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PubMed1968

Oxidative decarboxylation of retinoic acid in microsomes of rat liver and kidney.

Liver and kidney microsomes have been found to catalyze a rapid decarboxylation of retinoic acid in vitro. The reaction requires NADPH and Fe(2+), and is further stimulated by the presence of pyrophosphate. Thiamine pyrophosphate contained sufficient iron as an impurity to provide strong enhancement of the reaction in the absence of added iron. The decarboxylation could also be shown to occur nonenzymatically in the presence of ascorbate, Fe(2+), and boiled microsomes, but there was little autoxidation resulting in decarboxylation. The reaction was strongly inhibited by chelating agents, N,N'-diphenyl-p-phenylene diamine, phenazine methosulfate, and ferricyanide, and resembled lipid peroxidation in both its cofactor requirements and response to inhibitors. The product of the reaction appeared to lack only the C-15 of the original retinoic acid molecule. It was not retained by diethylaminoethyl cellulose, was more polar than retinoic acid upon silicic acid chromatography, had a lower UV absorption maximum (295 m micro ) than the starting product, and seemed to have an aldehyde group at C-14. The physiological significance of the decarboxylation remains to be assessed, but its rapidity makes it important to in vitro work on retinoic acid.

Acids↗
PubMed1979

[Decarboxylation of malonyl-CoA and biosynthesis of mevalonic acid in rat liver].

Biosynthesis of mevalonic acid (MVA), total formation of 14CO2 from [1,3-14C]malonyl-CoA and the activity of malonyl-CoA decarboxylase in subcellular fractions of rat liver were studied. The dependence of the rate of MVA biosynthesis on malonyl-CoA concentration was found to be linear both in 140,000 g supernatant and solubilized microsomal fractions. It was shown that in a composite system (140,000 g supernatant fraction added to washed microsomes, 10 : 1) the optimal concentration ratio for the substrates of MVA biosynthesis (malonyl-CoA and acetyl-CoA) is 1 to 2. In the absence of acetyl-CoA decarboxylation of [1,3-14C]malonyl-CoA was prevalent. In all subcellular fractions studied decarboxylation of [1,3-14C]malonyl-CoA prevailed over its incorporation into MVA, total non-saponified lipid fraction and fatty acids. The degree of malonyl-CoA, decarboxylation was not correlated with the rate of its incorporation into MVA, i. e. the increase in the 14CO2 formation was not accompanied by stimulation of [1,3-14C]malonyl-CoA incorporation either into MVA or into total non-saponified lipid fractions. The incorporation of [1-14C]acetyl-CoA into MVA under the same conditions was considerably lower than that of [1,3-14C]malonyl-CoA. In all subcellular fractions under study the activity of malonyl-CoA decarboxylase was found. The experimental data suggest that a remarkable part of malonyl-CoA is incorporated into MVA without preliminary decarboxylation. A possible role of malonyl-CoA decarboxylase as an enzyme which protects the cell against accumulation of malonyl-CoA and its immediate metabolites -- malonate and methylmalonyl-CoA is disucssed.

Acyl Coenzyme A↗
PubMed1981

Stereochemistry and kinetic isotope effects in the decarboxylation of S-adenosylmethionine catalyzed by the pyruvyl enzyme, S-adenosylmethionine decarboxylase.

S-Adenosyl-5'-3-methylthio[1-3H]propylamine was prepared by decarboxylation of S-adenosylmethionine in tritiated water, catalyzed by S-adenosylmethionine decarboxylase from Escherichia coli. Degradation of this product to 3-methylthio[1-3H]propylamine followed by oxidation in a coupled assay system involving pea seedling amine oxidase, catalase, and aldehyde dehydrogenase indicated less than 4% of total counts in water and greater than 75% in NADH plus NAD+. These results allow the assignment of tritium in 3-methylthiopropylamine to the 1-R configuration, establishing that S-adenosylmethionine decarboxylase, a pyruvate-containing decarboxylase, operates via a retentive mode. Tabulation of the available stereochemical results for two pyruvate-containing and three pyridoxal phosphate-dependent amino acid decarboxylases indicates that stereochemistry has been conserved both within each class of amino acid decarboxylases and between structurally distinct classes of decarboxylases. Comparison of the specific activity of 3-methylthio[1-3H]propylamine to the tritiated water employed in the decarboxylation reaction leads to a primary tritium isotope effect of 4.5 under conditions of substrate concentration far in excess of Km. Although a portion of the tritium in 3-methylthiopropylamine could have arisen through an enzyme-catalyzed exchange into decarboxylated adenosylmethionine (leading to an underestimate of the kinetic tritium isotope effect), we are unable to detect enzymatic loss of tritium from decarboxylated S-adenosylmethionine. The magnitude of the observed isotope effect is discussed in the context of a kinetically significant exchange of an active site residue with solvent in the present of enzyme-bound S-adenosylmethionine.

Adenosylmethionine Decarboxylase↗
PubMed1995

Complementation of defective leucine decarboxylation in fibroblasts from a maple syrup urine disease patient by retrovirus-mediated gene transfer.

Maple syrup urine disease (MSUD) is a genetic disease caused by a deficiency of branched-chain keto acid dehydrogenase, a mitochondrial multienzyme complex responsible for the decarboxylation of leucine, isoleucine and valine. The complex consists of three subunits (E1, E2, and E3) and mutations in any subunit result in MSUD. No satisfactory treatment for MSUD is currently available. Here we report the successful use of retroviral gene transfer to restore leucine decarboxylation activity in fibroblasts derived from a MSUD patient containing a mutation in the E2 subunit. A full-length human E2 cDNA was inserted into a retroviral vector (MFG) and a stable CRIP producer line was generated. The amphotropic virus was then used to transduce mutant human fibroblasts. In untransduced mutant cells, 1-14C leucine decarboxylation activity was less than 2% that of the wild-type cells. Decarboxylation of 1-14C leucine in transduced mutant cells was restored to 93% of the wild-type level. Correct targeting of the expressed wild-type E2 protein to mitochondria was demonstrated by comparing the immunofluorescent pattern of E2 and a mitochondrial marker protein. Stable expression of enzyme activity has been obtained for at least 7 weeks. In contrast to most previous gene therapy attempts, which replace a single enzyme defect, the present results demonstrate complementation of a phenotype resulting from a gene defect whose product is a part of a multienzyme complex. Based on these results, studies can now be undertaken to investigate the feasibility of gene therapy to correct MSUD.

Amino Acid Oxidoreductases↗
PubMed1998

Stereochemically specific proton transfer in decarboxylation of 4-hydroxycinnamic acids by 4-hydroxycinnamate decarboxylase from Klebsiella oxytoca.

The stereochemical specificity in the decarboxylation of E-4-hydroxycinnamic acid catalyzed by E-4-hydroxycinnamate decarboxylase (4-HCD) of Klebsiella oxytoca was investigated. Unlike the pyrolytic decarboxylation of 8-deuterated E-4-hydroxycinnamic acid to yield an equimolecular mixture of 8-Z- and 8-E-deuterated 4-hydroxystyrenes, treating 8-deuterated E-4-hydroxycinnamic acid with the enzyme in H2O-based buffer yielded 8-Z-deuterated 4-hydroxystyrene selectively. The specific E-orientation in catalysis and the substrate specificity requiring 4-OH in the substrates suggest that decarboxylation by K. oxytoca 4-HCD occurs via a para-quinone methide intermediate. Stereoselective protonation and the liberation of CO2 by an intermediary molecule are most likely the key reaction steps in the stereochemical specificity of the newly incorporated hydrogen.

Biological Transport↗
PubMed1993

Microassay of decarboxylation reactions in cultured cells.

The currently described methods for determination of decarboxylation reaction rates in cultured cells require large quantities of cells and often involve cell manipulation prior to assay. We describe a simple microassay for the rapid measurement of various decarboxylation reaction rates in intact cultured cells. The assay is based on the traditional measurement of 14CO2 generated from 14C-labeled substrates. Key to the method is a novel modification of the standard petri dish. Pyruvate dehydrogenase, branched chain alpha-ketoacid dehydrogenase, alpha-ketoglutarate dehydrogenase, and ornithine decarboxylase activities were determined in adult cardiomyocyte cultures containing only 0.1-0.5 mg of protein per culture dish. Efficiency of 14CO2 collection ranged between 94 and 100%. Pharmacological enhancement or inhibition of pyruvate dehydrogenase activity was easily detected in the culture system. This new method simplifies the measurement of various decarboxylation reaction rates in cultured cells and allows rapid, reproducible measurements to be made on small numbers of cells without perturbation of the culture conditions or the cells themselves.

Animals↗
PubMed2002

Isolation from a shea cake digester of a tannin-tolerant Escherichia coli strain decarboxylating p-hydroxybenzoic and vanillic acids.

A facultatively anaerobic, mesophilic, Gram-negative, non-motile, non-sporulated bacterium, designated strain C2, was isolated from an anaerobic digester fed with shea cake rich in tannins and aromatic compounds and previously inoculated with anaerobic sludge from the pit of a slaughterhouse, after enrichment on tannic acid. The straight rods occurred singly or in pairs. Strain C2 fermented numerous carbohydrates (fructose, galactose, glucose, lactose, mannose, maltose, melibiose, raffinose, rhamnose, ribose, saccharose, sorbitol, trehalose, and xylose) and peptides (Biotrypcase, Casamino acids, and yeast extract), producing acid and gas, and had a G + C content of 51.6 +/- 0.1 mol %. Strain C2 was very closely related to Escherichia coli (= DSM 30083(T)) phylogenetically (similarity of 99%), genotypically (DNA homology of 79%), and phenotypically. The isolate tolerated tannic acid (hydrolyzable tannin) and decarboxylated by non-oxidative decarboxylation only p-hydroxybenzoic and vanillic acids to their corresponding phenol and guaicol, under anaerobic and aerobic conditions without further degradation. Adding glucose increased growth and the rate of conversion. High concentrations of p-hydroxybenzoic acid or vanillic acid inhibited growth, and decarboxylation could not occur completely, suggesting phenol toxicity. In contrast, the type strain of E. coli cannot metabolize p-hydroxybenzoic and vanillic acids, anaerobically or aerobically, with or without glucose added.

Aerobiosis↗
PubMed1989

Steady-state kinetic studies of the metal ion-dependent decarboxylation of oxalacetate catalyzed by pyruvate kinase.

Steady-state kinetic studies with differing divalent metals ions have been carried out on the pyruvate kinase-catalyzed, divalent cation-dependent decarboxylation of oxalacetate to probe the role of the divalent metal ion in this reaction. With either Mn2+ or Co2+, initial velocity patterns show that the divalent metal ion is bound to the enzyme in a rapid equilibrium prior to the addition of oxalacetate. Further, there is no change in the initial velocity patterns or the kinetic parameters in the presence or absence of K+, indicating that K+ is not required for oxalacetate decarboxylation. Dead-end inhibition of the decarboxylation reaction by the physiological substrate phosphoenolpyruvate indicates that phosphoenolpyruvate binds only to the enzyme-metal ion complex and not to free enzyme. The pKi values for both Mn2+ and Co2+ decrease below a pK of 7.0, and increase above a pK of 8.9. Since these pK values are the same for both ions, both of the observed pK values must be attributable to enzymatic residues. The pK of 7.0 is presumably that of a ligand to the metal ion, while the pK of 8.9 is probably that of the lysine involved in enolization of pyruvate in the normal physiological reaction. However, with Co2+ as divalent cation, the V for oxalacetate decreases above a pK of 8.0, the V/K decreases above two pK values averaging 7.8, and the pKi for oxalate decreases above a single pK of 7.3. These data indicate that metal-coordinated water is displaced during the binding of substrates or inhibitors and the other pK value observed in both V and V/K pH profiles (pK of 8.3 with Co2+ and 9.2 with Mg2+) is an enzymatic residue whose deprotonation disrupts the charge distribution in the active site and decreases activity.

Adenosine Triphosphate↗
PubMed1979

Decarboxylation of ornithine and lysine in rat tissues.

The possibility that arginine and lysine might be decarboxylated by rat tissues was investigated. No evidence for decarboxylation of arginine could be found. Lysine decarbosylase (L-lysine carboxy-lyase, EC 4.1.1.18) activity producing CO2 and cadaverine was detected in extracts from rat ventral prostate, androgen-stimulated mouse kidney, regenerating rat liver and livers from rats pretreated with thioacetamide. These tissues all have high ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) activities. Lysine and ornithine decarboxylase activities were lost to similar extents on inhibition of protein synthesis by cycloheximide and on exposure to alpha-difluoromethylornithine. A highly purified ornithine decarboxylase preparation was able to decarboxylate lysine and the ratio of ornithine to lysine decarboxylase activities was constant throughout purification. Kinetic studies of the purified preparation showed that the V for ornithine was about 4-fold greater than for lysine, but the Km for lysine (9 mM) was 100-times greater than that for ornithine (0.09 mM). These experiments indicate that all of the detectable lysine decarboxylase activity in rat and mouse tissues was due to the action of ornithine decarboxylase and that significant cadaverine production in vivo would occur only when ornithine decarboxylase activity is high and lysine concentrations substantially exceed those of ornithine.

Animals↗
PubMed1989

Hyperhistaminemia in patients with histidinemia due to increased decarboxylation of histidine.

Histidinemia results from a defect in the major catabolic pathway of histidine. Among the various alternative metabolic pathways, transamination, methylation and acetylation of histidine have been found to be increased, but increased decarboxylation to histamine has not been reported in histidinemia. In an attempt to confirm the possibility of increased decarboxylation of histidine, plasma histamine levels were determined by reversed-phase high speed liquid chromatography in histidinemic, atopic, and control groups. In the histidinemic group, plasma histamine levels were higher than those in the other two groups, and correlated positively with plasma histidine level. Serum IgE levels, the numbers of eosinophils and basophils, and the histaminopexic power in the histidinemic group were within the normal range. These results suggest that hyperhistaminemia is not due to allergic reactions but results from increased decarboxylation of histidine.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Studies on the active centre(s) of rat liver porphyrinogen carboxy-lyase. In vivo effect of hexachlorobenzene on decarboxylation site(s) of porphyrinogens.

1. The role of histidine on the decarboxylation of porphyrinogens of 7-, 6-, and 5-COOH III brought about by porphyrinogen carboxy-lyase (PCL) was studied. 2. For this purpose hepatic PCL from normal and hexachlorobenzene (HCB) treated rats were modified with diethylpyrocarbonate. 3. The results indicated that the enzyme from both normal and porphytic animals had histidine at the binding sites of all the porphyrinogens assayed. 4. Comparative studies between the enzyme from normal and porphyric rats suggested that in vivo HCB treatment affected the active site for the decarboxylation of 7-, 6- and 5-COOH porphyrinogens III at histidine residues. 5. On the other hand arginine modification by 2,3-butanedione treatment altered 5-COOH porphyrinogen III decarboxylation for both enzymes. However this amino acid was not involved at the binding site of this substrate.

Animals↗
PubMed1980

Rhythmic variations of valine and leucine decarboxylation in rat diaphragm.

Daily rhythmic variations of valine and leucine decarboxylation in the rat diaphragm were measured. Both valine and leucine decarboxylation increased during the hours of darkness and decreased during hours of light. Hypophysectomy eliminated the daily variation of decarboxylation. When food is available ad lib. to normal rats, the time of most active feeding coincides with the hours of darkness. Therefore, the period of darkness and maximum feeding coincides with the maximum oxidation of these two essential amino acids, valine and leucine, by diaphragm, and an active pituitary appears to be necessary to maintain this relationship. This model can be used to study interrelationships to behavioral, neurohumoral, and metabolic rhythms.

Animals↗
PubMed1992

NADPH activates a decarboxylation reaction catalysed by lamb liver 6-phosphogluconate dehydrogenase.

NADP-dependent lamb liver 6-phosphogluconate dehydrogenase catalyses the oxidative decarboxylation of 2-deoxy-6-phosphogluconate, an analogue of the natural substrate. The first products of the reaction are NADPH and 3-keto-2-deoxy-6-phosphogluconate. The NADPH, released from the enzyme, binds to the coenzyme site of the same or the other subunit, activating the decarboxylation reaction in which has not a redox role, since it can be substituted by an analogue devoid of enzymatic redox power. These findings are compared to those obtained with other NADP-dependent decarboxylating dehydrogenases.

Animals↗
PubMed1980

Identification of a decarboxylation product of retinoic acid.

The oxidative decarboxylation of retinoic acid was investigated utilizing a model system consisting of all-trans-retinoic acid, H2O2 and horseradish peroxidase. The decarboxylation products were purified by high-performance liquid chromatography on bonded, octadecylsilane columns. Based on mass spectral, nuclear magnetic resonance, ultraviolet and Fourier transform infrared analyses, the major decarboxylation product was identified as a 4-oxo-C19 aldehyde with a hydroxyl group on the side chain at C9, specifically 8-(2,6,6-trimethyl-3-oxocyclohex-1-enyl)2,6-dimethyl-6-hydroxyoctatrienal.

Aldehydes↗
PubMed1996

Why Saccharomyces cerevisiae can oxidize but not decarboxylate external pyruvate.

Protoplasts of the yeast Saccharomyces cerevisiae oxidized externally added pyruvate by pyruvate oxidase system but were not able to decarboxylate it anaerobically by pyruvate decarboxylase at pH 6.4 in isotonic solutions. The decarboxylation set in hypotonic solutions in which the integrity of the plasma membrane was being impaired. Yeast cells incubated with [1-14C]pyruvate accumulated radioactivity under conditions allowing oxidation of pyruvate, but virtually no pyruvate was taken up when the oxidation had been arrested by inhibition or mutation. In view of a large difference between Km for pyruvate of pyruvate decarboxylase (30 mM) and of pyruvate oxidase (0.16 mM), the results may be accounted for by the assumption that transport of pyruvate across the yeast plasma membrane is trans-inhibited by relatively high concentrations of intracellular pyruvate. This arrangement would allow utilization of external pyruvate by the cell energy-transforming machinery and, at the same time, prevent its wastage by futile decarboxylation.

Decarboxylation↗
PubMed1979

Decarboxylation and carboxylation of pyruvate in the living mice.

Mice received intravenously [1- or 2-14C]acetate, [1-, 2- or 3-14C] or [2-14C]pyruvate and were killed 1, 3, 5 or 15 min later. The radioactivity of CO2 or HCO3- of liver or carcass as well as the radioactivity of blood glucose were measured. The ratio of the radioactivity found in these compounds after [3-14C] or [2-14C-A1pyruvate injection suggests that in the fed aminals: 1. the decarboxylation of the pyruvate was more rapid than its carboxylation, 2. most of the neosynthesized glucose was derived from pyruvate molecules which had undergone a decarboxylation followed by a condensation to citrate, 3. 1/4 to 1/3 of the pyruvate was carboxylated and 2/3 to 3/4 was decarboxylated in animals receiving a diet poor in fats.

Acetates↗
PubMed1998

Resistance of aryl-substituted phenylalanines to decarboxylation in the rat.

1. The in vivo decarboxylation of analogues of DL-phenylalanine with methoxy, ethoxy or methylenedioxy substituents on the aromatic nucleus was assessed in the rat by measuring urinary excretion of the corresponding phenylacetic acids and beta-phenylethylamines. Only trace amounts of these amines and acids were excreted. 2. o-Tyrosine was readily decarboxylated, a property that may be attributed to the position and nature of the substituent on the aromatic nucleus. 3. Some phenylpyruvic acids derived from these amino acids exhibited a certain degree of decarboxylation to phenylacetic acids or reduction to phenyllactic acids in the rat.

Animals↗
PubMed2002

Characterization of the carboxylate delivery module of transcarboxylase: following spontaneous decarboxylation of the 1.3S-CO2- subunit by NMR and FTIR spectroscopies.

Transcarboxylase (TC) is a multisubunit enzyme that catalyzes the transfer of a carboxylate group from methylmalonyl-CoA (MMCoA) to pyruvate. The CO2- group is shuttled between the MMCoA and pyruvate binding sites by a biotin cofactor, covalently linked to the 1.3S subunit. Fully carboxylated 1.3S can be prepared in vitro using 1.3S, MMCoA, and catalytic amounts of the TC's MMCoA-binding subunit. The 1.3S-CO2- intermediate decarboxylates spontaneously over a period of hours, and this process was characterized by 1D and 2D NMR and FTIR spectroscopies. The NMR data yielded a first-order kinetic constant of 1.4 x 10(-3) min(-1) for the spontaneous decarboxylation. This rate was calculated from the 1D NMR spectrum by measuring the reappearance of biotin's ureido NH protons and the disappearance of peaks at 6.99 and 7.67 ppm assigned to Asn-8 and/or Asn-24 from the 1.3S's N-terminus. The latter peaks are absent in the 1D spectrum of non-carboxylated 1.3S due to exchange between two or more conformations within the N-terminus causing line broadening. It is proposed that interactions between the biotin-CO2- and the N-terminal amino acids perturb this conformational equilibrium causing some N-terminal residues to appear in the 1D NMR spectrum of the carboxylated form. Further details are apparent from a comparison of the 2D spectra of the 1.3S-CO2- and 1.3S proteins, where carboxylation causes several peaks from the C-terminal half to shift as well as the appearance of resonances due to some residues located at the N-terminal half of the protein. FTIR difference spectra were used also to follow spontaneous decarboxylation of the 1.3S-CO2-. For the carboxylated 1.3S, the difference spectra provided the vibrational signature of the CO2- on the biotin ring. A doublet was identified at 1695 and 1699 cm(-1) that increased in intensity with increasing t. This is assigned to an antisymmetric stretching vibration of the CO2- group bound to biotin on the 1.3S protein. Its position and profile provide further evidence for interactions occurring between the biotin-CO2- group and the 1.3S protein. These studies demonstrate the highly mobile, "poised" nature of the 1.3S protein engineered for its role as a CO2- translocator.

Acetyl-CoA Carboxylase↗