Tyrosine phenylethylamines

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. 

Figure 13.7 Synthesis and structure of the trace amines phenylethylamine, /)-tyramine and tryptamine. These are all formed by decarboxylation rather than hydroxylation of the precursors of the established monoamine neurotransmitters, dopamine and 5-HT. (1) Decarboxylation by aromatic L-amino acid decarboxylase (2) phenylaline hydroxylase (3) tyrosine hydroxylase (4) tryptophan hydroxylase...

Tyramine is produced by decarboxylation of tyrosine and is present in the CNS in higher (threefold) concentrations than m-tyramine, the hydroxylated derivative of phenylethylamine. In the periphery / -tyramine is easily hydroxylated to octopamine, which has some direct effects on ai adrenoceptors, unlike tyramine which functions by releasing NA. When tested on central neurons tyramine always produces the same effects as NA but they are slower and less marked, implying an indirect action. By contrast octopamine often produces the opposite effect to NA and it is probable that octopamine may have a functional role in the invertebrate CNS where it is found in higher concentrations (5pg/g) than in the mammalian brain (0.5ng/g). Neither tyramine nor octopamine have distinct behavioural effects, unlike phenylethylamine,... 

The deamination of primary amines such as phenylethylamine by Escherichia coli (Cooper et al. 1992) and Klebsiella oxytoca (Flacisalihoglu et al. 1997) is carried out by an oxidase. This contains copper and topaquinone (TPQ), which is produced from tyrosine by dioxygenation. TPQ is reduced to an aminoquinol that in the form of a Cu(l) radical reacts with O2 to form H2O2, Cu(ll), and the imine. The mechanism has been elucidated (Wihnot et al. 1999), and involves formation of a Schiff base followed by hydrolysis in reactions that are formally analogous to those involved in pyridoxal-mediated transamination. 

Phenylketonuria (PKU) is a group of inherited disorders caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH) that catalyses the conversion of phenylalanine to tyrosine, the first step in the pathway for catabolism of this amino acid. As a result, the concentration of phenylalanine in the liver and the blood increases. This high concentration in the liver increases the rate of a side reaction in which phenylalanine is converted to phe-nylpyruvic acid and phenylethylamine, which accumulate in the blood and are excreted in the urine. 

A number of very important natural and synthetic biochemicals belong to the phenylethylamine family. Two of these compounds, dopamine and epinephrine (adrenaline), are neurotransmitters, substances that carry chemical messages through the nervous system of humans and other animals. A third phenylethylamine, tyrosine, is an essential amino acid. And a familiar phenylethylamine found in plants is mescaline, whose chemical name is 2-(3,4,5-trimethoxy-phenyl)ethylamine. The primary natural sources of mescaline are four varieties of cactus two peyote species (Lophophora wiUiamsii and Lophophora diffusa), the San Pedro cactus (Trichocereus pacha-noi), and the Peruvian Torch cactus (Trichocereus peruvianus). 

Figure 6.35 ricinine PLP-dependent decarboxylation of L-tyrosine gives the simple phenylethylamine derivative... 

Perllissier H (2003) Dynamic kinetic resolution. Tetrahedron 59 8291-8327 Pictet A, Spengler T (1911) Formation of isoquinoline derivatives by the action of methylal on phenylethylamine, phenylalanine and tyrosine. Ber Dtsch Chem Ges 44 2030-2036... 

Aromatic amino acids that originate from the shikimate pathway also act as precursors to many alkaloids. Alkaloids that contain a phenylethylamine moiety are derived from L-tyrosine or its oxidation product L-dihydroxyphenylalanine (L-DOPA). Mescaline (N7) originating from the latter amino acid is known to occur in several cacti and is responsible for the hallucinogenic activity of peyote (Lophophora williamsii, Cactaceae). Lophocerine is a tetrahydroisoquinoline alkaloid derived from L-dopamine and found to occur in a different Lophophora species, L. schotti. 

Spenser and co-workers 123) have investigated the biosynthesis of berberine and related alkaloids elaborated by Hydrastis canadensis L. In separate feeding experiments, D-glucose-i C (uniformly labeled), DL-phenylalanine-2-i4C, DL-tyrosine-2-i4C DL-tyrosine-S-i C, and 3,4-dihydroxy-2-phenylethylamine-l-i4C (dopamine) were administered to the growing plants. Of the compounds tested tyrosine was the most efficient precursor of the major alkaloids, berberine and hydrastine, and dopamine was almost as good. Glucose was a much less efficient precursor, and the incorporation of phenylalanine into these alkaloids was almost negligible. 

Despite this result, proof that tyrosine gave rise to two dissimilar intermediates in the biosynthesis of both berberine and hydrastine was provided by the finding that only one molecule of dopamine is incorporated into these alkaloids (58). Degradation of the labeled berberine, obtained after administering 3,4-dihydroxy-2-phenylethylamine-l- C,... 

The foregoing results are in consonance with the ideas proposed many years ago by Robinson and others, and are best interpreted as tyrosine giving rise to 3,4-dihydroxy-2-phenylethylamine and 3,4-dihydroxy-phenylacetaldehyde which condense to form the 1-benzylisoquinoline intermediate, norlaudanosoline. Insertion of the C-1 unit of the berberine bridge would then complete the skeleton of the protoberberine alkaloids. 

Pictet, A., Spengler, T. Formation of Isoquinoline Derivatives by the Action of Methylal on Phenylethylamine, Phenylalanine and Tyrosine. Ber. 1911,44,2030-2036. 

DOPA to dopamine, by the cytosolic enzyme, DOPA decarboxylase. In the central and peripheral nervous systems, dopamine is converted to noradrenaline by dopamine-P-hydroxylase (DBH), which, though a relatively non-specific enzyme, is restricted to catecholamine-synthesizing cells. It can be inhibited by many drugs, which brings the risk of complex drug interactions. In the peripheral sympathetic nervous system, noradrenaline, in turn, is converted to adrenaline, by phenylethylamine N-methyl transferase, so inhibition of DBH can therefore, in principle, slow production of both adrenaline and noradrenaline but normally tyrosine hydroxylase is the rate-limiting step in the synthetic pathway. 

Decarboxylation of amino acids is a typical feature of the bacterial decomposition of proteins. Both phenylethylamine and tyramine were isolated from putrid meat by Barger and Walpole (30), who considered it extremely probable that they were derived from phenylalanine and tyrosine, respectively. No cell-free preparation of phenylalanine decarboxylase appears to have been reported, but decarboxylation by a crude Streptococcus faecalis preparation provides a valuable method of phenylalanine assay (887). Bacterial tyrosine decarboxylase has been studied in detail (495), especially by Gale and co-workers (summarized in 284). It requires pyridoxal phosphate as coenzyme (26, 326, 327) and, unlike mammalian tyrosine decarboxylase, also attacks dihydroxyphenylalanine. Decarboxylation normally only occurs in acid media and is considered primarily to be a protective mechanism tending to restore the pH to neu-... 

The relation of many of the simpler alkaloids to the aromatic amino acids is obvious. For example, germinating barley contains (241), besides tyrosine and tyramine, A -methyltyramine, JViV -dimethyltyramine (hordenine), and the trimethylammonium derivative (candicine). In this simple case the. AT-methylated derivatives are known to be derivable from isotopically labeled tyramine (538) and the methyl groups are known to arise from methionine by transmethylation (540, 586). Similarly AT-methyl derivatives of phenylethylamine, 3,4-dihydroxyphenylethylamine, and 3,4,5-trihy-droxyphenylethylamine are well known alkaloids (cf. review, 701). N-Methylated derivatives of tryptamine and hydroxytryptamine equally occur for example, eserine has an obvious relation to 5-hydroxy tryptamine. Methylated derivatives of metabolites of the aromatic amino acids also occur, for example, trigonelline (67), which is the betaine of nicotinic acid, and damascenine is probably similarly related to hydroxyanthranilic acid. 

Tyrosine decarboxylase (EC 4.1.1.25) was studied at a very early date by Belleau et al. (315, 316) and reinvestigated using more modern methods by Battersby et al. (317). These studies showed that decarboxylation to yield tyramine 312, X = OH, occurred with retention of configuration. Later work (318) showed that aromatic L-amino acid decarboxylase (EC 4.1.1.28) from Micrococcus percitreus catalyzed decarboxylation of phenylalanine 297a to phenylethylamine 312, X = H, with retention of configuration. 

The difficulties which may be encountered in establishing well-known pathways in a new plant are illustrated by feeding experiments with [2 - " C]tyrosine, [l, 2 - H2]dopamine, and 3-hydroxy-4-methoxy[ar- H]phenylethylamine in E. merkei The conversion of tyrosine into hordenine (63), established in barley could not be demonstrated. Nor were tyrosine and dopamine incorporated into salsoline (55), but all three of the labelled compounds were converted into 3,4-dimethoxyphenylethylamine. These results were rationalized as indicating a pathway that diverged after dopamine with appropriate methylation, giving either salsoline (55) or 3,4-dimethoxyphenylethylamine (a similar branch point is observed in L. williamsii for the biosynthesis of mescaline and tetrahydroiso-quinolines). Further, at the time of the experiments the required methyl-transferases for salsoline and hordenine biosynthesis were apparently blocked. In any event the pathway to 3,4-dimethoxyphenylethylamine is manifestly the dominant one, as this alkaloid and its iV-methyl derivatives are major constituent bases of this plant. 

Hordenine (anhaline, eremursine, peyocactine, 4-[2-(dimethylamino)ethyl]-phenol. For formula, data, and occurrence, see j phenylethylamine alkaloids. H. is biosynthesized from phenylalanine or tyrosine via tyramine and N-methyltyramine. H. is a sympathico-mimetic. It has diuretic effects, at higher doses it increases blood pressure, and is generally similar to ephedrine and tyramine. In addition H. is an antifee-dant for locusts. H. is used as a cardiac stimulant of low toxicity and as a disinfectant in cases of dysentery. Lit. Acta Crystallogr., Sect. C 47,1450 (1991) Beilstein EIV 13. 1790 Hager (5.) 5, 708 f. nj. Nat. Prod. 50, 422 (1987) 53,882 (1990) Karrer, No. 2471 see also phenylethylamine alkaloids. 

L-tyrosine Phenylethylamino alkaloids Phenylethylamine Adrenaline Anhalamine Dopamine Noradrealine Tyramine... 

Ala = Alanine, 6-Br-Trp = 6-bromotryptophan, Dide-Phe = a,P-dide-hydro-3,4,5-trihydroxyphenylalanine, Dide-Val = a,P-didehydro-valine, diOH-Sty = 3,4-dihydroxy-trans-styrylamine = [( )-l-amino-2-(3,4-dih-ydroxyphenyl)ethene], Gly = Glycine, lieu = Isoleucine, Leu = Leucine, N-Me = A-methyl, N,N-diMe = A,A-dimethyl-, P-OH = P-hydroxy, OH-Sty = 4-hydroxy-tra s-styrylamine = [( )-l-amino-2-(4-hydroxypheny-l)ethene], Phe = Phenylalanine, Phe-Et = Phenylethylamine, Pro= Proline, Sty = Styrylamine, Trp = Tryptophan, Tyr = Tyrosine, Val = Valine. 

The aromatic BA, tyramine and (3-phenylethylamine are prodnced, respectively, by decarboxylation of tyrosine and phenylalanine by the enzyme tyrosine decarboxylase (TDC) (Landete, De las Rivas, Marcobal, Munoz, 2007 Pessione et al, 2009). TDC was purified from the strain L brevis lOEB 9809 isolated from wine (Moreno-Arribas Lonvaud-Funel, 2001 Russo et al, 2012). Lucas and Lonvaud-Funel (2002) described that in L. brevis lOEB 9809, the tyramine biosynthetic pathway is encoded by a cluster of four genes (Figure 12.2). All strains carrying the TDC cluster produce both tyramine and 3-phenylethylamine, but the levels of the latter are four to... 

Hordenine and iV-methyltyramine are isolates fix)m the young roots of Hordeum vulgare var. hexastichon (Poaceae), and are simple phenylethylamine-type alkaloids. The biosynthetic precursor of these alkaloids is considered to be tyramine, derived from tyrosine. d/-[2- " C]-Tyrosine was fed to H. vulgare var. hexastichon 4 days after germination, and hordenine and N-methyltyramine were isolated after 11 days from the roots. Both alkaloids possessed label at the a-carbon. It was also found that d/-[2- " C]-tyrosine was more effectively incorporated into N-methyltyramine than into hordenine, and no tyramine was detected in the extract. So, the incorporated tyrosine was converted into tyramine and methylated immediately to give N-methyltyramine. Subsequent steps form hordenine by the methylation of N-methyltyramine [3]. 

The phenylethylamines originate by decarboxylation of the amino acids L-phenyl-alanine, L-tyrosine, and l-DOPA (Fig. 270). 

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