Decarboxylase, DOPA histidine

Steps in the formation of classical neurotransmitters. AADC, amino acid decarboxylase AChE, acetylcholinesterase CAT, choline acetyltransferase COMT, catechol-O-methyltransfeiase DBH, dopamine P-hydroxylase DA, dopamine DOPA, dibydroxyphenylalanine GABA-T, GABA transaminase GAD, glutamic acid decarboxylase HD, histidine decarboxylase 5-HTP, 5-hydroxytrytophan MAO, monoamine oxidase PNMT, phenylethanolamine N-methyltransferase TH, tyrosine hydroxylase TPH, tryptophan hydroxylase. 

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. 

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. 

Alanine and aspartic acid are produced commercially utilizing enzymes. In the case of alanine, the process of decarboxylation of aspartic acid by the aspartate decarboxylase from Pseudomonas dacunhae is commercialized. The annual world production of alanine is about 200 tons. Aspartic acid is produced commercially by condensing fumarate and ammonia using aspartase from Escherichia coli. This process has been made more convenient with an enzyme immobilization technique. Aspartic acid is used primarily as a raw material with phenylalanine to produce aspartame, a noncaloric sweetener. Production and sales of aspartame have increased rapidly since its introduction in 1981. Tyrosine, valine, leucine, isoleucine, serine, threonine, arginine, glutamine, proline, histidine, cit-rulline, L-dopa, homoserine, ornithine, cysteine, tryptophan, and phenylalanine also can be produced by enzymatic methods. 

Histamine, serotonin and the catecholamines (dopamine, epinephrine and norepinephrine) are synthesized from the aromatic amino acids histidine, tryptophan and phenylalanine, respectively. The biosynthesis of catecholamines in adrenal medulla cells and catecholamine-secreting neurons can be simply summarized as follows [the enzyme catalysing the reaction and the key additional reagents are in square brackets] phenylalanine — tyrosine [via liver phenylalanine hydroxylase + tetrahydrobiopterin] —> i.-dopa (l.-dihydroxyphenylalanine) [via tyrosine hydroxylase + tetrahydrobiopterin] —> dopamine (dihydroxyphenylethylamine) [via dopa decarboxylase + pyridoxal phosphate] — norepinephrine (2-hydroxydopamine) [via dopamine [J-hydroxylasc + ascorbate] —> epinephrine (jV-methyl norepinephrine) [via phenylethanolamine jV-methyltransferase + S-adenosylmethionine]. 

Apart from the similar distribution of the decarboxylase activities discussed above, further evidence that various aromatic L-amino acids are all decar-boxylated by a single enzyme is based on (a) failure to dissociate the activities during progressive purification of the enzyme (b) the occurrence of competitive substrate inhibition (r) the fact that all the decarboxylations are inhibited by the same inhibitors (d) under conditions which lead to changes in the ability of a tissue to decarboxylate one substrate, parallel changes occur in the ability to decarboxylate the other substrates. In practice, most of this evidence has been obtained by the use of histidine, DOPA and... 

That not only DOPA decarboxylase and 5-HTP decarboxylase, but also the histidine decarboxylase (having its optimum activity in the range pH... 

HTP and DOPA decarboxylase activities of partially purified extracts of hog kidney it has been stated that these compounds do not also inhibit histidine decarboxylase. This statement is misleading, however, as it refers to results obtained by earlier workers using a histidine decarboxylase of bacterial origin . ... 

In rats treated with the liver carcinogen diethylnitrosamine (DENA), the mean activities of histidine decarboxylase (measured at pH 8 0), DOPA decarboxylase and 5-HTP decarboxylase in the liver were significantly lower than the corresponding mean values in the livers of control rats. In both the control and DENA-treated series, however, a positive correlation was found between the activities of these three enzymes . When rats were maintained on a tryptophan-deficient diet, it was found that the mean activities of histidine decarboxylase (pH 8-0), DOPA decarboxylase and 5-HTP decarboxylase in the livers of the tryptophan-deficient animals were significantly... 

In some instances the results obtained by different groups of workers have been sufficiently at variance, particularly where weak substrates have been studied, for doubt to be cast on the existence of a general aromatic amino acid decarboxylase. Thus it has been claimed that some preparations which contain DOPA and 5-HTP decarboxylase activities do not decarboxylate histidine - . In these instances, the sensitivity or specificity of the analytical procedures are open to doubt, and the results require confirmation. In view of conflicting reports in the literature, further experiments should also be carried out to determine whether the mono- and dihydroxyphenylserines > are indeed substrates of non-specific histidine decarboxylase. The status of /)-tyrosine also requires clarification formerly it was not considered to be a substrate " , but recent evidence suggests that it may, in fact, be decarboxylated . 

Source of histidine decarboxylase pH/or Optimal activity Affinity for histidine (Km)mole/l Substrates Effect of benzene Effect of fx-Me-DOPA Effect of CL-Me histidine References... 

It has recently been reported that extracts of foetal rat liver can decarboxy-late not only histidine but also DOPA, 5-HTP and other aromatic L-amino acids i. This may mean that the specifie histidine decarboxylase has a wider substrate specifieity than was originally believed, or that the extract contains a mixture of the specific and non-specific enzymes. The rat glandular stomach provides an example of a tissue in which the presence of both enzymes has now been demonstrated . 

Several substituted histidines Table 4.8) have been tested as inhibitors of the histidine decarboxylase of guinea-pig kidney . From a consideration of the potencies of the substances tested, it was suggested that increasing the acidity of the nitrogens of the imidazole ring tended to produce stronger inhibitors. Similar studies on the inhibition of histamine formation by compounds related to DOPA or 5-HTP Table 4.8) showed that a-methyl-DOPA and DOPA are good inhibitors only the L-form of a-methyl-DOPA is an effective inhibitor of n-amino acid decarboxylase . The... 

Inhibition of Specific Histidine Decarboxylase The effect of inhibitors on specific histidine decarboxylase differs in certain important respects from their effect on non-specific histidine decarboxylase. In particular, the specific enzyme, unlike the non-specific enzyme, is scarcely affected by a-methyl-DOPA " >i i i . Conversely, the specific enzyme is subject to moderate inhibition by a-methylhistidine at concentrations which... 

Compounds MK 785 (XXVI) and MK 485 (XXVII), the a-hydrazino analogues of histidine and a-methyl-DOPA respectively, have been compared as inhibitors of the specific decarboxylase from foetal rats and the... 

Further reactions may occur after the formation of a Schiff base. Thus aldehydes react with substituted phenylethylamines under mild experimental conditions to form ultimately tetrahydroisoquinolines i . A particular case of this is the reaction between pyridoxal and DOPA [Figure 4.5). A similar reaction occurs between pyridoxal and histidine [Figure 4.5). The observation that DOPA decarboxylase is subject to substrate inhibition aroused... 

There is considerable doubt at present concerning the physiological significance of the non-specific histidine decarboxylase . Nevertheless, the possibility remains that some of the compounds which have been found to inhibit the formation of dopamine and 5-HT may also be useful inhibitors of histamine formation. Comparative potencies, in vitro andf vivo, of various substances as inhibitors of the non-specific decarboxylase with DOPA as substrate have been recorded in the literature . ... 

Such considerations do not, however, exclude the participation of the nonspecific enzyme as a source of body histamine. The non-specific histidine decarboxylase of guinea-pig kidney is known to have a high affinity for DOPA and 5-HTP, but a low affinity for histidine and phenylalanine . At first sight, then, it would appear that this enzyme is more likely to produce dopamine and 5-hydroxytryptamine than to form histamine or / -phenyl-ethylamine. It must be remembered, however, that the substrates DOPA and 5-HTP are not normally detectable in blood or tissues, while histidine and phenylalanine are present in amounts which compensate for the low affinity of the enzyme for these two amino acids. In terms of the capacity to form the corresponding amines, therefore, there is no reason to suppose that the decarboxylation of histidine is a less important function of the non-specific enzyme than is the decarboxylation of its other substrates. 

Histamine is synthesized from histidine in a single enzymatic step. The enzyme histidine decarboxylase requires pyridoxal phosphate, and its mechanism is very similar to that of DOPA decarboxylase (Fig. 48.8). 

Acetylcholine is formed from choline (which is also an important constituent of phospholipids) and acetyl CoA under the catalytic influence of choline acetyl-ase. It is hydrolised by acetylcholinesterase or choline esterase. Two important steps in the formation of noradrenaline from tyr dopa decarboxylase and dopamine hydroxylase. Adrenaline is formed from noradrenaline by phenyl ethanolamine A -methyltransferase. Both noradrenaline and adrenaline are metabolised by catechol 0-methyl transferase or monoamine oxidase. Some later steps in their metabolism involve aldehyde dehydrogenase and alcohol dehydrogenase (aldehyde reductase), After hydroxylation to its 5-hydroxy derivative, tryptophan is converted by 5-hydroxytryptophan decarboxylase to 5-hydroxytryptamine (serotonin). The major routes of serotonin metabolism involve either monoamine oxidase or hydroxyindole 0-methyltransferase. Histamine is synthesised from histidine by histidine decarboxylase, and is metabolised by either diamine oxidase or histamine Af-methyltransferase. Gamma aminobutyric acid is formed by glutamate decarboxylase and metabolised by... 

Aures D, Hakanson R, Schauer A. Histidine decarboxylase and dopa decarboxylase in the rat stomach. Properties and cellular localization. Eur J Pharmacol 3 217-234, 1968. 

That not only DOPA decarboxylase and 5-HTP decarboxylase, but also the histidine decarboxylase (having its optimum activity in the range pH 8-0-9 5) are the same enzyme is also suggested by inhibition studies, a-Methyl-DOPA, for example, is a potent inhibitor of all three enzymes other pc-methylamino-acids behave similarly . 

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