Monoamine oxidase catecholamine inactivation

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. 

Monoamine oxidase and catechol- O-methyltransferase are primarily responsible for the inactivation of catecholamines 214... 

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. 

Monoamine oxidase inhibitors inhibit serotonin inactivation in the extracellular compartment, just as they inhibit catecholamine inactivation. 

Catecholamine neurotransmitters are subsequently inactivated by enzymic methylation of the 3-hydroxyl (via catechol-O-methyltransferase) or by oxidative removal of the amine group via monoamine oxidase. Monoamine oxidase inhibitors are sometimes used to treat depression, and these drugs cause an accumulation of amine neurotransmitters. Under such drug treatment, simple amines such as tyramine in cheese, beans, fish, and yeast extracts are also not metabolized and can cause dangerous potentiation of neurotransmitter activity. 

The effect of released norepinephrine wanes quickly, because -90% is transported back into the axoplasm by a specific transport mechanism (norepinephrine transporter, NAT) and then into storage vesicles by the vesicular transporter (neuronal reuptake). The NAT can be inhibited by tricyclic antidepressants and cocaine. Moreover, norepinephrine is taken up by transporters into the effector cells (extraneuronal monoamine transporter, EMT). Part of the norepinephrine undergoing reuptake is enzymatically inactivated to normetanephrine via catecholamine O-methyltransferase (COMT, present in the cytoplasm of postjunctional cells) and to dihydroxymandelic acid via monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells). 

Epinephrine is well absorbed after oral administration but is rapidly inactivated in the gut mucosa. When intravenously injected or infused, the onset of drug effect is rapid (within 5 min for dopamine and 3-10 min for epinephrine) and the duration of drug effect is short (10 min for dopamine, 1 or 2 min for norepinephrine, and 15 min to hours for epinephrine depending on route of administration). Exogenous catecholamine in the circulation is rapidly and efficiently taken up by adrenergic neurons. Catecholamine is metabolized by monoamine oxidase, which is localized largely in the outer membrane of neuronal mitochondria, and by catechol-0-methyl transferase, which is found in the cytoplasm of most animal tissues, particularly the kidneys and the liver. 

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. 

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. 

Fig. 48.6. Inactivation of catecholamines. Methylation and oxidation may occur in any order. Methylated and oxidized derivatives of norepinephrine and epinephrine are produced, and 3-methoxy-4-hydroxymandelic acid is the final product. These compounds are excreted in the urine. MAO = monoamine oxidase COMT = catechol 0-methyltransferase SAM = S-adenosyhnethionine SAH = S-adenosylhomocysteine.

Inactivation ofH. The action of a H. is innnediately stopped by 1. enzymatic hydrolysis of a cyclic nucleotide second messenger to a mononucleotide (e.g. cAMF to S -AMP) or 2. enzymatic degradation of the H. Peptide and protein H. are inactivated by proteolytic enzymes, catecholamines by monoamine oxidases, steroid H. by oxidation or reduction (e. g. about 50% of estrogens in humans are oxidized to nones-trogenic catechols) and by converaon to readily excreted (in urine and bile) glucuronides or sulfates. 

The hormones are stored in special granules which are present in the sympathetic nerve endings and medullary cells and the net hormonal output depends on the rates of both the synthesis and release. Any catecholamine that diffuses from the synapse into the remainder of the neuron is destroyed by a monoamine oxidase. Sympathomimetic drugs such as ephedrine and the amphetamines act by inhibiting monoamine oxidase and slowing the removal of catecholamines and 5-hydroxytryptamine (serotonin) from within neurons. In this way they increase the sensitivity of the neuron to stimulation and act as antidepressants. Any catecholamines that are released into the bloodstream are rapidly removed and inactivated by the liver. 

Pargyline is a potent irreversible inhibitor of a flavin-linked monoamine oxidase (MAO) and has found clinical application. The latter catalyzes the inactivation of biologically important catecholamines. It forms a covalent bond with the enzyme via the flavin cofactor and the mode of action is believed to be as shown in Scheme 7.1. 

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