Catecholamines metabolism pathways

Tolcapone (Tasmar) and entacapone (Comtan) are used only in conjunction with carbidopa/L-dopa to prevent the peripheral conversion of L-dopa to dopamine (increasing the area under the curve of L-dopa by approximately 35%). Thus, on time is increased by about 1 hour. These agents significantly decrease off time and decrease L-dopa requirements. Concomitant use of nonselective MAO inhibitors should be avoided to prevent inhibition of the pathways for normal catecholamine metabolism. 

B. Aminochrome Formation as a Possible Minor Pathway for Catecholamine Metabolism... 

Metanephrines represent metabolites of the catecholamines urinary levels are greater than total catecholamines but less than those of VMA. In tumors, variations in the metabolic pathways can cause an increase in the metanephrines alone. 

Since dopamine is present in sympathetic nervous tissue as a precursor of norepinephrine, and it has a separate metabolic pathway that yields homovanillic acid (HVA), tumors such as neuroblastomas may cause elevations of the urinary dopamine and its metabolite HVA. In some cases these elevations have been observed with normal VMA, total catecholamine, and metanephrine. Urinary HVA is usually normal in patients with phenochromocytoma. Increased HVA is found in special fluids of patients with Parkinson s disease treated with L-dopa. 

Adrenal Conical Hormones. The adrenal gland is made up of two parts, the medulla and the cortex, each of which secretes characteristic hormones. The hormones of the adrenal medulla art- the catecholamines, epinephrine adrenalin and norepinephrine (noradrenalint. which are closely related chemically, dil lning only in that epinephrine has an added methyl group. See Table I. In fact, animal experiments have established a metabolic pathway lor Ihe biosynthesis of both compounds Irom Ihe ammo acid pheny lal.inine. which involves enzy malic oxidation and decarboxylation reactions It is also to he noted ihui the isomeric form of norepinephrine is most important the natural D-lonn (which incidentally, is levorntatory) has many times die uciiviiy of die synthetic isomer. Epinephrine has a pronounced action upon the circulatory system, increasing both blood... 

Two important pathways for catecholamine metabolism are O-methylation by COMT, which is cytoplasmically localized, and oxidative deamination by the mitochondrial localized enzyme MAO. There are large amounts of MAO in tissues such as the liver 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 bigb concentrations in certain foods such as cheese, and in wine. Normally, this tyramine is deaminated in the liver. However, if MAO is inhibited, the tyramine may then be converted into octopamine [104-14-57] which may indirecdy cause release of NE from nerve terminals to cause hypertensive crisis. Thus MAO, which is rdatively nonspecific, plays an important role in the detoxification of pharmacologically active amines ingested from the diet. 

The metabolic pathways of phenylalanine and tyrosine are identical, because the essential phenylalanine must be converted to tyrosine to become metabolized. Figure 20.22 illustrates this pathway, which is termed the liver pathway to distinguish it from those leading to catecholamine biosynthesis. It is localized in the cytosol, with the exception of tyrosine transaminase, which is also present in the mitochondria. 

Catechol-0-methyltransferase (COMT) is responsible for the second major pathway of catecholamine metabolism, catalyzing 0-methylation of dopamine to methoxytyramine, norepinephrine to normetanephrine, and epinephrine to metanephrine. COMT is not present in monoamine-producing neurons, which contain exclusively MAO, but is present along with MAO in most extraneuronal tissue. The membrane-bound isoform of COMT, which has high affinity for catecholamines, is especially abundant in adrenal chromaffin cells. As a result of the preceding and other differences in the expression of metabolizing enzymes, catecholamines produced at neuronal and adrenal medullary locations follow different neuronal and extraneuronal pathways of metabolism (Figure 29-5). 

Synthesis of steroid hormones (shown here) and of catecholamines (see Figure 21.32) and thyroid hormones (Figure 21.19), occur via straightforward metabolic pathways. 

MIBG I-MIBG was also used to image adrenal medulla and its neoplasms. It follows the same metabolic pathways as catecholamines, in particular that of norepinephrine, and is stored in surrenal cells cytoplasm. It enables the visualization of many neuroendocrine tumors that fix... 

Though less than 1% of the total iron in the body is utilized for enzymes and cofactors, the critical nature of these enzymes in such major metabolic pathways as the tricarboxylic acid cycle could easily explain brain effects of iron deficiency. Pollitt and Leibel (1976) also suggest that central catecholamine excess causes some of the behavioral disturbances attributed to iron deficiency. Monoamine oxidase is functionally deranged in iron-deficient rats. Children with iron-deficient anemia have elevated urinary norepinephrine excretion which is normalized within 1 wk after parenteral iron treatment. Potentially toxic excess heme precursors, protoporphyrins, may also mediate the behavioral effects of iron deficiency. 

The study of catecholamines and their metabolites has grown enormously in recent years since the advent of HPLC coupled to highly sensitive detection systems. The catecholamines play a major role in the function of the body s nervous system. Dopamine and noradrenaline exert a marked influence on the vascular system, whilst adrenaline, synthesized largely in the adrenal medulla, affects the rate of many metabolic processes, particularly carbohydrate metabolism. The major metabolic pathways of catecholamine inactivation are shown in Figure 1. Abnormal levels of these amines and their metabolites have been associated with a number of disease states, notably Parkinson s disease [1], neural tumours such as phaeochromocytoma[2] and hypertension [3]. 

The oxidation of catecholamines is catalysed by a number of enzymes which are widely distributed in the plant and animal kingdoms. The quinonoid pathway may exist as a minor but normal metabolic pathway for these substances in mammals. This question will be discussed in more detail later (see p. 318). In general, the enzymes responsible for the oxidation of the catecholamines, such as tyrosinase and ceruloplasmin, contain copper. 

It is now possible to obtain the catecholamines and many related compounds in a radioactively labelled form. The introduction of liquid-scintillation counting techniques, together with the availability of tritium-labelled compounds of very high specific activities (> 5 Ci/mmole), has been a very important factor in catecholamine research. The use of such radioactively labelled compounds has been critical for the elucidation of the pathways involved in catecholamine metabolism, and has provided the basis for many other recent advances in this field of research. The sensitivity with which tritiated catecholamines can be detected and accurately measured is very high, with a limit of the order of 1 pg (S x 10 moles). 

Certainly, such a complex system for metabolism of noradrenaline (which is shared with the other catecholamines) strongly suggests that its function extends beyond that of merely destroying transmitter sequestered from the synapse. However, as yet, little is known about the regulation of this pathway and any influence it might have on noradrenergic transmission. One crucial, additional role for MAO appears to be the... 

Figure 2.16. Pathways for the synthesis and metabolism of the catecholamines. A=phenylalanine hydroxylase+pteridine cofactor+Oj B tyrosine hydroxylase+ tetrahydropteridme+Fe+ +Oj C=dopa decarboxylase+pyridoxal phosphate D= dopamine beta-oxidase+ascorbate phosphate+Cu+ +Oj E=phenylethanolamine N-methyltransferase+S-adenosylmethionine l=monoamine oxidase and aldehyde dehydrogenase 2=catechol-0-methyltransferase+S-adenosylmethionine.

The methyl transferases (MTs) catalyze the methyl conjugation of a number of small molecules, such as drugs, hormones, and neurotransmitters, but they are also responsible for the methylation of such macromolecules as proteins, RNA, and DNA. A representative reaction of this type is shown in Figure 4.1. Most of the MTs use S-adenosyl-L-methionine (SAM) as the methyl donor, and this compound is now being used as a dietary supplement for the treatment of various conditions. Methylations typically occur at oxygen, nitrogen, or sulfur atoms on a molecule. For example, catechol-O-methyltransferase (COMT) is responsible for the biotransformation of catecholamine neurotransmitters such as dopamine and norepinephrine. A-methylation is a well established pathway for the metabolism of neurotransmitters, such as conversion of norepinephrine to epinephrine and methylation of nicotinamide and histamine. Possibly the most clinically relevant example of MT activity involves 5-methylation by the enzyme thiopurine me thy Itransf erase (TPMT). Patients who are low or lacking in TPMT (i.e., are polymorphic) are at... 

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. 

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. 

Figure 30-26 Some pathways of metabolism of the catecholamines. See also Fig. 25-5.

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