Tryptophan, decarboxylated

Widespread from Tryptophan decarboxylation Mucuna pruriens, Prosopisjuliflora (mesquite) (Fabaceae), Lycopersicon esculentum (Solanaceae)... 

Occurs in coal tar, in various plants and in faeces, being formed by the action of the intestinal bacteria on tryptophan. It can be prepared by the action of acid on the phenyl-hydrazone of pyruvic acid to give indole-2-carboxylate which can be decarboxylated to indole. 

One effective method for synthesis of tryptophan derivatives involves alkylation of formamido- or acetamido- malonate diesters by gramine[l,2]. Conversion to tryptophans is completed by hydrolysis and decarboxylation. These reactions were discussed in Chapter 12. An enolate of an a-nitro ester is an alternative nucleophile. The products can be converted to tryptophans by rcduction[3,4],... 

L-tryptophan by hydroxylation to 5-hydroxy-L-tryptophan by the enzyme, ttyptophan-5-hydroxylase. 5-Hydroxy-L-tryptophan is then rapidly decarboxylated by aromatic-L-amino acid deacarboxylase to 5-HT. The actions of 5-HT as a neurottansmitter ate terminated by neuronal reuptake and metabobsm. 

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. 

Application of the Bischler-Napieralski reaction to amides of tryptophan has been investigated. The cyclodehydration of acetyltrypto-phan under conventional conditions proved unsuccessful. Attempted ring closure of acetyltryptophan or its ethyl ester was accompanied by decarboxylation and aromatization, yielding... 

Decarboxylation of histidine to histamine is catalyzed by a broad-specificity aromatic L-amino acid decarboxylase that also catalyzes the decarboxylation of dopa, 5-hy-droxytryptophan, phenylalanine, tyrosine, and tryptophan. a-Methyl amino acids, which inhibit decarboxylase activity, find appfication as antihypertensive agents. Histidine compounds present in the human body include ergothioneine, carnosine, and dietary anserine (Figure 31-2). Urinary levels of 3-methylhistidine are unusually low in patients with Wilson s disease. 

Following hydroxylation of tryptophan to 5-hydroxy-tryptophan by hver tyrosine hydroxylase, subsequent decarboxylation forms serotonin (5-hydroxytrypta-... 

By contrast, the cytoplasmic decarboxylation of dopa to dopamine by the enzyme dopa decarboxylase is about 100 times more rapid (Am 4x 10 " M) than its synthesis and indeed it is difficult to detect endogenous dopa in the CNS. This enzyme, which requires pyridoxal phosphate (vitamin B6) as co-factor, can decarboxylate other amino acids (e.g. tryptophan and tyrosine) and in view of its low substrate specificity is known as a general L-aromatic amino-acid decarboxylase. 

The product of the hydroxylation of tryptophan, 5-hydroxytryptophan, is rapidly decarboxylated to 5-HT by a specific decarboxylase enzyme. This is generally thought to be a soluble enzyme which suggests that 5-HT is synthesised in the cytoplasm, before it is taken up into the storage vesicles. If this is the case, then considerable losses might be incurred from its metabolism by monoamine oxidase before it reaches the storage vesicles. Indeed, this could explain why 5-HT turnover seems to greatly exceed its rate of release. 

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...

FIGURE 10.3 Pathways for degradation of L-tryptophan by (a) tryptophanase, (b) deamination and oxidation, and (c) side-chain oxidation and decarboxylation to indole. 

Biogenic amines are decarboxylated derivatives of tyrosine and tryptophan that are found in animals from simple invertebrates to mammals. These compounds are found in neural tissue, where they function as neurotransmitters, and in non-neural tissues, where they have a variety of functions. The enzymes involved in biogenic amine synthesis and many receptors for these compounds have been isolated from both invertebrate and vertebrate sources. In all cases, the individual proteins that effect biogenic amine metabolism and function show striking similarity between species, indicating that these are ancient and well-conserved pathways. 

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.

Serotonin is synthesized from tryptophan in two steps. Tryptophan is hydroxylated by tryptophan hydroxylase, and 5-hydroxytryptophan is decarboxylated to give serotonin. Most serotonin in the body is found in the enterochromaffin cells of the intestinal tract and the pineal gland. Platelets take up and store serotonin but do not synthesize it. 

The initial hydroxylation of tryptophan, rather than the decarboxylation of 5-HTP, appears to be the rate-limiting step in serotonin synthesis. Therefore, the inhibition of this reaction results in a marked depletion of the content of 5-HT in brain. The enzyme inhibitor most widely used in experiments is parachlorophenylalanine (PCPA). In vivo, PCPA irreversibly inhibits tryptophan hydroxylase, presumably by incorporating itself into the enzyme to produce an inactive protein. This results in a long-lasting reduction of 5-HT levels. Recovery of enzyme activity, and 5-HT biosynthesis, requires the synthesis of new enzyme. Marked increases in mRNA for tryptophan hydroxylase are found in the raphe nuclei 1-3 days after administration of PCPA [6]. 

Since tryptophan (and its decarboxylation product, tryptamine) serve as precursors in many synthetic and biosynthetic routes to /J-carbolincs, it is not surprising that C-1 of the /J-carbolinc ring is the most common site of substitution (as it is the only ring atom of the /J-carbolinc ring system not derived from tryptophan). Indeed, this is the only site of substitution for many /J-carboline natural products. Two examples of naturally occurring /J-carbolines substituted only at C-1 which possess antitumor activity are manzamine A and manzamine C (Fig. 2). Owing to its greater simplicity and nearly equal antitumor activity, most initial synthetic efforts were directed toward manzamine C [11,12]. 

Vitamin Ba (pyridoxine, pyridoxal, pyridoxamine) like nicotinic acid is a pyridine derivative. Its phosphorylated form is the coenzyme in enzymes that decarboxylate amino acids, e.g., tyrosine, arginine, glycine, glutamic acid, and dihydroxyphenylalanine. Vitamin B participates as coenzyme in various transaminations. It also functions in the conversion of tryptophan to nicotinic acid and amide. It is generally concerned with protein metabolism, e.g., the vitamin B8 requirement is increased in rats during increased protein intake. Vitamin B6 is also involved in the formation of unsaturated fatty acids. 

Serotonin (5-hydroxytrptamine, 5-HT) synthesis involves an hydroxylation reaction (catalysed by tryptophan mono-oxygenase) and a decarboxylation step, similar to that in adrenaline (epinephrine) synthesis. 

Tryptophan is also an important starting point for biosynthetic reactions. The decarboxylation of tryptophan yields tryptamine, a molecule found in very low concentrations in the mammalian brain where it may function as a neurotransmitter or neuromodulator. It is found in high concentrations in some cheeses. 

Following the synthesis of 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase, the enzyme aromatic amino acid decarboxylase (also known as 5-HTP or dopa decarboxylase) then decarboxylates the amino acid to 5-HT. L-Aromatic amino acid decarboxylase is approximately 60% bound in the nerve terminal and requires pyridoxal phosphate as an essential enzyme. 

Figure 2.18. The major pathway leading to the synthesis and metabolism of 5-hydroxytryptamine (5-HT). Metabolism of tryptophan to tryptamine is a minor pathway which may be of functional importance following administration of a monoamine oxidase (MAO) inhibitor. Tryptamine is a trace amine. L-Aromatic amino acid decarboxylase is also known to decarboxylate dopa and therefore the term "L-aromatic amino acid decarboxylase" refers to both "dopa decarboxylase"...

For the preparation of 3,4-dihydro-/3-carbolines the Bischler-Napieralski reaction is widely used (510R74). Since this reaction requires rather drastic conditions, A-acetyl tryptophan and its analogs yielded l-methyl-/8-carboline (harman) rather than l-methyl-3,3-dihydro-j8-carboline-3-carboxylic acid derivatives owing to accompanying decarboxylation and aromatization (41JCS153 50JA2962). 

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. 

Dopamine is the decarboxylation product of DOPA, dihydroxyphenylalanine, and is formed in a reaction catalysed by DOPA decarboxylase. This enzyme is sometimes referred to as aromatic amino acid decarboxylase, since it is relatively non-specific in its action and can catalyse decarboxylation of other aromatic amino acids, e.g. tryptophan and histidine. DOPA is itself derived by aromatic hydroxylation of tyrosine, using tetrahydrobiopterin (a pteridine derivative see Section 11.9.2) as cofactor. 

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. 

Biogenic amines arise from amino acids by decarboxylation (see p. 62). This group includes 4-aminobutyrate (y-aminobutyric acid, GABA), which is formed from glutamate and is the most important inhibitory transmitter in the CNS. The catecholamines norepinephrine and epinephrine (see B), serotonin, which is derived from tryptophan, and histamine also belong to the biogenic amine group. All of them additionally act as hormones or mediators (see p. 380). 

True alkaloids derive from amino acid and they share a heterocyclic ring with nitrogen. These alkaloids are highly reactive substances with biological activity even in low doses. All true alkaloids have a bitter taste and appear as a white solid, with the exception of nicotine which has a brown liquid. True alkaloids form water-soluble salts. Moreover, most of them are well-defined crystalline substances which unite with acids to form salts. True alkaloids may occur in plants (1) in the free state, (2) as salts and (3) as N-oxides. These alkaloids occur in a limited number of species and families, and are those compounds in which decarboxylated amino acids are condensed with a non-nitrogenous structural moiety. The primary precursors of true alkaloids are such amino acids as L-ornithine, L-lysine, L-phenylalanine/L-tyrosine, L-tryptophan and L-histidine . Examples of true alkaloids include such biologically active alkaloids as cocaine, quinine, dopamine, morphine and usambarensine (Figure 4). A fuller list of examples appears in Table 1. 

Dietary tryptophan is the source of the formation of serotonin. Enzymes and cofactors necessary for serotonin synthesis are present in both the enterochromaf-lin cells of the gastrointestinal tract and neurons in the brain. Tryptophan is initially hydroxylated to form 5-hydroxytryptophan. Decarboxylation of the latter compound results in the formation of serotonin (Fig. 24.2). 

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