Enzyme monoamine oxidase

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... 

Experiments of this kind have provided a great deal of evidence in favour of exocytotic release of vesicular noradrenaline. For example, by administering reserpine (which causes noradrenaline to leak out of the vesicles into the cytoplasm) together with an inhibitor of the enzyme monoamine oxidase (which will prevent metabolism of cytoplasmic noradrenaline), it is possible to redistribute the noradrenaline stored within nerve terminals because it leaks from the vesicles but is preserved within the neuronal cytoplasm. Under these conditions, the total amount of transmitter in the terminals is unchanged but impulse-evoked release rapidly diminishes. 

Figure 9.4 The synthesis and metabolism of 5-HT. The primary substrate for the pathway is the essential amino acid, tryptophan and its hydroxylation to 5-hydrox5dryptophan is the rate-limiting step in the synthesis of 5-HT. The cytoplasmic enzyme, monoamine oxidase (MAOa), is ultimately responsible for the catabolism of 5-HT to 5-hydroxyindoleacetic acid...

In contrast, iproniazid, introduced in 1951 for treatment of tuberculosis, induced euphoria and was described as a psychic energiser . In fact, these patients, when given iproniazid, could become quite disruptive and this action was regarded as an undesirable side-effect However, its beneficial effects in depression were soon recognised and it was regarded as the first effective antidepressant drug. Studies of peripheral sympathetic neurons, later extended to noradrenergic neurons in the brain, showed that iproniazid irreversibly inhibits the catalytic enzyme, monoamine oxidase (MAO). Because only cytoplasmic monoamines are accessible to MAO, inhibition of this enzyme first increases the concentration of the pool of soluble transmitter but this leads to a secondary increase in the stores of vesicle-bound transmitter i.e. the pool available for impulse-evoked release (Fillenz and Stanford 1981). 

Inside the cytoplasm of the presynaptic neuron the monoamines are exposed to the mitochondrial outer membrane-bound enzyme monoamine oxidase (MAO). MAO breaks the monoamines down into inactive metabolites before they are taken up into the vesicles. However, if MAO is inhibited, then the monoamines enter the vesicles and are available for release. MAO inhibitors, such as moclobemide, have been used in the treatment of depression, since they increase the availability of noradrenaline and serotonin. Selegiline is used for Parkinson s disease, since it raises dopamine levels. 

MAO (monoamine oxidase) inhibitor Non-selective inhibitors of the enzyme monoamine oxidase. An example is iproniazid, one of the first-generation anti-... 

The primary catabolic pathway for 5-HT is oxidative deamination by the enzyme monoamine oxidase 237 In addition to classical synaptic transmission, 5-HT may relay information by volume transmission or paracrine neurotransmission 238 5 -HT may be involved in a wide variety of behaviors by setting the tone of brain activity in relationship to the state of behavioral arousal/activity 238... 

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. 

Competitive inhibitors bind to specific groups in the enzyme active site to form an enzyme-inhibitor complex. The inhibitor and substrate compete for the same site, so that the substrate is prevented from binding. This is usually because the substrate and inhibitor share considerable stmctural similarity. Catalysis is diminished because a lower proportion of molecules have a bound substrate. Inhibition can be relieved by increasing the concentration of substrate. Some simple examples are shown below. Thus, sulfanilamide is an inhibitor of the enzyme that incorporates j9-aminobenzoic acid into folic acid, and has antibacterial properties by restricting folic acid biosynthesis in the bacterium (see Box 11.13). Some phenylethylamine derivatives, e.g. phenelzine, provide useful antidepressant drags by inhibiting the enzyme monoamine oxidase. The cA-isomer maleic acid is a powerful inhibitor of the enzyme that utilizes the trans-isomer fumaric acid in the Krebs cycle. 

Since the enzyme that converts dopamine to norepinephrine (dopamine (3-hydroxylase) is located only within the vesicles, the transport of dopamine into the vesicle is an essential step in the synthesis of norepinephrine. This same transport system is essential for the storage of norepinephrine. There is a tendency for norepinephrine to leak from the vesicles into the cytosol. If norepinephrine remains in the cytosol, much of it will be destroyed by a mitochondrial enzyme, monoamine oxidase MAO). However, most of the norepinephrine that leaks out of the vesicle is rapidly returned to the storage vesicles by the same transport system that carries dopamine into the storage vesicles. It is important for a proper understanding of drug action to remember that this single transport system, called vesicular transport, is an essential element of both synthesis and storage of norepinephrine. 

Mechanism of Action An MAOI that inhibits the activity of the enzyme monoamine oxidase at CNS storage sites, leading to increased levels of the neurotransmitters epinephrine, norepinephrine, serotonin, and dopamine at neuronal receptor sites. Therapeutic Effect Relieves depression. 

Pharmacokinetics Phenylephrine is irregularly absorbed from and readily metabolized in the GI tract. After IV administration, a pressor effect occurs almost immediately and persists for 15-20 minutes. After IM administration, a pressor effect occurs within 10-15 minutes and persists for 50 minutes to 1 hour. After oral inhalation of phenylephrine in combination with isoproterenol, pulmonary effects occur within a few minutes and persist for about 3 hours. The pharmacologic effects of phenylephrine are terminated at least partially bythe uptake of the drug into the tissues. Phenylephrine is metabolized in the liver and intestine by the enzyme monoamine oxidase (MAO). The metabolites and their route and rate of excretion have not been identified. 

Monoamine oxidase inhibitors. The monoamine oxidase inhibitors (MAOIs) inhibit the intracellular catabolic enzyme monoamine oxidase. There are two types of monoamine oxidase MAO-A and MAO-B, both of which metabolize tyramine and dopamine. In addition, MAO-A preferentially metabolizes norepinephrine, epinephrine, and serotonin, and MAO-B preferentially metabolizes phenylethylamine (an endogenous amphetamine-like substance) and N-methylhistamine (Ernst, 1996). Some MAOIs are selective for A or B and some are nonselective (mixed). In addition, irreversible MAOIs (e.g., phenelzine, tranylcypromine) are more susceptible to the cheese effect than are the reversible agents (e.g., moclobemide). 

Iproniazid and other MOAIs act by inhibiting the action of the enzyme monoamine oxidase. This enzyme is found inside and outside of cells and helps break down several molecules, including the monoamine neurotransmitters norepinephrine. 

This group of drugs consists primarily of compounds that block the enzyme monoamine oxidase (MAO). While useful as hypotensive and antidepressant dmgs, their side effects can be serious. We discuss them briefly as enzyme inhibitors in chapter 8. 

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. 

Monoamine oxidase inhibitor (MAOl) A drug that inhibits the enzyme monoamine oxidase (MAO), thereby increasing the level of neurotransmitters and drugs metabolized by MAO. 

The enzyme, monoamine oxidase, exists in two forms MAO-A (intestinal mucosa and intraneuronally in the brain) and MAO-B (platelets and mainly extraneuronally in the brain). Serotonin is preferentially metabolised by MAO-A and noradrenaline (NA norepinephrine), and dopamine and lyramine by both forms. The first generation MAOI antidepressants (phenelzine, tranylcypromine, and isocarboxazid) inhibit both MAO-A and MAO-B and are thought to work by increasing the availability of 5-HT and NA in the synapse—with longer-term adaptive effects occurring as for the TCAs. These MAOls are irreversible, i.e. they permanently inactivate MAO. Thus, recovery of activity occurs slowly, over days, as new MAO molecules are synthesised. 

Both of these wonder drugs boost the synaptic efficacy of norepinephrine and serotonin, but they do so in quite different ways. Isoniazid blocks the action of the amine degrading enzyme monoamine oxidase, allowing the released amines to stay longer in the synaptic cleft (because they are... 

A further pathway of 1,2-dimethylhydrazine metabolism is A-dem ethylation, yielding monomethylhydrazine and formaldehyde. This can be catalysed by the mitochondrial enzyme monoamine oxidase (Coomes Trough, 1983) and, most probably, by microsomal cytochrome P450 (Fiala, 1977 Hietanen et al., 1986). 

Pyrazole also causes, both in vitro and in vivo, a reduction in the activity of the mixed function oxidase enzyme system (B-79MI10504), and has also been used to inhibit the copper-containing enzyme monoamine oxidase in vitro, as have several related heterocyclic compounds (80MI10507) such as indazole (78), isoxazole (75) and benzothiazole (79). 

Dopamine is oxidized to 3,4-dihydroxyphenylacetaldehyde by the enzyme monoamine oxidase. Inhibitors of acetylcholinesterase are widely used as insecticides inhibitors of monoamine oxidase are helpful in treating some neurological disorders. 

FIGURE 5—13. This figure represents the normal state of a monoaminergic neuron. This particular neuron is releasing the neurotransmitter norepinephrine (NE) at the normal rate. All the regulatory elements of the neuron are also normal, including the functioning of the enzyme monoamine oxidase (MAO), which destroys NE, the NE reuptake pump which terminates the action of NE, and the NE receptors which react to the release of NE. 

FIGURE 5—35. Serotonin is destroyed by the enzyme monoamine oxidase (MAO) and converted into an inactive metabolite. The 5HT neuron has a presynaptic transport pump selective for serotonin, which is called the serotonin transporter and is analogous to the norepinephrine (NE) transporter in NE neurons (Fig. 5-18) and to the DA transporter in DA neurons (Fig. 5-32). 

The first clincially effective antidepressants to be discovered were immediate inhibitors of the enzyme monoamine oxidase (MAO) (Table 6—4 and Figs. 5 — 15, 6—3, and 6—4). They were discovered by accident when an antituberculosis drug was... 

FIGURE 6—22. Tyramine is an amine present in food such as cheese. Indicated in this figure is how tyramine (depicted as cheese) acts to increase the release of norepinephrine (NE) (red circle 1). However, in normal circumstances, the enzyme monoamine oxidase (MAO) readily destroys the excess NE released by tyramine, and no harm is done (see red circle 2). 

In sympathetic nerve terminals, as well as the brain, the adrenal medulla, and sympathetic postganglionic terminals, there are osmophilic granules (synaptic vesicles) that are capable of storing high concentrations of catecholamine (a complex with adenosine triphosphate, or ATP, and protein). The stored amines are not metabolized by the intersynaptosomal mitochondrial enzyme (monoamine oxidase). 

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