PNMT

Fig. 2. Biosynthetic pathway for epinephrine, norepinephrine, and dopamine. The enzymes cataly2ing the reaction are (1) tyrosine hydroxylase (TH), tetrahydrobiopterin and O2 are also involved (2) dopa decarboxylase (DDC) with pyridoxal phosphate (3) dopamine-P-oxidase (DBH) with ascorbate, O2 in the adrenal medulla, brain, and peripheral nerves and (4) phenethanolamine A/-methyltransferase (PNMT) with. Cadenosylmethionine in the adrenal...

Trace Amines. Figure 1 The main routes of trace amine metabolism. The trace amines (3-phenylethylamine (PEA), p-tyramine (TYR), octopamine (OCT) and tryptamine (TRP), highlighted by white shading, are each generated from their respective precursor amino acids by decarboxylation. They are rapidly metabolized by monoamine oxidase (MAO) to the pharmacologically inactive carboxylic acids. To a limited extent trace amines are also A/-methylated to the corresponding secondary amines which are believed to be pharmacologically active. Abbreviations AADC, aromatic amino acid decarboxylase DBH, dopamine b-hydroxylase NMT, nonspecific A/-methyltransferase PNMT, phenylethanolamine A/-methyltransferase TH, tyrosine hydroxylase. 

CLIP Corticotropin-hke intermediate lobe peptide OHSD Hydroxysteroid dehydrogenase PNMT Phenylethanolamine-W-methyltransferase ... 

Figure 42-10. Biosynthesis of catecholamines. (PNMT, phenylethanolamine-N-methyltransferase.)...

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

PNMT catalyzes the N-methylation of norepinephrine to form epinephrine in the epinephrine-forming cells of the adrenal medulla. Since PNMT is soluble, it is assumed that norepinephrine-to-epinephrine conversion occurs in the cytoplasm. The synthesis of PNMT is induced by glucocorticoid hormones that reach the medulla via the intra-adrenal portal system. This special system provides for a 100-fold steroid concentration gradient over systemic arterial blood, and this high intra-adrenal concentration appears to be necessary for the induction of PNMT. 

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.

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... 

Ordinarily, low concentrations of catecholamines are free in the cytosol, where they may be metabolized by enzymes including monoamine oxidase (MAO). Thus, conversion of tyrosine to l-DOPA and l-DOPA to dopamine occurs in the cytosol dopamine then is taken up into the storage vesicles. In norepinephrine-containing neurons, the final P-hydroxylation occurs within the vesicles. In the adrenal gland, norepinephrine is N-methylated by PNMT in the cytoplasm. Epinephrine is then transported back into chromaffin granules for storage. 

Bohn, M. C., Bloom, E., Goldstein, M. and Black, I. B. Glucocorticoid regulation of phenylethanolamine N-methyl-transferase (PNMT) in organ culture of superior cervical ganglia. Dev. Biol. 105 130-136,1984. 

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). 

Some of the catecholamine will enter the target cell rather than be recaptured by the neurone. Inactivation is brought about by the second enzyme, COMT which uses S-adenosyl methionine as a methyl donor as does PNMT (involved with catecholamine... 

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. 

Figure 16.11 Control of catecholamine biosynthesis in the adrenal medulla. TH, tyrosine hydroxylase DBH, dopamine hydroxylase PNMT, phenylethanolamine methyl-transferase ACTH, adrenocorticotropic hormone. The heavy arrows indicate major sites of regulation. (Reproduced by permission from Axelrod, J. Reisine TD. Stress hormones their interaction and regulation. Science 224 452-459, 1984.)...

Mekenyan, O., Mercier, C., Bonchev, D. and Dubois, J.-E. (1993a). Comparative Study of DARC/PELCO and OASIS Methods. 2. Modeling PNMT Inhibitory Potency of Benzylamines and Amphetamines. Eur.J.Med.Chem., 28, 811-819. 

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.

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... 

Levels of phenylethanolamine-N-methyltransferase (PNMT) have been found to be significantly raised in discrete brain stem regions in both SHR and DOCA-salt hypertensive rats.33 Administration of SKF 7698 (7), a PNMT inhibitor, normalized pressure in DOCA rats. The possibility that the effect was due to the adrenolytic action of (7) was not excluded. The best of a new series of PNMT inhibitors with much reduced a-blocking properties is SKF 6 139 (8).3 ... 

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