Neurotransmitter amino acid decarboxylation

Many important neurotransmitters are primary or secondary amines, derived from amino acids in simple pathways. In addition, some polyamines that form complexes with DNA are derived from the amino acid ornithine, a component of the urea cycle. A common denominator of many of these pathways is amino acid decarboxylation, another PLP-requiring reaction (see Fig. 18-6). 

Glycine and glutamate are amino acids that serve directly as neurotransmitters are. y-Aminobutyric acid (GABA), the decarboxylation product of glutamate, is also a neurotransmitter. Amino acid metabolites that function in neurotransmission include histamine (from histidine), serotonin (from tryptophan), and catecholamines (epinephrine, dopamine, and norepinephrine), which are derived from tyrosine. 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

The synthesis and metabolism of trace amines and monoamine neurotransmitters largely overlap [1]. The trace amines PEA, TYR and TRP are synthesized in neurons by decarboxylation of precursor amino acids through the enzyme aromatic amino acid decarboxylase (AADC). OCT is derived from TYR. by involvement of the enzyme dopamine (3-hydroxylase (Fig. 1 DBH). The catabolism of trace amines occurs in both glia and neurons and is predominantly mediated by monoamine oxidases (MAO-A and -B). While TYR., TRP and OCT show approximately equal affinities toward MAO-A and MAO-B, PEA serves as preferred substrate for MAO-B. The metabolites phenylacetic acid (PEA), hydroxyphenylacetic acid (TYR.), hydroxymandelic acid (OCT), and indole-3-acetic (TRP) are believed to be pharmacologically inactive. 

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...

Decarboxylation of amino acids yields bioactive amines including CNS neurotransmitters. 

Pyridoxal phosphate is a required coenzyme for many enzyme-catalyzed reactions. Most of these reactions are associated with the metabolism of amino acids, including the decarboxylation reactions involved in the synthesis of the neurotransmitters dopamine and serotonin. In addition, pyridoxal phosphate is required for a key step in the synthesis of porphyrins, including the heme group that is an essential player in the transport of molecular oxygen by hemoglobin. Finally, pyridoxal phosphate-dependent reactions link amino acid metabolism to the citric acid cycle (chapter 16). 

Some rather important indole derivatives influence our everyday lives. One of the most common ones is tryptophan, an indole-containing amino acid found in proteins (see Section 13.1). Only three of the protein amino acids are aromatic, the other two, phenylalanine and tyrosine being simple benzene systems (see Section 13.1). None of these aromatic amino acids is synthesized by animals and they must be obtained in the diet. Despite this, tryptophan is surprisingly central to animal metabolism. It is modified in the body by decarboxylation (see Box 15.3) and then hydroxylation to 5-hydroxytryptamine (5-HT, serotonin), which acts as a neurotransmitter in the central nervous system. 

The catecholamines noradrenaline (norepinephrine) and adrenaline (epinephrine) are amines derived via decarboxylation of amino acids. Noradrenaline is a mammalian neurotransmitter, and adrenaline, the... 

The neurotransmitter 5-hydroxytryptamine (5-HT, serotonin) is formed from tryptophan by hydroxylation then decarboxylation, paralleling the tyrosine — dopamine pathway. The non-specific enzyme aromatic amino acid decarboxylase again catalyses the decarboxylation. 

Histamine, serotonin, melatonin, and the catecholamines dopa, dopamine, norepinephrine, and epinephrine are known as "biogenic amines."They are produced from amino acids by decarboxylation and usually act not only as hormones, but also as neurotransmitters. 

Whilst the term biogenic amine strictly encompasses all amines of biological origin, for the purpose of this article it will be employed to refer to the catecholamine (dopamine, noradrenaline) and serotonin group of neurotransmitters. These neurotransmitters are generated from the amino acid precursors tyrosine and tryptophan, respectively, via the action of the tetrahydrobiopterin (BH4)-dependent tyrosine and tryptophan hydroxylases. Hydroxylation of the amino acid substrates leads to formation of 3,4-dihydroxy-l-phenylalanine ( -dopa) and 5-hydroxytryptophan, which are then decarboxylated via the pyridoxalphosphate-dependent aromatic amino acid decarboxylase (AADC) to yield dopamine and serotonin [4]. In noradrenergic neurones, dopamine is further metabolised to noradrenaline through the action of dopamine-jS-hydroxylase [1]. 

FIGURE 22-29 Biosynthesis of some neurotransmitters from amino acids. The key step is the same in each case a PLP-dependent decarboxylation (shaded in pink). 

The aromatic amino acids give rise to many plant substances. The PLP-dependent decarboxylation of some amino acids yields important biological amines, including neurotransmitters. 

Amino acids as neurotransmitters. The concentrations of glutamate and of its decarboxylation product y-aminobutyrate (GABA) are high in all regions... 

One of the best characterized physiological functions of (6R)-tetrahydrobio-pterin (BH4, 43) is the action as a cofactor for aromatic amino acid hydroxylases (Scheme 28). There are three types of aromatic amino acid hydroxylases phenylalanine hydroxylase [PAH phenylalanine monooxygenase (EC 1.14.16.1)], tyrosine hydroxylase [TH tyrosine monooxygenase (EC 1.14.16.2)] and tryptophan hydroxylase [TPH tryptophan monooxygenase (EC 1.14.16.4)]. PAH converts L-phenylalanine (125) to L-tyrosine (126), a reaction important for the catabolism of excess phenylalanine taken from the diet. TH and TPH catalyze the first step in the biosyntheses of catecholamines and serotonin, respectively. Catecholamines, i.e., dopamine, noradrenaline and adrenaline, and serotonin, are important neurotransmitters and hormones. TH hydroxylates L-tyrosine (126) to form l-DOPA (3,4-dihydroxyphenylalanine, 127), and TPH catalyzes the hydroxylation of L-tryptophan (128) to 5-hydroxytryptophan (129). The hydroxylated products, 127 and 129, are decarboxylated by the action of aromatic amino acid decarboxylase to dopamine (130) and serotonin (131), respectively. 

The excretion of amines is unusual in animals. Amines are highly toxic and one method employed by vertebrates to detoxify them is via monoamine oxidase, an enzyme which has been detected in H. diminuta (569). Amines can arise from the decarboxylation of the appropriate amino acid, e.g. glycine and alanine can give rise to methylamine and ethylamine, respectively. Another possible source of amines may be the reduction of azo or nitro compounds (39) and azo- and nitro-reductase activity has been reported from M. expansa (180, 181). Furthermore, the physiologically active amines octopamine, dopamine, adrenalin and serotonin (5-hydroxytryptamine) have been demonstrated in cestodes (283, 296, 435, 681, 682, 758, 859), where they probably function predominantly as neurotransmitters (see Chapter 2). 

A number of the products of the decarboxylation of amino acids shown in Table 9.2 are important as neurotransmitters and hormones, such as dopamine, noradrenaline, adrenaline, serotonin (5-hydroxytryptamine), histamine, and Y - aminobutyric acid (GABA), and as the diamines agmatine andput-rescine and the polyamines spermidine and spermine, which are involved in the regulation of DNA metabolism. The decarboxylation of phosphatidylser-ine to phosphatidylethanolamine is important in phospholipid metabolism (Section 14.2.1). 

Purines and pyrimidines are derived largely from amino acids. The biosynthesis of these precursors of DNA, RNA, and numerous coenzymes will be discussed in detail in Chapter 25. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. Histamine, a potent vasodilator, is derived from histidine by decarboxylation. Tyrosine is a precursor of the hormones thyroxine (tetraiodothyronine) and epinephrine and of melanin, a complex polymeric pigment. The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD + are synthesized from tryptophan. Let us now consider in more detail three particularly important biochemicals derived from amino acids. 

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