Methyl-DOPA decarboxylation

While a number of drugs, e.g. a-methyl dopa, inhibit the enzyme they have little effect on the levels of brain DA and NA, compared with inhibition of tyrosine hydroxylase and they also affect the decarboxylation of other amino acids. Some compounds, e.g. a-methyl dopa hydrazine (carbidopa) and benserazide, which do not easily enter the CNS have a useful role when given in conjunction with levodopa in the treatment of Parkinsonism (see Chapter 15) since the dopa is then preserved peripherally and so more enters the brain. 

Figure 15.4 The central and peripheral metabolism of levodopa and its modification by drugs, (a) Levodopa alone. After oral administration alone most dopa is rapidly decarboxylated to DA in the gut and blood with some o-methylated (COMT) to o-methyl/dopa (OMD). Only a small amount (3%) enters the CNS to be converted to DA. (b) After an extracerebral dopa decarboxylase inhibitor. Blocking just the peripheral dopa decarboxylase (DD) with inhibitors like carbidopa and benserazide, that cannot enter the CNS (extra cerebral dopa decarboxylase inhibitors, ExCDDIs), stops the conversion of levodopa to DA peripherally, so that more enters the CNS or is o-methylated peripherally to OMD.

FIGURE 27.5 Tyrosine is the biosynthetic precursor to a number of neurotransmitters. Each transformation is enzyme-catalyzed. Hydroxylation of the aromatic ring of tyrosine converts it to 3,4-dihydroxyphenylalanine (t-dopa), decarboxylation of which gives dopamine. Hydroxylation of the benzylic carbon of dopamine converts it to norepinephrine (noradrenaline), and methylation of the amino group of norepinephrine yields epinephrine (adrenaline). 

Figure 10. Metabolites of a-methyl DOPA which could act as false neurotransmitters. a-Methyl DOPA acts in the form of its decarboxylated...

CATECHOL-O-METHYLTRANSFERASE INHIBITORS Catechol-O-Methyltrans-ferase (COMT) metabolizes levodopa as well as dopamine, producing the pharmacologically inactive compounds 3-O-methyl DOPA (from levodopa) and 3-methoxytyramine (from dopamine) (Figure 20-7). Approximately 99% of an orally administered dose of levodopa does not reach the brain but, rather, is decarboxylated to dopamine, which causes nausea and hypotension. Addition of an AAD inhibitor (e.g., carbidopa) reduces the formation of dopamine but increases the fraction of levodopa that is methylated by COMT. COMT inhibitors will block this peripheral conversion of levodopa to 3-O-methyl DOPA, increasing both the plasma tj j of levodopa as well as the fraction that reaches the CNS. 

Alpha-methyl- DOPA (Aldomet) Decarboxylated to a-methyl dopamine then (3-hydroxylated to a-methyinorepinephrine, a potent a2 receptor agonist. Results in 4 mpathetic outflow from CNS. preganglionic sympathetic output, rapidly 4 blood pressure -but sympathetic system can respond with cardiac stimulation. Sedation, mild orthostatic hypotension, dry mouth, fever, nasal stuffiness, Coombs positive RBCs, salt and water retention, rebound hypertension. 

Decarboxylation of histidine to histamine is catalyzed by a broad-specificity aromatic L-amino acid decarboxylase that also catalyzes the decarboxylation of dopa, 5-hy-droxytryptophan, phenylalanine, tyrosine, and tryptophan. a-Methyl amino acids, which inhibit decarboxylase activity, find appfication as antihypertensive agents. Histidine compounds present in the human body include ergothioneine, carnosine, and dietary anserine (Figure 31-2). Urinary levels of 3-methylhistidine are unusually low in patients with Wilson s disease. 

Methyldopa (dopa = dihydroxy-phenylalanine), as an amino acid, is transported across the blood-brain barrier, decarboxylated in the brain to a-methyldopamine, and then hydroxylat-ed to a-methyl-NE The decarboxylation of methyldopa competes for a portion of the available enzymatic activity, so that the rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter a-methyl-NE can be stored however, unlike the endogenous mediator, it has a higher affinity for a2- than for ai-receptors and therefore produces effects similar to those of clonidine. The same events take place in peripheral adrenergic neurons. 

Dopamine may alternatively be formed from tyrosine via hydroxylation of L-dopa which is decarboxylated. However, inverse isotope dilution experiments to study the formation of dopamine and dopa have shown that this is probably a minor pathway in peyote (176). It has been shown that L-tyrosine is incorporated into alkaloids in peyote three times more efficiently than into protein (344). 4-Hydroxy-3-methoxyphenethylamine can be methylated to 3,4-dimethoxy-phenethylamine (homoveratrylamine), which may be viewed as a dead-end product in Scheme 2 (10, 203). Phenylalanine is probably not a precursor of the... 

Figure 12.4. Pathways in the metabolism of L-dopa (1) and its major decarboxylated product dopamine (2). Major (heavy arrows) and minor (light arrows) reactions are indicated. AD, aldehyde dehydrogenase AAD, aromatic L-amino acid decarboxylase COMT, catechol-O-methyltransferase DH, dopamine jS-hydroxylase MAO, monoamine oxidase PNMT, phenylethanolamine-N-methyl-transferase.

Figure 12.8. Dopamine potentiating or protective agents. These include MAO inhibitors (only selegiline is used clinically to treat PD), inhibitors of the peripheral decarboxylation of r-dopa, and inhibitors cf the 0-methylation of dopamine and L-dopa.

L-Dopa elimination is primarily by decarboxylation to dopamine. Additional pathways are by 3-O-methylation and transamination. With adequate decarboxylase inhibition, increased amounts of L-dopa are metabolized by the other pathways. The elimination half-life of L-dopa is about 1 hour, and this is extended to about U/2 hours with the addition of carbidopa. 30MD has a half-life of about 15 hours and accumulates with chronic dosing. 

SYNTHESIS, STORAGE, AND RELEASE OF CATECHOLAMINES Synthesis—The steps in the synthesis of DA, NE (known outside the U.S. as noradrenaline), and Epi (known as adrenahne) are shown in Eigure 6-A. Tyrosine is sequentially 3-hydroxylated and decarboxylated to form DA. DA is 3-hydroxylated to yield NE (the transmitter in postganglionic nerves of the sympathetic branch of the ANS), which is N-methylated in chromaffin tissue to give Epi. The enzymes involved are not completely specific consequently, other endogenous substances and some drugs are also substrates. 5-hydroxytryptamine (5-HT, serotonin) can be produced from 5-hydroxy-L-tryptophan by aromatic L-amino acid decarboxylase (AAD or dopa decarboxylase). AAD also converts dopa into DA, and methyldopa to a-methyl-DA, which is converted to a-methyl-NE by dopamine /3-hydroxylase (Dj3H Table 6-4). 

Serotonin, or 5-HT, is biosynthesized (3) from its dietary precursor L-tryptophan (Fig. 14.1). Serotonergic neurons contain tryptophan hydroxylase (L-tryptophan-5-monooxygenase) that converts tryptophan to 5-hydroxytryptophan (5-HTP) in what is the rate-limiting step in 5-HT biosynthesis and aromatic L-amino acid decarboxylase (previously called 5-HTP decarboxylase) that decarboxylates 5-HTP to 5-HT. This latter enzyme also is responsible for the conversion of L-DOPA to dopamine (see Chapter 12). The major route of metabolism for 5-HT is oxidative deamination by monoamine oxidase (MAO-A) to the unstable 5-hydroxyindole-3-acetaldehyde, which is either reduced to 5-hydroxytryptophol ( 15%) or oxidized to 5-hydroxyindole-3-acetic acid ( -85%). In the pineal gland, 5-HT is acetylated by 5-HT N-acetyltransferase to N-acetylserotonin, which undergoes O-methylation by 5-hydroxyindole-O-methyltransferase to melatonin. 

Norepinephrine is biosynthesized in the neurons of both the central nervous system and the autonomio nervous system, whereas EPI is formed in the ohromaffin cells of the adrenal medulla. Both NE and EPI are derived from L-tyrosine by a series of enzyme-catalyzed reactions (Fig. 44.4 depicts the overall pathway). L-Tyrosine hydroxylase hydroxylates the meta position of L-tyrosine, producing L-dihydroxyphenylalanine (L-DOPA) and is the rate-limiting step. The L-DOPA is then decarboxylated by L-aromatic amino acid decarboxylase to form dopamine, which is converted to NE by the action of dopamine p-hydroxylase. Dopamine p-hydroxylase occurs in storage vesicles of the nerve ending, and the NE formed is stored there until it is released into the synaptic cleft. In the chromaffin cells, the formed NE is converted to EPI by N-methylation catalyzed by phenylethanolamine N-methyltransferase. 

There is a general agreement that the natural phenethylamines are biogenetically linked to the naturally occurring aromatic amino acids, such as phenylalanine, tyrosine, A/ -methyltyrosine and 3 4 dihydroxy-phenylalanine (dopa). This derivation involves only very simple and biologically plausible reactions, such as decarboxylation, oxidation, and 0- and fV-methylation. 

Noradrenaline (NAdr = norepinephrine, NE) is formed by the stereospecific oxidation of the fl-carbon of dopamine, which itself is formed by the decarboxylation of l-DOPA (L-3,4-dihydroxyphenylalanine). Epinephrine (Adr) is formed by the Af-methylation of norepinephrine. Thus, a compound that blocks the enzyme dopa decarboxylase (responsible for the decarboxylation of dopa) causes a decline in the level of catecholamines, such as dopamine and norepinephrine, and hypotensive activity is expected. The absolute stereostructures of norepinephrine and epinephrine were determined by the transformation of each of these alkaloids into R-mandelic acid [1]. 

Adrenaline is a derivative of tyrosine, and its synthesis and that of noradrenaline is shown in Figure 24.6. Adrenaline and noradrenaline are both amines which, as shown in Figure 24.6, are derived from tyrosine. Tyrosine is first hydroxylated to give dihydroxyphenylalanine (DOPA) and this is then decarboxylated to form dopamine, a natural metabolite which is used in the treatment of Parkinsons disease. Dopamine is converted to noradrenaline by the insertion of a hydroxyl group in the side chain and adrenaline is formed by the methylation of noradrenaline using 5-adenosylmethionine as the methyl donor. Adrenaline is secreted by... 

Dopamine is formed within the brain from both L-dopa and l-3-O-methyldopa, but the latter is probably demethylated first. Administration of either amino acid to man or to animals [487, 494,499] enhances brain levels of dopamine and noradrenaline, and of their O-methylated metabolites, the former effect being further enhanced by monoamine oxidase inhibitors and inhibitors of catechol 0-methyl transferase. Cerebral 3-O-methyldopamine arises by methylation of dopamine rather than by decarboxylation of L-3-O-methyldopa, while the increases in cerebral and urinary homovanillic acid levels after L-dopa arise by oxidative deamination and 3-O-methylation of dopamine formed at the periphery and the neuron. The accumulation of the long-lived amino acid, L-3-O-methyldopa, in the brain, and its slow conversion to dopamine, may well explain why the therapeutic effects of L-dopa in Parkinsonism disappear only slowly upon discontinuation of treatment. Indeed, preliminary studies in man [494] indicate that l-3-O-methyldopa exerts a therapeutic action in Parkinsonism without the com-comitant side effects normally associated with L-dopa therapy. The relevant information regarding the fate and mode of action of L-dopa in the central nervous system is summarised in Figure 5.8. 

Dopamine (4) serves as key intermediate in the biosynthesis of the stress hormone adrenaline (7). Two different routes are available for the biosynthesis of 4 from tyrosine (1). Hydroxylation of the aromatic ring, catalyzed by tyrosine hydroxylase, affords l-DOPA (2), which is converted to dopamine (4) via a decarboxylation step. Alternatively, tyrosine decarboxylase-mediated decarboxylation of tyrosine delivers tyramine that can be hydroxylated to afford the important bioactive intermediate 4. Hydroxylation of the benzylic position in 4 then leads to the formation of norepinephrine, also known as noradrenaline (6), which upon methylation of the amine is converted to epinephrine (adrenaline, 7) [1]. 

The naturally occurring catecholamines—dopamine (DA) (1), / -norepinephrine (/ -NE) (2), and / -epinephrine (/J-EPI) (3)— have many imiK)rtant biological functions. These catecholamines are produced in vivo from L-tyrosine. Tyrosine is first converted to dihydroxyphenylalanine (DOPA) by aromatic hydroxylation. L-DOPA is then decarboxylated to give DA, which is subsequently converted to / -NE by p-hydroxylation. DA is a vital neurotransmitter in the central nervous system (CNS) and has actions on the kidneys and heart. Norepinephrine is also present as a neurotransmitter in the CNS, and is the principal neurotransmitter of the peripheral sympathetic nervous system. Epinephrine, which is elaborated from / -NE by N-methylation in the adrenal medulla, has potent actions on the heart, smooth muscle, and other organs (/). 

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