Catechol-O-methyltransferases

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... 

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). 

Catechol-O-Methyltransferase. Figure 2 Some substrates of COMT. 

Catechol-O-Methyltransferase. Figure 4 Rat model of Parkinson s disease. Comparison of entacapone, tolcapone and CGP 28014 in the rat turning model of Parkinson s disease [4]. 

Catechol-O-Methyltransferase and its Inhibitors Anti-Parkinson Drugs... 

Catechol-O-Methyltransferases Anti-Parkinson Dtugs Antipsychotic Dtugs... 

A newer classification of antiparkinson drugs is the catechol-O-methyltransferase (COMT) inhibitors. Examples of the COMT inhibitors are entacapone (Comtan) and tolcapone (Tasmar). 

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... 

Epinephrine is administered by a variety of different routes in anaphylaxis, except for the oral route, which is not feasible because of rapid inactivation of epinephrine in the gastrointestinal tract by catechol-O-methyltransferase and monoamine oxidase [9]. The initial intramuscular epinephrine doses of 0.3-0.5 mg currently recommended for adults with anaphylaxis are low compared with the doses required for resuscitation following cardiac arrest [1, 2,4,18]. 

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."°... 

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... 

FIGURE 29-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopa decarboxylase, monoamine oxidase, and catechol-O-methyltransferase. Carbidopa does not cross the blood-brain barrier. Large, neutral amino acids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport across the brain (plasma compartment to brain compartment). Food and anticholinergics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals. 

Ach, acetylcholine CNS, central nervous system CD, carbidopa COMT, catechol-O-methyltransferase D1, a class of dopamine receptors which includes D, and D5 subtypes D2, a class of dopamine receptors which includes D2, D3, and D4 subtypes DA, dopamine LD, levodopa MAO, monoamine oxidase MD, maintenance dose NMDA, N-methyl-D-aspartate. 

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. 

Once returned to the presynaptic terminal, dopamine is repackaged into synaptic vesicles via the vesicular monoamine transporter (VMAT) or metabolized to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO). Two alternative pathways are available for dopamine catabolism in the synapse, depending on whether the first step is catalyzed by MAO or catechol-O-methyltransferase (COMT). Thus, dopamine can be either deaminated to 3,4-dihydroxyphenylacetic acid (DOPAC) or methylated to 3-methoxytyramine (3-MT). In turn, deamination of 3-MT and methylation of DOPAC leads to homovanillic acid (HVA). In humans, cerebrospinal fluid levels of HVA have been used as a proxy for levels of dopaminergic activity within the brain (Stanley et al. 1985). 

Figure 7.6 Metabolism of MDMA in humans. Abbreviations CYP2D6, cytochrome P450 2D6 CYP3A4, cytochrome P450 3A4 COMT, catechol-O-methyltransferase. (Adapted from de la Torre and co-workers.56)...

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

Fig. 24.6 Mutant allele frequencies of SNPs in distinct ethnic populations. B2AR-/I2 adrenoreceptor, COMT-catechol-O-methyltransferase. Glu27 and TPMT 3C allele frequencies were used for the B2AR and TPMTgenes, respectively.

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