Catechol-0-methyltransferase enzyme

Karhunen T, Tilgmann C, Ulmanen I, Julkunen I, Panula P (1994) Distribution of catechol-0-methyltransferase enzyme in rat tissues. J Histochem Cytochem 42 1079-1090... 

A potential factor affecting the catalytic power of enzyme-catalyzed reactions in which the enzyme forces the attacking moiety into the valence shell of the entity under attack. Compression is thought to be manifested in the transition state complex. The results of kinetic isotope effect measurements have suggested that compression events factor in the catechol methyltransferase re-actionh... 

As part of their program of study of neuroamine metabolism in mammals, Davis and co-workers investigated the biotransformations of nor-laudanosoline (87) by rat liver and by brain preparations. They were successful in isolating a catechol O-methyltransferase enzyme system from rat liver which performed methylations of 87 to give two unidentified products (94) and later they obtained soluble enzyme preparations from rat brain and liver which, in the presence of [14C]methyl-5 -adenosylmethio-nine, gave three radioactive metabolites identified by mass spectral analysis as 90, 93, and a ring A monomethyl derivative of 93 (95, 96). 

Sipila J, Taskinen J. CoMFA modeling of human catechol O-methyltransferase enzyme kinetics. / Chem Inf Comput Sci 2004 44 97-104. 

Also obtained from 3,4-dihydroxy-5-tert-butylacetophenone in propylene glycol by incubation for 2 h at 37° with 0.5 M phosphate buffer (pH = 7.9), 0.5 M magnesium chloride, S-adenosylmethionine and catechol O-methyltransferase (enzyme). This enzyme solution was prepared from the blood of an adult male rat [1952]. 

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

Catechol O-methyltransferase (COMT) is a widespread enzyme that catalyzes the transfer of the methyl group of S-adenosyl-l-methionine (AdoMet) to one of the phenolic group of the catechol substrate (Fig. 1). High COMT activity is found in the liver, kidney and gut wall... 

These drugs are thought to prolong the effect of levodopa by blocking an enzyme, catechol-O-methyltransferase (COMT), which eliminates dopamine. When given with levodopa, the COMT inhibitors increase the plasma concentrations and duration of action of levodopa... 

Because LCEC had its initial impact in neurochemical analysis, it is not, surprising that many of the early enzyme-linked electrochemical methods are of neurologically important enzymes. Many of the enzymes involved in catecholamine metabolism have been determined by electrochemical means. Phenylalanine hydroxylase activity has been determined by el trochemicaUy monitoring the conversion of tetrahydro-biopterin to dihydrobiopterin Another monooxygenase, tyrosine hydroxylase, has been determined by detecting the DOPA produced by the enzymatic reaction Formation of DOPA has also been monitored electrochemically to determine the activity of L-aromatic amino acid decarboxylase Other enzymes involved in catecholamine metabolism which have been determined electrochemically include dopamine-p-hydroxylase phenylethanolamine-N-methyltransferase and catechol-O-methyltransferase . Electrochemical detection of DOPA has also been used to determine the activity of y-glutamyltranspeptidase The cytochrome P-450 enzyme system has been studied by observing the conversion of benzene to phenol and subsequently to hydroquinone and catechol... 

A common way to benefit from the ability to combine different molecular orbital methods in ONIOM is to combine a DFT or ab-initio description of the reactive region with a semi-empirical treatment of the immediate protein environment, including up to 1000 atoms. Due to the requirement for reliable semi-empirical parameters, as discussed in Section 2.2.1, this approach has primarily been used for non-metal or Zn-enzymes. Examples include human stromelysin-1 [83], carboxypeptidase [84], ribonucleotide reductase (substrate reaction) [85], farnesyl transferase [86] and cytosine deaminase [87], Combining two ab-initio methods of different accuracy is not common in biocatalysis applications, and one example from is an ONIOM (MP2 HF) study of catechol O-methyltransferase [88],... 

The primary mechanism used by cholinergic synapses is enzymatic degradation. Acetylcholinesterase hydrolyzes acetylcholine to its components choline and acetate it is one of the fastest acting enzymes in the body and acetylcholine removal occurs in less than 1 msec. The most important mechanism for removal of norepinephrine from the neuroeffector junction is the reuptake of this neurotransmitter into the sympathetic neuron that released it. Norepinephrine may then be metabolized intraneuronally by monoamine oxidase (MAO). The circulating catecholamines — epinephrine and norepinephrine — are inactivated by catechol-O-methyltransferase (COMT) in the liver. 

Catechol-O-methyltransferase (COMT) An enzyme that inactivates dopamine and noradrenaline. 

The catecholamine may then be inactivated through methylation of the meta-hydroxyl group catalyzed by the enzyme catechol-O-methyltransferase. Also, an agent may interfere with reuptake... 

Two enzymes are concerned in the metabolism of catecholamines, namely monoamine oxidase, which occurs mainly intraneuronally, and catechol-O-methyltransferase, which is restricted to the synaptic cleft. The importance of the two major forms of monoamine oxidase, A and B, will be considered elsewhere. 

The process of oxidative deamination is the most important mechanism whereby all monoamines are inactivated (i.e. the catecholamines, 5-HT and the numerous trace amines such as phenylethylamine and tryptamine). Monoamine oxidase occurs in virtually all tissues, where it appears to be bound to the outer mitochondrial membrane. Whereas there are several specific and therapeutically useful monoamine oxidase inhibitors, inhibitors of catechol-O-methyltransferase have found little application. This is mainly due to the fact that at most only 10% of the monoamines released from the nerve terminal are catabolized by this enzyme. The main pathways involved in the catabolism of the catecholamines are shown in Figure 2.16. 

At a concentration of 6-3 mM, guanethidine had no effect on catechol-0-methyltransferase [440]. No other guanidines appear to have been tested against this enzyme. In contrast, the inhibition by guanidines of monoamine oxidase, the other important enzyme involved in noradrenaline destruction, has been... 

The effect of released norepinephrine wanes quickly, because approx. 90% is actively transported back into the axoplasm, then into storage vesicles (neuronal re-uptake). Small portions of norepinephrine are inactivated by the enzyme catechol-0-methyltransferase (COMT, present in the cytoplasm of postjunctional cells, to yield normeta-nephrine), and monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells, to yield 3,4-dihydroxymandelic acid). 

Other Proteins The ouabain-binding site on (Na /K -adenosine-5 -triphosphatase, 46, 523 penicillin isocyanates for /3-lactamase, 46, 531 active site-directed addition of a small group to an enzyme the ethylation of ludferin, 46, 537 mandelate racemase, 46, 541 d imethylpyrazole carboxamidine and related derivatives, 46, 548 labeling of catechol O-methyltransferase with N-haloace-tyl derivatives, 46, 554 affinity labeling of binding sites in proteins by sensitized photooxidation, 46, 561 bromocolchicine as a iabei for tubuiin, 46, 567. 

Either hydroxyl group of catechol can be methylated by catechol O-methyltransferase, albeit at different rates (/.c., the enzyme does not exhibit absolute regiospecifi-city). The / cat value for the 3-hydroxyl group is about 1 s whereas that at the 4-position is about 0.1 or 0.2 s b The mechanism has been reported to be ordered with SAM binding first, followed by magnesium ion, and then catechol. Interestingly, it appears that the rate-limiting step is the actual catalytic event. 

Adrenaline and noradrenaline are unstable in aqueous solution where they are subjected to spontaneous oxidation. In vivo this mechanism is only relevant under pathophysiological conditions of an catecholamine excess, since two enzymes, the catechol-O-methyltransferase (COMT) and the monoamineoxidase (MAO), inactivate physiological amounts of the transmitters. There are at least two subtypes of the enzyme MAO, A and B, which can be inhibited selectively for therapeutic purposes, for example by moclobemide and selegiline. 

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... 

The second most important mechanism for removing norepinephrine from the synapse is the escape of neuronally released norepinephrine into the general circulation and its metabolism in the Uver. The liver has two enzymes that perform this function catechol-O-methyltransferase (COMT) and MAO. 

Mechanism of Action An antiparkinson agent that inhibits the enzyme catechol-O-methyltransferase (COMT), potentiating dopamine activity and increasing the duration of action of levodopa. Therapeutic Effect Relieves signs and symptoms of Parkinson s disease. 

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