Deamination of catecholamines

MAO catalyzes the oxidative deamination of catecholamines, 5-hydroxytryptamine (serotonin), and other monoamines, both primary such as NE, and secondary such as EP. It is one of several oxidase-type enzymes whose coenzyme is the flavin-adenine-dinucleotide (FAD) covalently bound as a prosthetic group (Fig. 9-3). The isoalloxazine ring system is viewed as the catalytically functional component of the enzyme. In a narrow view N-5 and C-4a is where the redox reaction takes place (i.e., +H+, +le or -H+, -le), although the whole chromophoric N-5-C-4a-C-4-N-3-C-2-N-l region undoubtedly participates. Figure 9-3 is a proposed structure of MAO isolated from pig brain (Salach et al., 1976).4... 

Since MAO is also predominantly localized in glial cells (see Section 4.1.1), deamination of catecholamines appears to be linked to GSH-Px content (Maker et al., 1981 Spina and Cohen,... 

Deamination of catecholamine by monoamine oxidase (Spina and Cohen 1989) may contribute to the formation of cytotoxic free radicals in the presence of transition metals such as iron, copper and manganese (Donaldson etal. 1981, Riederer etal. 1989, Obata and Yamanaka 1997). Obata and Yamanaka (2002) examined the effect of iron-fill) (50 iM) on the generation of hydroxyl radicals in the extracellular fluid of rat myocardium. The... 

Degradation of catecholamines The catecholamines are inacti vated by oxidative deamination catalyzed by monoamine oxidase (MAO), and by O-methylation carried out by catechol-O-methyl-transferase (COMT, Figure 21.15). The two reactions can occur in either order. The aldehyde products of the MAO reaction are axi dized to the corresponding acids. The metabolic products of these reactions are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine. 

The biological function of amine oxidases involves the oxidation of biogenic amines formed during normal biological processes. In mammals, the monoamine oxidases are involved in the control of the serotonin catecholamine ratios in the brain, which in turn influence sleep and EEG patterns, body temperature, and mental depression. Two groups of amine oxidases are involved in the oxidative deamination of naturally occurring amines as well as foreign compounds. 

Monoamine oxidases catalyze oxidative deamination of many primary, secondary, and tertiary amines. They have a wide tissue distribution including brain, liver, and intestine. A variety of endogenous amines, such as catecholamines, and pharmacological substances are metabolized. The products of primary amines are the corresponding aldehydes, ammonia, and hydrogen peroxide. 

COMT hypothesis. According to this hypothesis. St. John s wort increases the levels of catecholamines at the brain synapses by inhibiting their inactivation by oxidative deamination (MAOl) and by catechol functionalization (catechol-0-methyltransferase [COMTl). Recent studies have shown that hypericins possess such activities only at pharmacologically excessive concentrations. If true, these effects at normal doses are small and do nothing to alleviate depression. Other hypotheses suggest hormonal effects or effects on the dopaminergic system. Hyperforin has become a candidate for the major antidepressant constituent of St. John s wort. 

Serotonin is not a substrate for COMT and follows simpler pathways of metabolism than those for catecholamines (Figure 29-6). Deamination of serotonin to the aldehyde intermediate is preferentially followed by oxidation to 5-hydroxyindoleacetic acid (5-HIAA) catalyzed by... 

Isolated deficiencies of MAO A and B are extremely rare and are associated with distinct clinical and neurochemical phenotypes. Deficiency of MAO A is associated with a behavioral disorder characterized by increased aggressiveness. Plasma and urinary levels of deaminated metabolites of catecholamines are severely decreased, whereas levels of normetanephrine and metanephrine are increased. An increased ratio of plasma normetanephrine to DHPG has therefore been proposed to provide a sensitive marker for the deficiency state. In contrast, deficiency of MAO B is associated with a mild phenotype, the only biochemical alteration is increased urinary excretion of phenylethyiamine. 

Normetanephrine andmetanephrine are metabolic products of norepinephrine and epinephrine, respectively, and are formed by the action of catechol-0-methyltransferase without deamination. As a result of active neuronal reuptake and deamination of norepinephrine, normetanephrine normally represents <5% of the total norepinephrine excretion products in urine. Metanephrine, however, even with its lower urinary concentration relative to normetanephrine, represents a major excretion product of epinephrine. The metanephrines are excreted in both conjugated and unconjugated forms. Unlike the catecholamines, total metanephrine excretion is not significantly influenced by diet. As a result, the total metanephrines are routinely measured after acid hydrolysis or sulfatase pretreatment. 

In summary, unlike with cholinergic neurons, where termination of action is rapidly accomplished by a single efficient process, hydrolysis of the neurotransmitter by AChE, in the case of catecholamines, a multiple of processes occur simultaneously. A major intraneural reuptake process, a dilution effect by diffusion away from the synaptic cleft, which includes uptake (U2) into extraneural tissue, oxidative deamination by MAO and m-methylation of the catechol moiety by COMT. 

Also in view of the results discussed earlier, it seems that inhibitors like hydroquinones, dexamethasone may increase the amount of catabolic enzymes associated with stress conditions as well as the in vivo release of phenyl radicals, facihtating depigmentation (15, 220). Stress not only releases inhibitors of tyrosinase, e.g. catecholamines, but also induces TAT in vivo (1) causing deamination of tyrosine and yielding p-hydroxy-phenylpyruvic acid, which is an inhibitor of tyrosinase. Stress has also a great effect on the immune system (127) and on brain-immune system interaction as well (179). 

It may be possible to get around some of these difficulties by studying 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG), a deaminated-O-methylated metabolite of catecholamines which is... 

MAO within adrenergic nerves is apparently involved in the control of the steady-state concentration of NA, both in the CNS and in sympathetic nerves. Inhibition of MAO may increase the NA content of tissues to several times that found under normal conditions. Intraneuronal MAO is also responsible for the degradation of catecholamines released from storage vesicles by reserpine, as described in Paragraph 5.2.4. There is some evidence that catechol deaminated metabolites, such as 3,4-dihydroxy mandelic acid, are formed primarily by the action of MAO within adrenergic nerves. On the other hand, extraneuronal MAO oxidatively deaminates only compounds which have previously been O-methylated. 

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... 

Two important pathways for catecholamine metaboHsm are 0-methylation by COMT, which is cytoplasmicaHy localized, and oxidative deamination by the mitochondrial localized enzyme MAO. There are large amounts of MAO in tissues such as the fiver and the heart which are responsible for the removal of most of the circulating monoamine, including some taken in from the diet. Tyramine is found in high concentrations in certain foods such as cheese, and in wine. Normally, this tyramine is deaminated in the fiver. However, if MAO is inhibited, the tyramine may then be converted into octopamine [104-14-37] which may indirecdy cause release of NE from nerve terminals to cause hypertensive crisis. Thus MAO, which is relatively nonspecific, plays an important role in the detoxification of pharmacologically active amines ingested from the diet. 

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. 

Most hormones have a half-life in the blood of only a few minutes because they are cleared or metabolized very rapidly. The rapid degradation of hormones allows target cells to respond transiently. Polypeptide hormones are removed from the circulation by serum and cell surface proteases, by endocytosis followed by lysosomal degradation, and by glomerular filtration in the kidney. Steroid hormones are taken up by the liver and metabolized to inactive forms, which are excreted into the bile duct or back into the blood for removal by the kidneys. Catecholamines are metaboli-cally inactivated by O-methylation, by deamination, and by conjugation with sulfate or glucuronic acid. 

There are two enzymes capable of metabolizing catecholamines. The first is monoamine oxidase (MAO), a mitochondrial enzyme that oxidatively deaminates catecholamines, tyramine, serotonin, and histamine. MAO is further subclassified as either monoamine oxidase A, which metabolizes norepinephrine and is inhibited by tranylcypromine, and monoamine oxidase B, which metabolizes dopamine and is inhibited by 1-deprenyl. Catechol-O-methyltransferase (COMT), a soluble enzyme present mainly in the liver and kidney, is also found in postsynaptic neuronal elements. About 15% of norepinephrine is metabolized postsynaptically by COMT. 

Transamination and Oxidative Deamination Catalyzed by Di-hydroxyphenylalanine (DOPA) Decarboxylase DOPA decarboxylase catalyzes the decarboxylation of dihydroxyphenylalanine to yield dopamine (and hence the other catecholamine neurotransmitters see Figure 13.4) and... 

HPLC measurements of plasma catechols are usually limited to dopamine, norepinephrine, and epinephrine. However, with an alumina adsorption extraction procedure it is also possible to simultaneously measure several other catechols by HPLC or microchip electrophoresis. These catechols include DHPG, the deaminated metabolite of norepinephrine and epinephrine DOPAC, the deaminated metaboHte of dopamine and 3,4-dihydroxyphenylalanine (r-dopa), the immediate precursor of dopamine. All are present in plasma at concentrations many fold higher than the catecholamines, making their detection relatively simple once appropriate chromatographic separation is achieved. 

There are two enzymes capable of metabolizing catecholamines. The first is monoamine oxidase (MAO), a mitochondrial enzyme that oxidatively deaminates catecholamines, tyramine, serotonin, and histamine. MAO is further subclassified... 

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