Catecholamines catabolism

The Other enzyme in catecholamine catabolism is catecholamine 0-methyltransferase (COMT), a cytoplasmic enzyme that uses S-adenosyl-methionine to methylate the 3-OH of catecholamines and render them inactive. The methylated compounds are not taken up into the synapse. 

The major enzymes in catecholamine catabolism are catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). COMT transfers a methyl group from S-adenosyhnethionine (SAM) (Chapter 47) to the oxygen at position 3 of the aromatic ring (Fig. 48.1). The pathway taken is a lottery depending on whether the noradrenaline and adrenaline are first of aU methylated (by COMT) or alternatively oxidatively deaminated (by MAO). If chance determines methylation has priority, then the methylated amines normetadrenaline and metadrenaline are formed prior to the MAO reaction and subsequent oxidation to HMMA (hydroxymethoxyman-... 

An end product of catecholamine catabolism. It is excreted in the urine in large amounts in patients with catecholamine secreting tumours such as phaeochromocytoma and neuroblastoma. 

COMT has not been extensively purified, because of the instability of the enzyme in purified preparations. The most highly purified preparations from rat liver suggest a molecular weight of 29,000. Little is known about the active centre of the enzyme or its mechanism of catalysis. In both the CNS and peripheral tissues the maximum activity of COMT is at least one order of magnitude less than that of MAO. This may be related to the more restricted rdle of COMT for catecholamine catabolism, whereas MAO is involved in the catabolism of many other amines. 

The action of catecholamines released at the synapse is modulated by diffusion and reuptake into presynaptic nerve terminals. Catecholamines diffuse from the site of release, interact with receptors and are transported back into the nerve terminal. Some of the catecholamine molecules may be catabolized by MAO and COMT. The cate-cholamine-reuptake process was originally described by Axelrod [18]. He observed that, when radioactive norepinephrine was injected intravenously, it accumulated in tissues in direct proportion to the density of the sympathetic innervation in the tissue. The amine taken up into the tissues was protected from catabolic degradation, and studies of the subcellular distribution of catecholamines showed that they were localized to synaptic vesicles. Ablation of the sympathetic input to organs abolished the ability of vesicles to accumulate and store radioactive norepinephrine. Subsequent studies demonstrated that this Na+- and Cl -dependent uptake process is a characteristic feature of catecholamine-containing neurons in both the periphery and the brain (Table 12-2). 

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. 

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. 

MAO-A and MAO-B are the major catabolic isoenzymes of catecholamines and serotonin in the mammalian brain. The two isoenzymes have 70% amino acid identity, identical exon-intron organization, and are encoded by two different genes that reside closely between bands Xpll.23 to Xp22.1 of the X chromosome. 

One of the best characterized physiological functions of (6R)-tetrahydrobio-pterin (BH4, 43) is the action as a cofactor for aromatic amino acid hydroxylases (Scheme 28). There are three types of aromatic amino acid hydroxylases phenylalanine hydroxylase [PAH phenylalanine monooxygenase (EC 1.14.16.1)], tyrosine hydroxylase [TH tyrosine monooxygenase (EC 1.14.16.2)] and tryptophan hydroxylase [TPH tryptophan monooxygenase (EC 1.14.16.4)]. PAH converts L-phenylalanine (125) to L-tyrosine (126), a reaction important for the catabolism of excess phenylalanine taken from the diet. TH and TPH catalyze the first step in the biosyntheses of catecholamines and serotonin, respectively. Catecholamines, i.e., dopamine, noradrenaline and adrenaline, and serotonin, are important neurotransmitters and hormones. TH hydroxylates L-tyrosine (126) to form l-DOPA (3,4-dihydroxyphenylalanine, 127), and TPH catalyzes the hydroxylation of L-tryptophan (128) to 5-hydroxytryptophan (129). The hydroxylated products, 127 and 129, are decarboxylated by the action of aromatic amino acid decarboxylase to dopamine (130) and serotonin (131), respectively. 

Be familiar with the biosynthesis and catabolism of catecholamines, their structures, control of their secretion, their effects on target tissues, and diagnostic uses of their catabolic products. 

Insulin is probably the most important inhibitor of lipolysis. In contrast to adults, in whom catecholamines represent the most important stimulators of lipolysis, thyrotropin (TSH) is the most important stimulator of lipolysis in the newborn. Plasma free fatty acid concentrations rise markedly in the first hours after birth in response to a marked increase in the TSH concentration and a fall in the insulin concentration. The fatty acids released from lipid stores are oxidized by some extrahepatic tissues (e.g., heart and skeletal muscle, kidney, intestine, and lung). Because the respiratory quotient (the ratio of carbon dioxide production to oxygen use) falls from a value of 1.0 (showing that carbohydrate oxidation is the primary source of energy) to a value of 0.8 to 0.9 (showing increasing oxidation of protein or fatty acids) at 2 to 12 hours of age, at a time when protein catabolism is usually insignificant, fatty acid oxidation must represent... 

Released dopamine can be reutilized by neuronal reuptake and re-storage in vesicles or can be catabolized like other endogenous catecholamines by the enzymes MAO and COMT (p. 86). 

Catechol O-methyltransferase plays an important role in the catabolism of catecholamine neurotransmitters such as dopamine, norepinephrine, and epinephrine, and inactivation of catechol estrogens and catechol xenobiotics. Several different methods have been developed. 

There is a great deal of evidence that deficiency of serotonin (5-hydroxytryptamine) is a factor in depressive illness, and many antidepressant drugs act to decrease its catabolism or enhance its interaction with receptors. A key enzyme involved in the synthesis of serotonin (and the catecholamines) is aromatic amino acid decarboxylase, which is pyridoxal phosphate-dependent. Therefore, it has been suggested that vitamin Be deficiency may result in reduced formation of the neurotransmitters and thus be a factor in the etiology of depression. Conversely, it has been suggested that supplements of vitamin Be may increase aromatic amino acid decarboxylase activity, and increase amine synthesis and have a mood-elevating or antidepressant effect. There is little evidence that vitamin Be deficiency affects the activity of aromatic amino acid decarboxylase. In patients with kidney failure, undergoing renal dialysis, the brain concentration of pyridoxal phosphate falls to about 50% of normal, with no effect on serotonin, catecholamines, or their metabolites (Perry etal., 1985). 

In cirrhotic patients, a reduced synthesis rate of most proteins is found at an early stage, with albumin synthesis being the least compromised factor at first. Fat storage, muscle mass and protein turnover are reduced. This ultimately leads to catabolism (so-called stress metabolism) and increasing muscular atrophy (so-called wasting syndrome). The latter condition can also result from sympathicotonia with elevated catecholamine values similarly, decreased values of IGFl inhibit the formation of muscle tissue. 

Severe bum trauma causes an elevation of semm catecholamines and triggers a hypermetabolic response that is mediated by P-ARs (61-63). This hypermeta-bolic response causes protein catabolism, muscle wasting, and the loss of lean body mass and can persist up to 9 mo after the injury in some patients. Propranolol is one of several drugs that have been used to treat the hypermetabolic... 

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