Catecholamines degradation

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

Catecholamines degrade rapidly via oxidative reactions and are catalyzed by oxygen, pH s >6, heavy metal ions, heat, and UV-VIS radiation. UV-VIS radiation is more deleterious than temperature, and UV is 15 times more deleterious than VIS radiation. The degradation rates, of individual catecholamines, vary and are dependent on the position of their phenolic groups and the type of N-substituents in the aminoalkyl side chain. For instance, norepinephrine is more stable than epinephrine, and epinephrine is more stable than isoprenaline. 

The derivatives have an optimum fluorescence at an excitation wavelength of 340 nm and an emission wavelength of 455 nm. The adduct is relatively stable at a pH of 9-11 but it rapidly degrades to a non-fluorescent residue at low pH values. Consequently, when used as a pre-column derivatizing reagent the pH of the mobile phase should be kept fairly high, o-phthalaldehyde has been employed for derivatization in the analysis of dopamine (29), catecholamines (30) and histamines (31). 

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. 

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). 

Caffeine in tea and coffee inhibits the phosphodiesterase that degrades cAMP. The resultant increase in cAMP levels, therefore, mimics the action of mediators such as the catecholamines that modulate adenylate cyclase. Caffeine and the related theophylline (both purine alkaloids, see Box 11.12) are thus effective stimulants of the CNS. 

The metabolism of catecholamines is much slower and more complex than that of ACh. The degradative pathways are shown in figure 4.7. The principal, although nonspecific, enzyme in the degradation is monoamine oxidase (MAO), which dehydrogenates... 

Dopamine metabolism was covered in the discussion of general catecholamine biochemistry. Dopamine is stored in synaptic vesicles, and this storage can be manipulated. Although the reuptake of released DA is the major deactivating mechanism, MAO and COMT act enzymatically on DA in the same way as on NE. However, following the degradative pathway of NE, DA will finally be metabolized to homovanillic acid (3-methoxy-4-hydroxy-phenylacetic acid), since it lacks the P-hydroxyl group. 

Catecholamines are absorbed from the intestines, but are rapidly degraded in gut and liver by enzymes MAO and COMT. Thus they are inactive on oral administration. 

Effects on growth and calorigenesis are accompanied by a pervasive influence on metabolism of drugs as well as carbohydrates, fats, proteins, and vitamins. Many of these changes are dependent upon or modified by activity of other hormones. Conversely, the secretion and degradation rates of virtually all other hormones, including catecholamines, cortisol, estrogens, testosterone, and insulin, are affected by thyroid status. 

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. 

From amines Amines obtained from the diet, and monoamines that serve as hormones or neurotransmitters, give rise to ammonia by the action of amine oxidase (see p. 284 for the degradation of catecholamines). 

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. 

Increased degradation of triacylglycerols The activation of hormone-sensitive lipase (see p. 187) and subsequent hydrolysis of stored triacylglycerol are enhanced by the elevated catecholamines epinephrine and, particularly, norepinephrine. These compounds, which are released from the sympathetic nerve endings in adipose tissue, are physiologically important activators of hormone-sensitive lipase (Figure 24.13, ) ... 

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