higher animals hence, adequate dietary availability of choline is ncces.sary. ... 

Discovery. The majority of both old and new antidepressants act by virtue of their ability to inhibit monoamine transporter mechanisms in the brain. The concept that neurotransmitters are inactivated by uptake of the released chemical into the nerve terminal from which it had been released or into adjacent cells is less than 40 years old. Before this it was generally assumed that the inactivation of norepinephrine and the other monoamine neurotransmitters after their release from nerves was likely to involve rapid enzymatic breakdown, akin to that seen with acetylcholinesterase. The degradation of monoamines by the enzyme monoamine oxidase vas known early on, and in the 1950s a second enzyme catechol-O-methyl transferase (COMT) vas discovered and was thought to play a key role in inactivating norepinephrine and other catecholamines. 

Chan YP, Siu TS. Simultaneous quantitation of catecholamines and O-methylated metabolites in urine by isocratic ion-pairing high-performance liquid chromatography with amperometric detection. J Chromatogr 1988 459 251-60. 

Waldmeier PC, Antonin KH, Feldtrauer JJ, Grunenwald C, Paul E, Lauber J, Bieck P. Urinary excretion of O-methylated catecholamines, tyramine and phenyl-ethylamine by volunteers treated with tranylcypromine and CGP 11305 A. Eur J Clin Pharmacol 1983 25 361-8. 

In rabbit p-OH-phenylacetate major metab. Also, (3-oxid., oxid. deam., m-hydrox. and m-O-methyl. important finding depending on sequence, octoparaine (approx. 1%) and/or catecholamines are formed (l4). 

T. Oeltmann, R. Carson, J.R. Shannon, T. Ketch and D. Robertson, Assessment of O-methylated catecholamine levels in plasma and urine for diagnosis of autonomic disorders, Auton. Neurosci., 116, 1-10 (2004). 

Figure 9-1. Biosynthesis of catecholamines. Denotes enzyme in transformation AADC = aromatic L-amino acid decarboxylase COMT = catechol-o-methyl transferase DBH = dopamine-B-hydroxylase MAO = monoamine oxidase PNMT = phenylethanolamine-N-methyl transferase TH = tyrosine hydroxylase.

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