Decarboxylation of aromatic amino acids

The pH dependence of the decarboxylation rate of some aromatic amino acids has been studied in dilute solutions of strong acids and in acetate buffers, at a constant ionic strength of ju = 0.1 N. The results can be fitted into a rate equation with two terms, viz. 

This corresponds to parallel first-order decompositions of H2S+ and HS, or to parallel second-order reactions of HS and S with H30+. In the example of 4-aminosalicylic acid, fen2s [H2S+] represents a relatively small correction term [250]. In the cases of 4-aminobenzoic acid [78] and anthranilic acid [77], however, feH2s [H2S+] is the more important term at pH values below 4. Equation (68) is equivalent to the following equation for the dependence of the first-order rate coefficient on 

Weak general catalysis by acetic acid (just above the limits of experimental error) has been found in the decarboxylation of 4-aminobenzoic acid in the pH region near 5 [78]. Under similar conditions, general catalysis cannot be detected in the decarboxylation of anthranilic acid [77]. The solvent isotope effects are (feH S)H 0/(feD2s)D2o = 4.9 for 4-aminobenzoic acid at 85 °C [78] and rh Q/kno = 4.7 for anthranilic acid in 0.1 M aqueous hydrochloric acid at 5 °C [251]. The latter result (ratio 

The magnitude of the solvent isotope effect and the absence of a carbon isotope effect confirm that proton transfer is rate-determining in the reactions referring to s. As far as the reactions referring to are concerned, the experimental values of these rate coefficients for the decarboxylation of 2- and 4-aminobenzoic acids, as well as the Arrhenius parameters, are comparable to those of the substituted salicylic acids if expected substituent effects are taken into account (Table 21) there is a correlation between log A and Ea. Therefore, it is reasonable to expect that the mechanism is the same. The observed general catalysis supplies additional evidence for rate-determining proton transfer from H30+ to S (sigma complex formation) in the decarboxylation of 4-aminobenzoic acid. 

4 CHANGE OF THE RATE-DETERMINING STEP IN STRONGLY ACIDIC 

---

Consequently, the experimental findings for the dependence of fe on [H+] in the decarboxylation of aromatic amino acids indicate that the ratedetermining step changes from slow protonation at low [H+] to slow carbon—carbon bond cleavage at high [H +]. (This conclusion on the basis of the pH dependence is independent of all other evidence such as isotope effects and general catalysis.)... 

The increase of the rate coefficient with increasing acidity of the solution is probably caused by an additional reaction between ArCOOH and H30+, according to rate eqn. (68) (involving [H30+]) as observed also in the decarboxylation of aromatic amino-acids. This assumption is confirmed by comparisons of isotope effect data. According to Bourns results [247] of carbon isotope effects (Table 22), carbon—carbon bond cleavage is still relatively unimportant in the transition state of the reaction in 1 M HC104. On the other hand, the solvent isotope effect is decreased from ca. 6 in 0.02 M HC1 to 2.0 in 1.0 M HC1 (Table 24) [259]. If the reaction sequence... 

Methyldopa was described by Sourkes [229] in 1954 as an inhibitor of the enzyme dopa decarboxylase. As can be seen from the diagram on p. 103, this enzyme acts as a catalyst in the decarboxylation of aromatic amino acids to amines, including the decarboxylation of dopa [173] to dopamine, the immediate precursor of norepinephrine. 

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. 

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

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. 

Dopamine is synthesized in the terminals of dopaminergic fibers originating with the amino acid tyrosine and, subsequently, L-dihydroxyphenylalanine (L-dopa or levodopa), the rate-limiting metabolic precursor of dopamine. Fortunately, L-dopa is significantly less polar than dopamine and can gain entry into the brain via an active process mediated by a carrier of aromatic amino acids. Although L-dopa is itself basically pharmacologically inert, therapeutic effects can be produced by its decarboxylation to dopamine within the CNS. 

Catecholamines are endogenous compounds and are synthesized in the brain, the adrenal medulla, and by some sympathetic nerve fibers. The biosynthesis of catecholamines begins with the hydroxylation of tyrosine by tyrosine hydroxylase to form L-dopa, which is decarboxylated by aromatic amino acid decarboxylase to form dopamine. Norepinephrine... 

Figure 7 Biosynthesis of aromatic amino acids and products derived from phenylalanine or from intermediates of the shikimate pathway. Biosynthetically equivalent positions are indicated by colored bars. The atoms indicated by the blue bars are equivalent to atoms from phosphoenol pyruvate precursor followed by the loss of one carbon atom by decarboxylation.

Specific decarboxylases are known for a majority of the amino acids, and several are prime targets for inactivation by virtue of their substantial medicinal importance. These include aromatic-amino-acid decarboxylase, which is responsible for the production of dopamine (DOPA) orithine decarboxylase, which supplies the p amine putrescine and glutamate decarboxylase, which converts glutamate to the inhibitory neurotransmitter y-aminobutyric acid (GABA). The accepted mechanism of these enzymes involves decarboxylation of the amino acid to yield a resonance-stabilized carbanion at the a-carbon of the substrate. The intermediate is then protonated with retention of configuration to yield product (Walsh, 1979, p. 800). 

Fears have been expressed [510, 511] that long-term administration of L-dopa may induce a state of pyridoxine deficiency, since excess dietary pyridoxine, which is rapidly converted in vivo to the decarboxylase coenzyme pyridoxine-5 -phosphate [512], can nullify the beneficial effects of the amino acid [513-515]. Pyridoxine apparently both complexes with L-dopa and produces an accelerated decarboxylation of the amino acid in extracerebral tissues, both processes effectively reducing the amount of available dopamine in the striatum [512, 516]. The decarboxylase inhibitor MK-485 (37) prevents this reversal of the therapeutic effect by pyridoxine [517] and, more significantly, pyridoxine actually enhances the effects of L-dopa when given in conjunction with such an inhibitor [518]. The mechanism involved in this potentiation reflects enhancement by pyridoxine of dopa decarboxylase activity within the striatum in the presence of complete inhibition of extracerebral decarboxylase. The use of combinations of L-dopa, pyridoxine, and inhibitors of aromatic L-amino-acid decarboxylase, may lead to a more... 

Tryptophan-Derived Indole and Indole Monoterpene Alkaloids As for alkaloids derived from tyrosine and phenylalanine, those derived from tryptophan are formed after decarboxylation of the amino acid (into tryptamine) and possible hydroxylation of the aromatic carbocycle (e.g., serotonin) and N-methylation (e.g., psilocin). As previously, tryptamine can also react through Pictet-Spengler reactions to form tetrahydro-p-carbolines, which can be aromatized, for example, into harmine (Scheme 1.8) [16]. 

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. 

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 shikimate pathway is the major route in the biosynthesis of ubiquinone, menaquinone, phyloquinone, plastoquinone, and various colored naphthoquinones. The early steps of this process are common with the steps involved in the biosynthesis of phenols, flavonoids, and aromatic amino acids. Shikimic acid is formed in several steps from precursors of carbohydrate metabolism. The key intermediate in quinone biosynthesis via the shikimate pathway is the chorismate. In the case of ubiquinones, the chorismate is converted to para-hydoxybenzoate and then, depending on the organism, the process continues with prenylation, decarboxylation, three hydroxy-lations, and three methylation steps. - ... 

Although the absence of paracellular transport across the BBB impedes the entry of small hydrophilic compounds into the brain, low-molecular-weight lipophilic substances may pass through the endothelial cell membranes and cytosol by passive diffusion [7]. While this physical barrier cannot protect the brain against chemicals, the metabolic barrier formed by the enzymes from the endothelial cell cytosol may transform these chemicals. Compounds transported through the BBB by carrier-mediated systems may also be metabolized. Thus, l-DOPA is transported through the BBB and then decarboxylated to dopamine by the aromatic amino acid decarboxylase [7]. 

Dopamine synthesis in dopaminergic terminals (Fig. 46-3) requires tyrosine hydroxylase (TH) which, in the presence of iron and tetrahydropteridine, oxidizes tyrosine to 3,4-dihydroxyphenylalanine (levodopa.l-DOPA). Levodopa is decarboxylated to dopamine by aromatic amino acid decarboxylase (AADC), an enzyme which requires pyri-doxyl phosphate as a coenzyme (see also in Ch. 12). 

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"...

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. 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

The well-known application of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine as a diene in inverse electron demand Diels-Alder cyclizations was adapted for the synthesis of purines <1999JA5833>. The unstable, electron-rich dienophile 5-amino-l-benzylimidazole was generated in situ by decarboxylation of 5-amino-l-benzyl-4-imidazolecarboxylic acid under mildly acidic conditions (Scheme 54). Collapse of the Diels-Alder adduct by retro-Diels-Alder reaction and elimination of ethyl cyanoformate, followed by aromatization by loss of ammonia, led to the purine products. The reactions proceeded at room temperature if left for sufficient periods (e.g., 25 °C, 7 days, 50% yield) but were generally more efficient at higher temperatures (80-100 °C, 2-24 h). The inverse electron demand Diels-Alder cyclization of unsubstituted 1,3,5-triazine was also successful. This synthesis had the advantage of constructing the simple purine heterocycle directly in the presence of both protected and unprotected furanose substituents (also see Volume 8). 

---