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PubMed2001

Computational studies on nonenzymatic and enzymatic pyridoxal phosphate catalyzed decarboxylations of 2-aminoisobutyrate.

A computational study of nonenzymatic and enzymatic pyridoxal phosphate-catalyzed decarboxylation of 2-aminoisobutyrate (AIB) is presented. Four prototropic isomers of a model aldimine between AIB and 5'-deoxypyridoxal, with acetate interacting with the pyridine nitrogen, were employed in calculations of both gas phase and water model (PM3 and PM3-SM3) decarboxylation reaction paths. Calculations employing the transition state structures obtained for the four isomers allow the demonstration of stereoelectronic effects in transition state stabilization as well as a separation of the contributions of the Schiff base and pyridine ring moieties to this stabilization. The unprotonated Schiff base contribution (approximately 16 kcal/mol) is larger than that of the pyridine ring even when it is protonated (approximately 10 kcal/mol), providing an explanation of the catalytic power of pyruvoyl-dependent amino acid decarboxylases. An active site model of dialkylglycine decarboxylase was constructed and validated, and enzymatic decarboxylation reaction paths were calculated. The reaction coordinate is shown to be complex, with proton transfer from Lys272 to the coenzyme C4' likely simultaneous with C alpha--CO(2)(-) bond cleavage. The proposed concerted decarboxylation/proton-transfer mechanism provides a simple explanation for the observed specificity of this enzyme toward oxidative decarboxylation.

Aminoisobutyric Acids↗
PubMed1988

Rat liver gamma-butyrobetaine hydroxylase catalyzed reaction: influence of potassium, substrates, and substrate analogues on hydroxylation and decarboxylation.

Interaction of rat liver gamma-butyrobetaine hydroxylase (EC 1.14.11.1) with various ligands was studied by following the decarboxylation of alpha-ketoglutarate, formation of L-carnitine, or both. Potassium ion stimulates rat liver gamma-butyrobetaine hydroxylase catalyzed L-carnitine synthesis and alpha-ketoglutarate decarboxylation by 630% and 240%, respectively, and optimizes the coupling efficiency of these two activities. Affinities for alpha-ketoglutarate and gamma-butyrobetaine are increased in the presence of potassium. gamma-Butyrobetaine hydroxylase catalyzed decarboxylation of alpha-ketoglutarate was dependent on the presence of gamma-butyrobetaine, L-carnitine, or D-carnitine in the reaction and exhibited Km(app) values of 29, 52, and 470 microM, respectively. gamma-Butyrobetaine saturation of the enzyme indicated a substrate inhibition pattern in both the assays. Omission of potassium decreased the apparent maximum velocity of decarboxylation supported by all three compounds by a similar percent. beta-Bromo-alpha-ketoglutarate supported gamma-butyrobetaine hydroxylation, although less effectively than alpha-ketoglutarate. The rat liver enzyme was rapidly inactivated by 1 mM beta-bromo-alpha-ketoglutarate at pH 7.0. This inactivation reaction did not show a rate saturation with increasing concentrations of beta-bromo-alpha-ketoglutarate. None of the substrates or cofactors, including alpha-ketoglutarate, protected the enzyme against this inactivation. Unlike beta-bromo-alpha-ketoglutarate, beta-mercapto-alpha-ketoglutarate did not replace alpha-ketoglutarate as a cosubstrate. Both beta-mercapto-alpha-ketoglutarate and beta-glutathione-alpha-ketoglutarate were noncompetitive inhibitors with respect to alpha-ketoglutarate.

Animals↗
PubMed2004

Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions.

Acyl-CoA dehydrogenases (ACDs) are a family of flavoenzymes that metabolize fatty acids and some amino acids. Of nine known ACDs, glutaryl-CoA dehydrogenase (GCD) is unique: in addition to the alpha,beta-dehydrogenation reaction, common to all ACDs, GCD catalyzes decarboxylation of glutaryl-CoA to produce CO(2) and crotonyl-CoA. Crystal structures of GCD and its complex with 4-nitrobutyryl-CoA have been determined to 2.1 and 2.6 A, respectively. The overall polypeptide folds are the same and similar to the structures of other family members. The active site of the unliganded structure is filled with water molecules that are displaced when enzyme binds the substrate. The structure strongly suggests that the mechanism of dehydrogenation is the same as in other ACDs. The substrate binds at the re side of the FAD ring. Glu370 abstracts the C2 pro-R proton, which is acidified by the polarization of the thiolester carbonyl oxygen through hydrogen bonding to the 2'-OH of FAD and the amide nitrogen of Glu370. The C3 pro-R proton is transferred to the N(5) atom of FAD. The structures indicate a plausible mechanism for the decarboxylation reaction. The carbonyl polarization initiates decarboxylation, and Arg94 stabilizes the transient crotonyl-CoA anion. Protonation of the crotonyl-CoA anion occurs by a 1,3-prototropic shift catalyzed by the conjugated acid of the general base, Glu370. A tight hydrogen-bonding network involving gamma-carboxylate of the enzyme-bound glutaconyl-CoA, with Tyr369, Glu87, Arg94, Ser95, and Thr170, optimizes orientation of the gamma-carboxylate for decarboxylation. Some pathogenic mutations are explained by the structure. The mutations affect protein folding, stability, and/or substrate binding, resulting in inefficient/inactive enzyme.

Acyl Coenzyme A↗
PubMed2005

Role of Q52 in catalysis of decarboxylation and transamination in dialkylglycine decarboxylase.

Dialkylglycine decarboxylase (DGD) is a pyridoxal phosphate dependent enzyme that catalyzes both decarboxylation and transamination in its normal catalytic cycle. DGD uses stereoelectronic effects to control its unusual reaction specificity. X-ray crystallographic structures of DGD suggest that Q52 is important in maintaining the substrate carboxylate in a stereoelectronically activated position. Here, the X-ray structures of the Q52A mutant and the wild type (WT) DGD-PMP enzymes are presented, as is the analysis of steady-state and half-reaction kinetics of three Q52 mutants (Q52A, Q52I, and Q52E). As expected if stereoelectronic effects are important to catalysis, the steady-state rate of decarboxylation for all three mutants has decreased significantly compared to that of WT. Q52A exhibits an approximately 85-fold decrease in k(cat) relative to that of WT. The rate of the decarboxylation half-reaction decreases approximately 10(5)-fold in Q52I and approximately 10(4)-fold in Q52E compared to that of WT. Transamination half-reaction kinetics show that Q52A and Q52I have greatly reduced rates compared to that of WT and are seriously impaired in pyridoxamine phosphate (PMP) binding, with K(PMP) at least 50-100-fold greater than that of WT. The larger effect on the rate of l-alanine transamination than of pyruvate transamination in these mutants suggests that the rate decrease is the result of selective destabilization of the PMP form of the enzyme in these mutants. Q52E exhibits near-WT rates for transamination of both pyruvate and l-alanine. Substrate binding has been greatly weakened in Q52E with apparent dissociation constants at least 100-fold greater than that of WT. The rate of decarboxylation in Q52E allows the energetic contribution of stereoelectronic effects, DeltaG(stereoelectronic), to be estimated to be -7.3 kcal/mol for DGD.

Amination↗
PubMed2005

Generation of decarboxylated and dehydrogenated betacyanins in thermally treated purified fruit extract from purple pitaya (Hylocereus polyrhizus) monitored by LC-MS/MS.

Pigments of purple pitaya [Hylocereus polyrhizus (F.A.C. Weber) Britton and Rose] fruits were submitted to extraction and were decarboxylated during heating experiments in acidified ethanolic and aqueous solutions. Groups of betacyanins with different decarboxylation levels were identified in the heating products by LC-DAD and LC-MS/MS. The main decarboxylation products were 2-decarboxy-betacyanins, 17-decarboxy-betacyanins, and 2,17-bidecarboxy-betacyanins. The structures of other compounds were assigned to 2,15,17-tridecarboxy-betacyanins and 14,15-dehydrogenated derivatives (neo-derivatives) of all decarboxylated betacyanins found.

Cactaceae↗
PubMed2001

An unusual decarboxylative Maillard reaction between L-DOPA and D-glucose under biomimetic conditions: factors governing competition with Pictet-Spengler condensation.

In 0.1 M phosphate buffer at pH 7.4 and 37 degrees C, the tyrosine metabolite L-3,4-dihydroxyphenylalanine (L-DOPA) reacts smoothly with D-glucose to afford, besides diastereoisomeric tetrahydroisoquinolines 1 and 2 by Pictet-Spengler condensation, a main product shown to be the unexpected decarboxylated Amadori compound N-(1-deoxy-D-fructos-1-yl)-dopamine (3). Under similar conditions, dopamine gave only tetrahydroisoquinoline products 4 and 5, whereas L-tyrosine gave exclusively the typical Amadori compound 6. Fe(3+) and Cu(2+) ions, which accumulate in relatively high levels in parkinsonian substantia nigra, both inhibited the formation of 3. Cu(2+) ions also inhibited the formation of 1 and 2 to a similar degree, whereas Fe(3+) ions increased the yields of 1 and 2. Apparently, the formation of 3 would not be compatible with a simple decarboxylation of the initial Schiff base adduct, but would rather involve the decarboxylative decomposition of a putative oxazolidine-5-one intermediate assisted by the catechol ring. These results report the first decarboxylative Maillard reaction between an amino acid and a carbohydrate under biomimetic conditions and highlight the critical role of transition metal ions in the competition with Pictet-Spengler condensation.

Chromatography, High Pressure Liquid↗
PubMed2003

Construction of a cis-cyclopropane via reductive radical decarboxylation. Enantioselective synthesis of cis- and trans-1-arylpiperazyl-2-phenylcyclopropanes designed as antidopaminergic agents.

(1S,2S)-, (1S,2R)-, and (1R,2S)-1-(2,4-Dimethylphenyl)piperazyl-2-phenylcyclopropane (2a, 3, and ent-3, respectively), which were designed as conformationally restricted analogues of haloperidol (1), a clinically effective antipsychotic agent, were synthesized from chiral epichlorohydrins using the Barton reductive radical decarboxylation as the key step. (1S,2R)-1-(tert-Butyldiphenylsilyloxy)methyl-2-carboxy-2-phenylcyclopropane (5), which was prepared from (S)-epichlorohydrin ((S)-7), was converted into its N-hydroxypyridine-2-thione ester 12, the substrate for the reductive radical decarboxylation. When 12 was treated with TMS3SiH in the presence of Et3B or AIBN, the decarboxylation and subsequent hydride attack on the cyclopropyl radical intermediate from the side opposite to the bulky silyloxymethyl moiety occurred, resulting in selective formation of the corresponding reductive decarboxylation product 4-cis with the cis-cyclopropane structure. From 4-cis, the cis-cyclopropane-type target compound 3 was readily synthesized. Starting from (R)-epichlorohydrin ((R)-7), ent-3 was similarly synthesized. Epimerization of the cyclopropanecarboxamide ent-16-cis, a synthetic intermediate for ent-3, on treatment with a base prepared from Bu2Mg and i-Pr2NH in THF occurred effectively to give the corresponding trans isomer 16-trans, which was converted into 2a with the trans-cyclopropane structure.

Cyclopropanes↗
PubMed1987

The solid-state decarboxylation of the diammonium salt of moxalactam.

This paper reports studies of the solid-state chemistry of the diammonium salt of moxalactam. The methods employed include X-ray crystallography, molecular mechanics calculations, thermogravimetric analysis, and high-pressure liquid chromatography. The crystal structure shows that the malonic acid amide functionality in crystals of the diammonium salt is not planar. If the common decarboxylation mechanism is operating, then considerable rotation would be required for this functionality to attain coplanarity. Simultaneous HPLC and thermogravimetric analysis studies indicate that the decarboxylation of the diammonium salt of moxalactam is preceded by desolvation. Molecular mechanics calculations indicate that the barrier to rotation of the malonic acid amide functionality is relatively small in the dehydrated crystals, perhaps explaining the facile decarboxylation of this antibiotic. Alternatively, the amorphous desolvated crystals may allow enough molecular freedom for the malonic acid amide functionality to attain coplanarity and decarboxylate.

Chromatography, High Pressure Liquid↗
PubMed1988

Carbon isotope effects on the decarboxylation of carboxylic acids. Comparison of the lactate oxidase reaction and the degradation of pyruvate by H2O2.

The isotope effect at C-1 on the H2O2-catalysed decarboxylation of pyruvate (used as a model reaction for the enzymic reaction) increases between pH 3 and 10 from 1.0007 +/- 0.0004 to 1.0283 +/- 0.0014 (25 degrees C). This result indicates a change in the rate-determining step from formation of the tetrahedral intermediate to decarboxylation of this intermediate. Practically no isotope fractionation at C-1 (1.0011 +/- 0.0002, pH 6.0, 25 degrees C) is found in the lactate oxidase-catalysed decarboxylation of lactate, which is indicative for the existence of an irreversible O2-dependent step prior to the enzyme-catalysed decarboxylation. In addition, the result provides further evidence that dissociation of pyruvate and H2O2 from the enzyme can be excluded. The isotope effect at C-2 of lactate in the enzymic reaction (1.0048 +/- 0.0004) is attributed to the hydrogen transfer step from lactate to the coenzyme.

Carbon Isotopes↗
PubMed1972

Decarboxylation of 3,4-dihydroxyphenylalanine (DOPA) by erythrocytes: a reaction promoted by methemoglobin and other ferriheme proteins.

The decarboxylation of DOPA by erythrocyte hemolysates differs from DOPA decarboxylation catalyzed by aromatic aminoacid decarboxylases that contain vitamin B(6) in several significant respects. The ability of erythrocyte hemolysates to decarboxylate DOPA is associated with interaction between DOPA and methemoglobin; the ferriheme protein is reduced and DOPA is decarboxylated, probably after oxidation to a quinone intermediate. An analogous reaction takes place between DOPA and other ferriheme proteins, such as metmyoglobin and cytochrome c. This phenomenon may be of significance in relation to the side effects observed in patients with Parkinson's disease who are treated with very large doses of DOPA.

Animals↗
PubMed1980

Decarboxylation of alpha-ketoisovaleric acid after oral administration in man.

The keto analogues of essential amino acids represent a promising therapeutic modality in hereditary and acquired disorders of nitrogen metabolism. The utilization of these substances in humans has been assayed primarily by nitrogen balance studies. A simple and accurate breath excretion test for 14CO2 enabled us to measure the decarboxylation of 1-14C-alpha-ketoisovaleric acid (KIV, the keto analogue of valine) in two normal and six diseased subjects. Normal volunteers as well as patients with gastrectomy, hepatic failure, renal failure, and myotonic dystrophy were tested in 5-g protein diets supplemented with essential amino acids and KIV (in place of valine). The normal volunteers and the gastrectomy patient were then restudied on 120 g protein/day. With low protein intake, 13 to 32% of ingeted KIV underwent rapid decarboxylation, and this proportion appeared to correlate inversely with damage to organ systems containing the branched-chain keto acid dehydrogenase. With high protein intake, the proportion decarboxylated rose to 44 to 53%. Thse results confirm that the decarboxylation of KIV in man varies under different conditions of dietary intake and metabolic disease. The 14CO2 brewth excretion test is applicable to other related analyses of carboxylic acid metabolism in human subjects.

Adult↗
PubMed1985

Binding of latamoxef (moxalactam) and its decarboxylated derivative to Escherichia coli and Pseudomonas aeruginosa penicillin-binding proteins.

The binding of latamoxef (moxalactam) and of a decarboxylated derivative to Escherichia coli and Pseudomonas aeruginosa penicillin-binding proteins (PBPs) was measured by competition experiments with 125I-radiolabelled penicillin X. Latamoxef and the decarboxylated derivative were highly bound to most of the PBPs, with the exception of PBP-2. As the two compounds possess a phenolic side-chain, they also could be radiolabelled with 125I. The proteins thus labelled by these derivatives were qualitatively the same as those labelled by 125I-penicillin X, except for PBP-2 which was not labelled by the iodo derivatives of latamoxef and its decarboxylated derivative, and PBP-1c (in E. coli) which is labelled only poorly by the radioactive penicillin. No important difference between latamoxef and its decarboxylated derivative was found, and the same observation was made for penicillin G and carbenicillin. Thus, it was concluded that the carboxylic group of latamoxef does not play an important role in affinity for the targets.

Bacterial Proteins↗
PubMed1978

Enzymatic decarboxylation of L-threo-3,4-dihydroxyphenylserine in rat heart.

Decarboxylation of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) by the higher speed supernatant of the rat heart homogenate and the regional distribution of L-threo-DOPS decarboxylase activity were examined. Decarboxylation was demonstrated to occur specifically with L-isomer but not with D-isomer. Addition of pyrogallol was necessary for maximal recovery of norepinephrine. The optimal condition for decarboxylation of L-threo-DOPS by the rat heart enzyme was similar to conditions required with the enzymes from brain and kidney. Under the optimal conditions, Km and Vmax for L-threo-DOPS were 2.1 mM and 6.4 nmoles/mg protein/15 min, respectively. Decarboxylation of L-threo-DOPS was markedly inhibited by D-threo-DOPS and D-DOPA. The L-aromatic amino acid decarboxylase activity was highest in the right auricle followed by the atrial body, the left auricle, the right ventricle and the left ventricle.

Animals↗
PubMed1986

Chemistry of maduramicin. II. Decarboxylation, abnormal ketalization and dehydration.

The behavior of the free acid and ammonium salt of maduramicin towards heat and alcohols is examined. In refluxing lower alcohols the free acid material is decarboxylated. In addition a bisketal decarboxylated compound as well as an A-ring monoketal decarboxylated derivative are formed. Heating the ammonium salt of the ionophores in suspension in water, or dissolved in inert solvents such as heptane or xylene can cause decarboxylation as well as concomitant dehydration of the F-ring. Reaction of dansyl chloride with the free acid of maduramicin can cause dehydration of the B-ring under very mild conditions.

Chemical Phenomena↗
PubMed1996

In vivo demonstration of enzyme activity in endocrine pancreatic tumors: decarboxylation of carbon-11-DOPA to carbon-11-dopamine.

METHODS: We used PET to characterize the uptake and decarboxylation of 11C-L-DOPA in vivo in two patients with endocrine pancreatic tumors: one glucagonoma and one gastrinoma. RESULTS: With L-DOPA labeled with 11C in the beta position, in which the radioactive label follows the molecule through decarboxylation to dopamine, significant uptake was observed in the tumors. With L-DOPA labeled in the carboxyl group, in which the label is rapidly eliminated from the tissue as 11CO2 if decarboxylation takes place, an almost complete lack of uptake is noted. CONCLUSION: This study shows that, using selective position labeling, an in vivo action of enzymatic activity can be observed with PET and that significant decarboxylation occurs in the tested endocrine pancreatic tumors. Also, marked retention of radioactivity occurs after treatment with somatostatin analogs. It is hypothesized that this is a reflection of a reduction of exocytosis which is induced by this treatment.

Aged↗
PubMed1988

Oxidative decarboxylation of salsolinol-1-carboxylic acid to 1,2-dehydrosalsolinol: evidence for exclusive catalysis by particulate factors in rat kidney.

The decarboxylation of salsolinol-1-carboxylic acid (1-methyl-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline-1-carboxylic acid), a novel endogenous catecholic adduct of dopamine and pyruvic acid, was examined in nuclei-free homogenates of rat liver, whole brain, and kidney, as well as in buffer only. Liquid chromatographic analysis of incubations for varying times (30 min to 5 h) showed that the tetrahydroisoquinoline substrate decarboxylated oxidatively, forming one product, 1-methyl-6,7-dihydroxy-3,4-dihydroisoquinolines (1,2-dehydrosalsolinol). No salsolinol was apparent, even with added NADPH. In buffer, decarboxylation occurred by an apparent oxygen radical-mediated process: it was stimulated by cupric ion or elevated pH, and was suppressed by EDTA, superoxide dismutase, metal ion removal with Chelex-100, or low pH (less than 6). In liver or brain, the conversion was qualitatively and quantitatively similar to that in buffer; thus there was no evidence for enzyme involvement. In kidney, however, dehydrosalsolinol formation was significantly greater than that in liver, brain, or buffer, and preboiling reduced it nearly to buffer values. The heat-labile kidney activity, displaying a pH maximum ca. 9, was localized in the particulate fractions. It was blocked completely by N-ethylmaleimide. Added superoxide dismutase was only slightly inhibitory; catalase and dimethyl sulfoxide, a hydroxyl radical trap, were uneffective. Lack of inhibition by indomethacin ruled against peroxidative involvement of kidney prostaglandin synthetase. Physiological amounts of a cofactor for amino acid decarboxylases, pyridoxal-5'-phosphate, also had no effect. The oxidative decarboxylation of 1-carboxylated salsolinol by kidney fractions appears mainly due to a sulfhydryl-containing particulate factor unique to or relatively concentrated in that organ. Its identity, substrate specificity, and possible significance, particularly in alcoholism, where elevated salsolinol-1-carboxylic acid levels have been reported, remain to be ascertained.

Animals↗
PubMed1986

Decarboxylation of 1,2,3,4-tetrahydro-beta-carboline-1-carboxylic acids in brain homogenate and catalysis by pyridoxal-5'-phosphate.

[Carboxyl-14C] labelled 1,2,3,4-tetrahydro-beta-carboline-1-carboxylic acid (I) and 1-methyl-1,2,3,4-tetrahydro-beta-carboline-1-carboxylic acid (II) were synthesized and their decarboxylation was studied in mouse brain homogenate and buffer. The decarboxylation rates of (I) and (II) in the homogenate were about 6-fold and 4-fold, respectively, as compared with the rates in phosphate buffer. The increase could not be prevented by preheating the homogenate, but was partially abolished by addition of 1 mM EDTA. The decarboxylation was increased dose-dependently when pyridoxal-5'-phosphate was included in the buffer, 400 microM being sufficient to exceed the rate in homogenate for both (I) and (II). Mass spectrometric examination of the decarboxylation products indicated that both (I) and (II) were degraded mainly to corresponding 1,2,3,4-tetrahydro-beta-carbolines, but some 3,4-dihydro analogues also were detectable. In conclusion, the results outline a way through which these pharmacologically active beta-carbolines are readily formed under conditions that may be regarded as physiological.

Animals↗
PubMed1987

Age dependence in capacity-limited jejunal decarboxylation of levodopa in rats.

The extent of levodopa decarboxylation in a jejunal preparation permitting continuous in situ collection of the mesenteric blood was compared in rats 5 to 104 weeks old. The fraction of the absorbed amount that was metabolized (decarboxylated) in the jejunal segment was relatively high (approximately 0.7 to 0.8) in 9- to 15-week-old rats, whereas the fraction in relatively aged (52- and 104-week-old) and young (5- and 7-week-old) rats was considerably less (approximately 0.4 or less). These fractions were found to correlate better with the extent of relative contribution of the intestine in producing the overall first-pass effect of this drug after oral administration. In addition, kinetic studies on the jejunal metabolism of levodopa in vitro showed that a capacity-limited (i.e. saturable) decarboxylation rate was highest in 11-week-old rats. Therefore, the capacity-limited decarboxylation rate in the small intestine may be a determining factor in the age-dependent systemic availability of this drug when administered orally.

Aging↗