Decarboxylation decarboxylase

The lyases comprise enzyme class 4. They are enzymes cleaving C-C, C-0, C-N and other bonds by elimination, not by hydrolysis or oxidation. Lyases also catalyse addition to donble bonds. The types of reactions catalysed by lyases are decarboxylation (decarboxylase), hydration/dehydration (hydratase/dehydratase), ammonia addition/deamination (ammonia-lyase), cyanohydrin formation/cleavage (oxynitrilase),... 

A very important naturally occuring thiazole derivative is thiamine pyrophosphate (473). It is the prosthetic group in a variety of enzymes which catalyze decarboxylation (decarboxylase) and aldol-type condensation (aldolase) reactions. The catalytic active site of the molecule is at C-2 of the thiazole ring . The same activity of (473) is shown by other thiazolium salts and therefore these compounds have been widely exploited as catalysts in reactions of importance such as the benzoin condensation (see Section 3.06.12.2). 

Synthesis. Histamine [51-45-6] 2-(4-imidazolyl)ethylarnine (1) is formed by decarboxylation of histidine by the enzyme L-histidine decarboxylase (Fig. 1). Most histamine is stored preformed in cytoplasmic granules of mast cells and basophils. In humans mast cells are found in the loose connective tissue of all organs, especially around blood and lymphatic vessels and nerves. These cells are most abundant in the organs expressing allergic diseases the skin, respiratory tract, and gastrointestinal tract. 

Aspartic acid decarboxylase cataly2es the decarboxylation of asparatic acid to yield P-alanine (10), a precursor for the biosynthesis of pantothenic acid (67). FiaaHy, (R)-pantothenic acid is obtaiaed by coupling P-alaniae (10) with (R)-pantoate (22) ia the presence of pantothenate synthetase ... 

Ornithine decarboxylase is a pyridoxal dependent enzyme. In its catalytic cycle, it normally converts ornithine (7) to putrisine by decarboxylation. If it starts the process with eflornithine instead, the key imine anion (11) produced by decarboxylation can either alkylate the enzyme directly by displacement of either fluorine atom or it can eject a fluorine atom to produce viny-logue 12 which can alkylate the enzyme by conjugate addidon. In either case, 13 results in which the active site of the enzyme is alkylated and unable to continue processing substrate. The net result is a downturn in the synthesis of cellular polyamine production and a decrease in growth rate. Eflornithine is described as being useful in the treatment of benign prostatic hyperplasia, as an antiprotozoal or an antineoplastic substance [3,4]. 

In general, pyruvate decarboxylase (EC 4.1.1.1) catalyzes the decarboxylation of a 2-oxocar-boxylic acid to give the corresponding aldehyde6. Using pyruvic acid, the intermediately formed enzyme-substrate complex can add an acetyl unit to acetaldehyde already present in the reaction mixture, to give optically active acetoin (l-hydroxy-2-butanone)4 26. Although the formation of... 

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. 

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 2. Mechanism of PDH. The three different subunits of the PDH complex in the mitochondrial matrix (E, pyruvate decarboxylase E2, dihydrolipoamide acyltrans-ferase Ej, dihydrolipoamide dehydrogenase) catalyze the oxidative decarboxylation of pyruvate to acetyl-CoA and CO2. E, decarboxylates pyruvate and transfers the acetyl-group to lipoamide. Lipoamide is linked to the group of a lysine residue to E2 to form a flexible chain which rotates between the active sites of E, E2, and E3. E2 then transfers the acetyl-group from lipoamide to CoASH leaving the lipoamide in the reduced form. This in turn is oxidized by E3, which is an NAD-dependent (low potential) flavoprotein, completing the catalytic cycle. PDH activity is controlled in two ways by product inhibition by NADH and acetyl-CoA formed from pyruvate (or by P-oxidation), and by inactivation by phosphorylation of Ej by a specific ATP-de-pendent protein kinase associated with the complex, or activation by dephosphorylation by a specific phosphoprotein phosphatase. The phosphatase is activated by increases in the concentration of Ca in the matrix. The combination of insulin with its cell surface receptor activates PDH by activating the phosphatase by an unknown mechanism.

Mutation of the dihydrolipoate reductase component impairs decarboxylation of branched-chain a-keto acids, of pyruvate, and of a-ketoglutarate. In intermittent branched-chain ketonuria, the a-keto acid decarboxylase retains some activity, and symptoms occur later in life. The impaired enzyme in isovaleric acidemia is isovaleryl-CoA dehydrogenase (reaction 3, Figure 30-19). Vomiting, acidosis, and coma follow ingestion of excess protein. Accumulated... 

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. 

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. 

Histamine is synthesised by decarboxylation of histidine, its amino-acid precursor, by the specific enzyme histidine decarboxylase, which like glutaminic acid decarboxylase requires pyridoxal phosphate as co-factor. Histidine is a poor substrate for the L-amino-acid decarboxylase responsible for DA and NA synthesis. The synthesis of histamine in the brain can be increased by the administration of histidine, so its decarboxylase is presumably not saturated normally, but it can be inhibited by a fluoromethylhistidine. No high-affinity neuronal uptake has been demonstrated for histamine although after initial metabolism by histamine A-methyl transferase to 3-methylhistamine, it is deaminated by intraneuronal MAOb to 3-methylimidazole acetic acid (Fig. 13.4). A Ca +-dependent KCl-induced release of histamine has been demonstrated by microdialysis in the rat hypothalamus (Russell et al. 1990) but its overflow in some areas, such as the striatum, is neither increased by KCl nor reduced by tetradotoxin and probably comes from mast cells. 

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 15.4 The central and peripheral metabolism of levodopa and its modification by drugs, (a) Levodopa alone. After oral administration alone most dopa is rapidly decarboxylated to DA in the gut and blood with some o-methylated (COMT) to o-methyl/dopa (OMD). Only a small amount (3%) enters the CNS to be converted to DA. (b) After an extracerebral dopa decarboxylase inhibitor. Blocking just the peripheral dopa decarboxylase (DD) with inhibitors like carbidopa and benserazide, that cannot enter the CNS (extra cerebral dopa decarboxylase inhibitors, ExCDDIs), stops the conversion of levodopa to DA peripherally, so that more enters the CNS or is o-methylated peripherally to OMD.

Blocking the conversion to DA would appear stupid unless this could be restricted to the periphery. More dopa would then be preserved for entry into the brain, where it could be decarboxylated to DA as usual. Drugs like carbidopa and benserazide do precisely that and are used successfully with levodopa. They are known as extracerebral dopa decarboxylase inhibitors (ExCDDIs). Carbidopa (a-methyldopa hydrazine) is structurally similar to dopa but its hydrazine group (NHNH2) reduces lipid solubility and CNS penetration (Fig. 15.4). 

Hydroxybenzoate decarboxylase (EC 4.1.1.61) of anaerobe C. hydroxyben-zoicum was purified and characterized for the first time. ° It has an apparent molecular mass of 350 kDa and consists of six identical subunits of 57kDa. The temperature optimum for the decarboxylation is approximately 50°C, the optimum pH being 5.6-6.2. The activation energy for decarboxylation of 4-hydroxybenzoate is 65kJmor (20-37°C). The enzyme also catalyzes the decarboxylation of... 

A 3,4-dihydroxybenzoate decarboxylase (EC 4.1.1.63) was purified from C. hydroxybenzoicum and characterized for the first time. The estimated molecular mass of the enzyme is 270 kDa. The subunit molecular mass is 57kDa, suggesting that the enzyme consists of five identical subunits. The temperature and pH optima are 50°C and pH 7.0, respectively. The Arrhenius energy for decarboxylation of 3,4-dihydroxybenzoate was 32.5 kJ mol for the temperature range from 22 to 50°C. The and for 3,4-dihydroxybenzoate were 0.6 mM and 5.4 X 10 min respectively, at pH 7.0 and 25°C. The enzyme catalyzes the reverse reaction, that is, the carboxylation of catechol to 3,4-dihydroxybenzoate, at pH 7.0. The enzyme does not decarboxylate 4-hydroxybenzoate. Although the equilibrium of the reaction is on the side of catechol, it is postulated that C. hydroxybenzoicum uses the enzyme to convert catechol to 3,4-dihydroxybenzoate. ... 

Pyrrole-2-carboxylate decarboxylase attains equilibrium in the course of either decarboxylation or carboxylation (Fig. 8). The decarboxylation of 100 mM pyrrole-2-carboxylate was in equilibrium after Ih, resulting in an equilibrium constant of 0.3 M." Due to this balanced equilibrium, the enzyme also catalyzed the reverse carboxylation of pyrrole after the addition of HCO3, leading to a similar equilibrium constant of 0.4 M and a shift of the [pyrrole]/[pyrrole-2-carboxylate] ratio toward the acid. 

Figure 8 Decarboxylation of pyrrole-2-carboxylate (a) and carboxylation of pyrrole (b) by pyrrole-2-carboxylate decarboxylase.

Also, decarboxylations of malonate-type compounds have been confirmed to proceed with retention of configuration. Indeed, malonyl-CoA decarboxylase from uropygial gland is enantioselective to the substrate as well as the product. Only... 

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