Phenylethanolamine iV-methyltransferase

The general scheme of the biosynthesis of catecholamines was first postulated in 1939 (29) and finally confirmed in 1964 (Fig. 2) (30). Although not shown in Figure 2, in some cases the amino acid phenylalanine [63-91-2] can serve as a precursor it is converted in the liver to (-)-tyrosine [60-18-4] by the enzyme phenylalanine hydroxylase. Four enzymes are involved in E formation in the adrenal medulla and certain neurons in the brain tyrosine hydroxylase, dopa decarboxylase (also referred to as L-aromatic amino acid decarboxylase), dopamine-P-hydroxylase, and phenylethanolamine iV-methyltransferase. Neurons that form DA as their transmitter lack the last two of these enzymes, and sympathetic neurons and other neurons in the central nervous system that form NE as a transmitter do not contain phenylethanolamine N-methyl-transferase. The component enzymes and their properties involved in the formation of catecholamines have been purified to homogeneity and their properties examined. The human genes for tyrosine hydroxylase, dopamine- 3-oxidase and dopa decarboxylase, have been cloned (31,32). It is anticipated that further studies on the molecular structure and expression of these enzymes should yield interesting information about their regulation and function. 

Antibacterial, antihelmintic, antiviral activity, anaesthetic, inflammatory [327], analgetic [328], inhibitors of phenylethanolamine IV-methyltransferase in pharmaceutical composition [329], high electroconductivity [330], in manufacture of epoxy polymers [331], in photography [332-335], metal corrosion inhibition [336-338]... 

Phenylethanolamine iV-methyltransferase Largely in adrenal gland Cytoplasmic S -Adenosyl methionine (CH3 donor) Nonspecific Inhibition leads to decrease in adrenal catecholamines under control of glucocorticoids... 

A/-Methylations are catalysed by several enzymes such as nicotinamide A -methyltransferase, histamine methyltransferase, phenylethanolamine iV-methyltransferase (noradrenaline Af-methyltransferase) and a non-specific amine N-methyltransferase (arylamine iV-methyltransferase, tryptamine iV-methyltransferase). S-Methylations are catalysed by the membrane-bound thiol methyltransferase and the cytosolic thiopurine methyltransferase. 

Grunewald, G. L, Dahanukar, V. H., Jalluri, R. K., Ctiscione, K. R. Synthesis, biochemical evaluation and classical and three-dimensional quantitative structure-activity relationship studies of 7-substituted-l,2,3,4-tetrahydroisoquinolines and their relative affinities toward phenylethanolamine iV-methyltransferase and the 012-adrenoreceptor. J. Med. Chem. 1999, 42, 118-134. 

A number of methyltransferases are able tc methylate small molecules (46,47). Thus, re. actions of methylation fulfill only two of the three criteria defined above, because the methyl group is small compared with the substrate. The main enzyme responsible for O-methylation is catechol 0-methyltransferas (EC 2.1.1.6 COMT), which is mainly cytosolic but also exists in membrane-bound form. Several enzymes catalyze reactions of xenobiotic N-methylation with different substrate specificities, e.g., nicotinamide iV-methyltrans-ferase (EC 2.1.1.1), histamine methyltrans-ferase (EC 2.1.1.8), phenylethanolamine N-methy 1 transferase (noradrenal ine A-meth-yltransferase EC 2.1.1.28), and nonspecific amine N-methyltransferase (arylamine N-methyltransferase, tryptamine JV-methyl-transferase EC 2.1.1.49) of which some isozymes have been characterized. Reactions of xenobiotic S-methylation are mediated by the membrane-bound thiol methyltransferase (EC 2.1.1.9) and the cytosolic thiopurine methyltransferase (EC 2.1.1.67) (3). 

Three basic types of N-methylation reactions have been recognized (reactions 2-4, Fig. 13.15). A number of primary amines (e.g., amphetamine) and secondary amines (e.g., tetrahydroisoquinolines) have been shown to be in vitro substrates of amine iV-methyltrans-ferase, whereas some phenylethanolamines and analogs are methylated by phenyletha-nolamine N-methyltransferase (reaction 2). However, such reactions are seldom of significance in vivo, presumably because of effective oxidative N-demethylation. A comparable situation involves the N-41 group in an imidazole ring (reaction 3), exemplified by histamine (49). A therapeutically relevant example is that of theophylline (16) whose iV(9)-meth-ylation is masked by N-demethylation in adult but not newborn humans. 

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