Monoamine oxidase neurotransmitters degradation

Monoamine oxidase (MAO) inhibitors Drugs used to treat depressions that inhibit the activity of the enzyme monoamine oxidase, which degrades the neurotransmitters of norepinephrine and serotonin (Chapter 9). 

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. 

This condition is cansed by a deficiency of one or more of the monoamine nenrotransmitters in the brain (e.g. noradrenaline, dopamine, 5-hydroxytryptamine). One means of increasing the concentration of the neurotransmitters is to inhibit one of the enzymes that degrade the neurotransmitter in the brain. For the monoamines, a key degradative enzyme is monoamine oxidase, which catalyses the reaction... 

Dopamine, norepinephrine and epinephrine are products of the metabolism of dietary phenylalanine. This is an interesting sequence of reactions in that we will be discussing not only the three neurotransmitters formed but also considering the DOPA precursor and its use in the treatment of Parkinson s Disease. These molecules are also called catecholamines. Catechol is an ortho dihydroxyphenyl derivative. Degradation of the final product in the pathway, epinephrine, can be accomplished by oxidation (monoamine oxidase - MAO)or methylation (catecholamine 0-methyl transferase - COMT). The diagram on the next page illustrates the scheme of successive oxidations which produce the various catecholamines. 

The first generation of antidepressants, MAO (monoamine oxidase) inhibitors, inhibited neurotransmitter degradation by inhibiting monoamine deoxidase, a flavin containing enzyme, found in the mitochondria of neurons and other cell types, that oxidatively deaminates naturally occurring sympathomimetic monoamines, such as norepinephrine, dopamine, and serotonin within the presynapse. In 1952, isoniazid and its isopropyl derivative, iproniazid (1), were developed for the treatment of tuberculosis, where it was subsequently found that these agents had a mood enhancing effect on... 

Monoamine oxidase inhibitors MAO is found in neural and other tissues, such as the gut and liver. In the neuron, this enzyme functions as a "safety valve" to oxidatively deaminate and inacti vate any excess neurotransmitter molecules (norepinephrine, dopamine, or serotonin) that may leak out of synaptic vesicles when the neuron is at rest. The MAO inhibitors2 may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and, therefore, to both accumu late within the presynaptic neuron and to leak into the synaptic space. This causes activation of norepinephrine and serotonin receptors, and may be responsible for the antidepressant action of these drugs. 

An example of a class of drugs that interrupt neurotransmitter degradation is the monoamine oxidase (MAO) inhibitors. MAO is a mitochondrial enzyme that exists in two forms (A and B). Its major role is to oxidize monoamines such as norepinephrine, serotonin, and dopamine by removing the amine grouping from the neurotransmitters. Under normal circumstances, MAO acts as a safety valve to degrade any excess transmitter molecules that may spill out of synaptic vesicles when the neuron is in a resting state. MAO inhibitors prevent this inactivation. In their presence, any neurotransmitter molecules that leak out of the synaptic vesicles survive to enter the synapse intact. Receptors are thus exposed to a greater amount of the neurotransmitter. 

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). 

Finally, there is the process of neurotransmitter "waste management." Certain enzymes operate to biologically degrade neurotransmitters—a necessary process. Yet in some circumstances this process gets out of hand Excessive enzymatic activity may abnormally deplete neurotransmitters. This is the case in some forms of clinical depression, in which the enzyme monoamine oxidase (MAO) can cause a significant inactivation of necessary neurotransmitters. 

Another way both NE and 5-HT cells can shut down is when the naturally occurring enzyme, monoamine oxidase (MAO) becomes too active, excessively degrading neurotransmitters. This results in major depression, but often a depression with its own unique symptomatic signature (see "Atypical depression," above). 

Wliile the cyclics block the uptake of amines, MAOls prc cnt the breakdown of the neurotransmitters (Cohen, 1997 Cooperrider, 1988 Meyer Quenzer, 2005). The enzyme monoamine oxidase metabolizes a variety of neurotransmitters, including norepinephrine and serotonin. MAOls inhibit this degradation process and thus enhance the availability of the transmitter within the neuron. Thii.s, the actions of the cyclics and MAOls each arc consistent u ith the hypothesis that decreased brain catecholamine activity causes depression and that these antidepressants (using different mechanisms) reverse this process by increasing catecholamine activity in the brain. 

Monoamine oxidase is the enzyme principally responsible for degradation of amine neurotransmitters (norepinephrine, epinephrine, serotonin, and dopamine). In general, monoamine oxidase inhibitors... 

MONOAMINE-OXIDASE-INHIBITORS(MAOIs) acton monoamine-oxidase (MAO) enzymes that are involved in the degradation of monoamines in the peripheral and central nervous system. Monoamine oxidase occurs within cells bound to the surface of the mitochondria. It is found not only within monoaminergic neurons, but also in the liver and intestinal epithelium. The enzyme converts amines to their corresponding aldehydes, which in the periphery are converted to their carboxylic acids by aldel e dehydrogenase. Neurotransmitters degraded by monoamine oxidase include dopamine. 5-hydnngrtryptamine and noradrenaline. 

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. 

Central Nervous System. Dopamine monooxygenase (DMO) is an enzyme that requires copper, as a cofactor and uses ascorbate as an electron donor. This enzyme catalyzes the conversion of dopamine to norepinephrine, the important neurotransmitter. There are soluble and membrane-bound forms of the enzyme, the latter being found in the chromaffin granules of the adrenal cortex. Monoamine oxidase, one of the numerous amine oxidases, is a copper-containing enzyme that catalyzes the degradation of serotonin in the brain and is also involved in the metabolism of the catecholamines. 

When neurotransmitters are released into the synapse they are either taken up by transporters back into the neuron to be used again or are degraded. Recall that the monoamines serotonin, dopamine, and norepinephrine have similar chemical structures and, as such, they follow the same pathways of synthesis and breakdown. All monoamines are degraded by an enzyme called monoamine oxidase. MAOIs bind irreversibly (i.e., form covalent bonds) to the reactive site of monoamine oxidase. 

The catecholamines epinephrine, norepinephrine, and dopamine are inactivated by oxidation reactions catalyzed by monoamine oxidase (MAO) (Figure 15.10). Because MAO is found within nerve endings, catecholamines must be transported out of the synaptic cleft before inactivation. (The process by which neurotransmitters are transported back into nerve cells so that they can be reused or degraded is referred to as reuptake.) Epinephrine, released as a hormone from the adrenal gland, is carried in the blood and is catabolized in nonneural tissue (perhaps the kidney). Catecholamines are also inactivated in methylation reactions catalyzed by catechol-O-methyltransferase (COMT). These two enzymes (MAO and COMT) work together to produce a large variety of oxidized and methylated metabolites of the catecholamines. 

Whereas acetylcholine is degraded by a membrane-anchored acetylcholine esterase (ACE) in the synaptic cleft (choline is afterwards taken up presynaptically), the biogenic amines adrenaline, noradrenaline, serotonin, and dopamine are taken up by the presynaptic membrane by transporters (Fig. 3) or by extraneuronal cells in which they are degraded by a catecholamine O-methyltransferase (COMT). These transporter have similar structure and contain 12 transmembrane regions. Once in the presynapse, the neurotransmitters are either degraded by monoamine oxidase (MAO) or taken up by synaptic vesicles. A proton pumping ATPase of the vesicle membrane (V-type ATPase as in plant vacuoles) causes an increase of hydrogen ion concentrations in the vesicles. Uptake of the neurotransmitter serotonin, adrenaline and noradrenaline could be partly achieved either via a diffusion of the free base into the vesicles where they become protonated and concentrated by an "ion trap" mechanism and via specific proton-coupled antiporters. The excitatory amino acids, acetylcholine and ATP cannot diffuse and enter the vesicles via specific transporters. 

Experiments using both knock-out and pharmacological approaches have demonstrated that serotonin plays a role in modulating synaptogenesis in rodents. Monoamine oxidase (MAO) is an enzyme which degrades neurotransmitters such as noradrenaline, dopamine, and serotonin. There are two distinct forms of the enzyme, A and B, which are encoded by two separate genes, both with 15 exons and lying adjacent to each other on human Xpl 1.23-11.4 [77]. Both MAO A and B deaminate dopamine but have some different characteristics with respect to time of expression and other enzymatic activities MAOA preferentially deaminates serotonin and noradrenaline and its maximal activity appears in the fetal brain. MAOB mainly deaminates neurotransmitters... 

A monoamine oxidase is an enzyme that degrades compounds with an amino group, including neurotransmitters consequently, it can control a person s mental state. 

Aggressive behavior is related to the monoamine neurotransmitters serotonin, dopamine, and noradrenaline. The enzymes monoamine oxidase (MAO) A and B play roles in the metabolism of catecholamines in the brain and peripheral tissues. MAOA degrades dopamine, serotonin, and noradrenaline. 

Monoamine oxidases (MAOs) are mitochondrial outer membrane-bound flavoenzymes that catalyze the degradation of biogenic amines, more specifically the oxidative deamination of several important neurotransmitters, including 5-hydroxytiyptamine (5-HT) (or serotonin), histamine, and the catecholamines dopamine, noradrenaline, and adrenaline. There are two isoforms... 

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