Epinephrine phenylethanolamine

Neural cells convert tyrosine to epinephrine and norepinephrine (Figure 31—5). While dopa is also an intermediate in the formation of melanin, different enzymes hydroxylate tyrosine in melanocytes. Dopa decarboxylase, a pyridoxai phosphate-dependent enzyme, forms dopamine. Subsequent hydroxylation by dopamine P-oxidase then forms norepinephrine. In the adrenal medulla, phenylethanolamine-A -methyltransferase uti-hzes S-adenosyhnethionine to methylate the primary amine of norepinephrine, forming epinephrine (Figure 31-5). Tyrosine is also a precursor of triiodothyronine and thyroxine (Chapter 42). 

D. Phenylethanolamine-ZV-methyltransferase (PNMT) Catalyzes the Production OF Epinephrine ... 

Figure 1. Biosynthetic pathways for biogenic amines. In Drosophila and vertebrates decarboxylation of DOPA and 5-hydroxy-tryptophan is catalyzed by the same enzyme, DDC. In vertebrates this enzyme is called amino acid decarboxylase (AADC). Only vertebrates further metabolize dopamine to norepinephrine and epinephrine. TH, tryosine hydroxylase DDC, DOPA decarboxylase DBH, dopamine b-hydroxylase PNMT, phenylethanolamine N-methyltransferase. Tryp-OH tryptophan hydroxylase.

Epinephrine is synthesized from NE in the adrenal medulla. Norepinephrine is methylated by phenylethanolamine-N-m ethyl transferase. Neurons containing this enzyme are also found in the CNS. 

In cells that synthesize epinephrine, the final step in the pathway is catalyzed by the enzyme phenylethanolamine /V-methyltransferase. This enzyme is found in a small group of neurons in the brainstem that use epinephrine as their neurotransmitter and in the adrenal medullary cells, for which epinephrine is the primary hormone secreted. Phenylethanolamine N-methyltransferase (PNMT) transfers a methyl group from S-adenosylmethionine to the nitrogen of norepinephrine, forming a secondary amine [5]. The coding sequence of bovine PNMT is contained in a... 

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). 

Synthesis of noradrenaline (norepinephrine) is shown in Figure 4.7. This follows the same route as synthesis of adrenaline (epinephrine) but terminates at noradrenaline (norepinephrine) because parasympathetic neurones lack the phenylethanolamine-N-methyl transferase required to form adrenaline (epinephrine). Acetylcholine is synthesized from acetyl-Co A and choline by the enzyme choline acetyltransferase (CAT). Choline is made available for this reaction by uptake, via specific high-affinity transporters, within the axonal membrane. Following their synthesis, noradrenaline (norepinephrine) or acetylcholine are stored within vesicles. Release from the vesicle occurs when the incoming nerve impulse causes an influx of calcium ions resulting in exocytosis of the neurotransmitter. 

This enzyme [EC 2.1.1.28], also known as phenylethanol-amine A -methyltransferase, catalyzes the reaction of S-adenosyl-L-methionine with phenylethanolamine to produce 5-adenosyl-L-homocysteine and A -methylphenyl-ethanolamine. The enzyme will act on a number of phe-nylethanolamines and will catalyze the conversion of noradrenalin (or norepinephrine) into adrenalin (or epinephrine). 

In noradrenergic neurons, the end product is norepinephrine. In the adrenal medulla, the synthesis is carried one step further by the enzyme phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine. The human adrenal medulla contains approximately four times as much epinephrine as norepinephrine. The absence of this enzyme in noradrenergic neurons accounts for the absence of significant amounts of epinephrine in noradrenergic neurons. The structures of these compounds are shown in Figure 9.4. 

Newer MAOI drugs are selective for the MAO-A subtype of the enzyme, and are less likely to interact with foods or other drugs. Monoamine oxidase (MAO) inactivates monoamine substances, many of which are, or are related to, neurotransmitters. The central nervous system mainly contains MAO-A, whose substrates are adrenaline (epinephrine), noradrenaline (norepinephrine), metanephrine, and 5-hydroxyti7ptamine (5-HT), whereas extra-neuronal tissues, such as the liver, lung, and kidney, contain mainly MAO-B which metabolises p-phenylethylamine, phenylethanolamine, o-tyramine, and benzylamine. 

Tyrosine is converted to dopa by the rate-limiting enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin, and is inhibited by a-methyltyrosine. Dopa is decarboxylated to dopamine by L-aromatic amino acid decarboxylase, which requires pyridoxal phosphate (vitamin B6) as a coenzyme. Carbidopa, which is used with levodopa in the treatment of parkinsonism, inhibits this enzyme. Dopamine is converted to norepinephrine by dopamine P-hydroxylase, which requires ascorbic acid (vitamin C), and is inhibited by diethyldithiocarbamate. Norepinephrine is converted to epinephrine by phenylethanolamine A -methyltransferase (PNMT), requiring S-adeno-sylmethionine. The activity of PNMT is stimulated by corticosteroids. 

A series of tetrahydrothiadiazoloisoquinolines that could potentially reduce the formation of epinephrine by inhibiting phenylethanolamine-jV-methyltransferase has been prepared <89JMC1566>. 

The secretion of epinephrine by the adrenal medulla is controlled directly by nerve impulses and also by the other stress hormones, namely, corticosteroids. This is illustrated in Figure 16.11. Nerve impulses have a major stimulatory effect on tyrosine and dopamine hydroxylases, whereas glucocorticoids have a major effect on phenylethanolamine methyltransferase. Tyrosine hydroxylase is considered the rate-controlling enzyme in the biosynthesis... 

Histamine, serotonin and the catecholamines (dopamine, epinephrine and norepinephrine) are synthesized from the aromatic amino acids histidine, tryptophan and phenylalanine, respectively. The biosynthesis of catecholamines in adrenal medulla cells and catecholamine-secreting neurons can be simply summarized as follows [the enzyme catalysing the reaction and the key additional reagents are in square brackets] phenylalanine — tyrosine [via liver phenylalanine hydroxylase + tetrahydrobiopterin] —> i.-dopa (l.-dihydroxyphenylalanine) [via tyrosine hydroxylase + tetrahydrobiopterin] —> dopamine (dihydroxyphenylethylamine) [via dopa decarboxylase + pyridoxal phosphate] — norepinephrine (2-hydroxydopamine) [via dopamine [J-hydroxylasc + ascorbate] —> epinephrine (jV-methyl norepinephrine) [via phenylethanolamine jV-methyltransferase + S-adenosylmethionine]. 

The additional presence of phenylethanolamine N-methyltransferase in adrenal medullary chromaffin cells leads to further conversion of norepinephrine to epinephrine (Figure 29-2). Since phenylethanolamine N-methyitransferase is a cytosolic enzyme, this step depends on leakage of norepinephrine from vesicular storage granules into the ceU cytoplasm and the transfer of a methyl group from S-adenosylmethionine to norepinephrine. Epinephrine is then translocated into chromaffin granules where the amine is stored, awaiting release. 

However, because phenylethanolamine-N-methyl-transferase (PNMT) is expressed mainly in adrenal chromaffin cells, more than 90% of circulating epinephrine is derived from the adrenal meduUa. This contrasts with... 

Norepinephrine diifuses into the cytosol, where it is converted to epinephrine by methylation of its amino group. This reaction, in which the methyl group is donated by S-adenosylmethionine, is catalyzed by S-adenosyl-L-methionine phenylethanolamine-N-methyltransferase (PNMT). Epinephrine enters the granules and remains there until it is released. 

Dopamine, norepinephrine, and epinephrine act as neurotransmitters and/or hormones. (PNMT is an abbreviation for phenylethanolamine-N-methyltransferase.)... 

As described, the secretion of epinephrine in response to stress, trauma, extreme exercise, or hypoglycemia causes a rapid mobilization of energy stores, that is, glucose from the liver and fatty acids from adipose tissue. The reaction in which NE is methylated to form E is mediated by the enzyme phenylethanolamine-N-methyltransferase (PNMT). Although the enzyme occurs predominantly in the chromaffin cells of the adrenal medulla, it is also... 

Transferases are enzymes that catalyze the transfer of functional groups from one molecule to another. For example, a transaminase catalyzes the transfer of an amino functional group, and a kinase catalyzes the transfer of a phosphate group. Kinases play a major role in energy-harvesting processes involving ATP. In the adrenal glands, norepinephrine is converted to epinephrine by the enzyme phenylethanolamine-N-methyltransferase (PNMT), a transmethylase. 

The next enzyme in the biosynthetic pathway to norepinephrine and epinephrine, dopamine p-hydroxylase. has been the subject of extensive research into its chemical mechanism and the subject of many enzyme inhibition studies. The inhibitors known to date, however, are primarily of basic biochemical research interest and have no therapeutic relevance. The same is true of phenylethanolamine-N-methyltransferase. the last enzyme in the biosynthesis of epinephrine in the adrenal medulla. 

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