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At least 19 recordsLinked to original sources

Molecular and isotopic analyses of the hydroxy acids, dicarboxylic acids, and hydroxicarboxylic acids of the Murchison meteorite.

The hydroxymonocarboxylic acids, dicarboxylic acids, and hydroxydicarboxylic acids of the Murchison meteorite were analyzed as their tert-butyldimethylsilyl derivatives using combined gas chromatography-mass spectrometry. The hydroxydicarboxylic acids have not been found previously in meteorites. Each class of compounds is numerous with carbon chains up to C8 or C9 and many, if not all, chain and substitution position isomers represented at each carbon number. The alpha-hydroxycarboxylic acids and alpha-hydroxydicarboxylic acids correspond structurally to many of the known meteoritic alpha-aminocarboxylic acids and alpha-aminodicarboxylic acids, a fact that supports the proposal that a Strecker synthesis was involved in the formation of both classes of compounds. Isotopic analyses show these acids to be D-rich relative to terrestrial organic compounds as expected; however, the hydroxy acids appear to be isotopically lighter than the amino acids with respect to both carbon and hydrogen. The latter finding would not be expected if both classes of compounds came exclusively from common precursors as would have been the case for a Strecker synthesis.

Carbon Isotopes↗

High-performance liquid chromatographic analyses of hydroxymonocarboxylic acids and dicarboxylic acids in urine as their 2-nitrophenylhydrazides.

Both hydroxymonocarboxylic acids and dicarboxylic acids in urine were converted into their 2-nitrophenylhydrazides without lengthy and cumbersome sample workup and were separated from each other by two-step extraction with diethyl ether at different pH values. HPLC analysis of each acid group was achieved isocratically within 30 min. By the use of a visible-range detector (400 nm) the detection limits ranged from 1 to 2 pmol and from 2 to 5 pmol per injection for the hydroxymonocarboxylic acids and dicarboxylic acids, respectively. The analytical results showed good recovery and reproducibility. Analysis profiles of the two acid groups in normal and diabetic subjects could be performed with 200 microliters of urine. The present method is superior over previously published methods because of its great simplicity and its time-, cost-, and labor-saving nature.

Chemical Phenomena↗

Engineering the acetyl-CoA transportation system of candida tropicalis enhances the production of dicarboxylic acid.

Dicarboxylic acids (DCAs) can be obtained by oxidizing alkanes by Candida tropicalis. Through alpha-monocarboxylic acids (MCAs), alpha- and omega-oxidation yield alpha- or omega-DCAs, respectively. However, both MCAs and DCAs may be degraded to acetyl-CoA by beta-oxidation, resulting in a limited DCA yield. Acetyl-CoA can be transported into the mitochondrion for the TCA cycle by carnitine acetyltransferase (CAT), by which the energy generation and beta-oxidation are connected. In this paper, we present a method to reconstruct the metabolic pathway by inhibiting the acetyl-CoA transportation system. Metabolic engineering is applied on the acetyl-CoA transportation system, but not the key enzymes in beta-oxidation. Starting with the original strain W10-1, cat heterozygote CZ-15 and cat homozygote CKC-11 were obtained by gene knockout. The CAT specific activity in CZ-15 was about 50% lower than that in W10-1, resulting in a 21.0% increase of the DCA concentration, and a 12% increase of the molar conversion of alkane, reaching 61.6%. However, no CAT activity was detected in CKC-11, and CKC-11 could not grow on alkane. These results indicate that inhibition of beta-oxidation via reconstruction of the transportation process between organelles can facilitate DCA production, but that totally blocking the & betagr;-oxidation would be harmful for energy supply. We thus provide a novel insight into regulation of the beta-oxidation system and metabolic flux. Further understanding of beta-oxidation and the acetyl-CoA transportation system in Candida tropicalis is reached through examination of fermentation data by metabolic flux analysis.

Acetyl Coenzyme A↗

Biosynthesis of Cutin: Enzymatic Conversion of omega-Hydroxy Fatty Acids to Dicarboxylic Acids by Cell-free Extracts of Vicia Faba Epidermis.

Long chain dicarboxylic acids are constituents of the protective biopolymers cutin and suberin of plants. Cell-free extracts from the excised epidermis of Vicia faba leaves catalyzed conversion of 16-hydroxy[G-(3)H]hexadecanoic acid to the corresponding dicarboxylic acid with nicotinamide-adenine dinucleotide phosphate as the preferred cofactor. This enzymatic activity, located largely in the 100,000g supernatant fraction, had a pH optimum near 8. This dehydrogenase showed an apparent Km of 1.25 x 10(-5)m and 3.6 x 10(-4)m for 16-hydroxyhexadecanoic acid and NADP, respectively. Modification of the substrate, either by esterification of the carboxyl group or by introduction of another hydroxyl group at C-10, resulted in a substantial (two-thirds) decrease in the rate of reaction, and hexadecanol was not a good substrate. The enzyme was inhibited by thiol reagents such as N-ethylmaleimide and p-chloromercuribenzoate. The aldehyde intermediate was trapped by the inclusion of dinitrophenyl hydrazine in the reaction mixture, and the 16-oxo compound was regenerated and identified. Furthermore, synthetic 16-oxo-[G-(3)H] hexadecanoic acid was readily converted to the dicarboxylic acid by the cell-free preparation. These results demonstrate that epidermis of Vicia faba contains an omega-hydroxyacid dehydrogenase and an omega-oxoacid dehydrogenase.

Journal Article↗

Identification of the peroxisomal beta-oxidation enzymes involved in the degradation of long-chain dicarboxylic acids.

Dicarboxylic acids (DCAs) are omega-oxidation products of monocarboxylic acids. After activation by a dicarboxylyl-CoA synthetase, the dicarboxylyl-CoA esters are shortened via beta-oxidation. Although it has been studied extensively where this beta-oxidation process takes place, the intracellular site of DCA oxidation has remained controversial. Making use of fibroblasts from patients with defined mitochondrial and peroxisomal fatty acid oxidation defects, we show in this paper that peroxisomes, and not mitochondria, are involved in the beta-oxidation of C16DCA. Additional studies in fibroblasts from patients with X-linked adrenoleukodystrophy, straight-chain acyl-CoA oxidase (SCOX) deficiency, d-bifunctional protein (DBP) deficiency, and rhizomelic chondrodysplasia punctata type 1, together with direct enzyme measurements with human recombinant l-bifunctional protein (LBP) and DBP expressed in a fox2 deletion mutant of Saccharomyces cerevisiae, show that the main enzymes involved in beta-oxidation of C16DCA are SCOX, both LBP and DBP, and sterol carrier protein X, possibly together with the classic 3-ketoacyl-CoA thiolase. This is the first indication of a specific function for LBP, which has remained elusive until now.

Carbon Radioisotopes↗

Simultaneous high performance liquid chromatographic separation of purines, pyrimidines, N-acetylated amino acids, and dicarboxylic acids for the chemical diagnosis of inborn errors of metabolism.

OBJECTIVES: To set up a novel simple, sensitive, and reliable ion-pairing HPLC method for the synchronous separation of several purines, pyrimidines, N-acetylated amino acids, and dicarboxylic acids for the chemical diagnosis and screening of inborn errors of metabolism (IEM). DESIGN AND METHODS: The separation was set up using a Hypersil C-18, 5-microm particle size, 250 x 4.6 mm column, and a step gradient using two buffers and tetrabutylammonium hydroxide as the pairing reagent. A highly sensitive diode array UV detector was set up at a wavelength between 200 and 300 nm that revealed purines and pyrimidines at 260 nm and other compounds at 206 nm. RESULTS: Compounds were determined in the plasma of 15 healthy adults, in the urine of 50 healthy subjects (1-3 years, 4-6 years, 8-10 years, 12-18 years, 25-35 years), and in 10 non-pathological amniotic fluid samples. To assess the validity of the chemical diagnosis of IEM, plasma and urine samples were analyzed in patients affected by Canavan disease (n = 10; mean age 4.6 +/- 2.3). Low plasma levels of N-acetylaspartate (16.96 +/- 19.57 micromol/L plasma; not detectable in healthy adults) and dramatically high urinary N-acetylaspartate concentrations (1872.03 +/- 631.86 micromol/mmol creatinine; 450 times higher than that which was observed in age-matched controls) were recorded. Neither N-acetylglutamate nor N-acetylaspartylglutamate could be detected in the plasma or urine of controls or patients with Canavan disease. CONCLUSIONS: The results demonstrate the suitability of the present ion-pairing HPLC separation with UV detection of cytosine, cytidine, creatinine, uracil, uridine, beta-pseudouridine, adenine, 3-methyladenine, hypoxanthine, xanthine, xanthosine, inosine, guanosine, ascorbic acid, thymine, thymidine, uric acid, 1-methyluric acid, orotic acid, N-acetylaspartate, N-acetylglutamate, N-acetylaspartylglutamate, malonic acid, methylmalonic acid, GSH, and GSSG as a reliable method for the prenatal and neonatal chemical diagnosis and screening of IEM using biological fluids.

Adolescent↗

Free acetate production by rat hepatocytes during peroxisomal fatty acid and dicarboxylic acid oxidation.

The fate of the acetyl-CoA units released during peroxisomal fatty acid oxidation was studied in isolated hepatocytes from normal and peroxisome-proliferated rats. Ketogenesis and hydrogen peroxide generation were employed as indicators of mitochondrial and peroxisomal fatty acid oxidation, respectively. Butyric and hexanoic acids were employed as mitochondrial substrates, 1, omega-dicarboxylic acids as predominantly peroxisomal substrates, and lauric acid as a substrate for both mitochondria and peroxisomes. Ketogenesis from dicarboxylic acids was either absent or very low in normal and peroxisome-proliferated hepatocytes, but free acetate release was detected at rates that could account for all the acetyl-CoA produced in peroxisomes by dicarboxylic and also by monocarboxylic acids. Mitochondrial fatty acid oxidation also led to free acetate generation but at low rates relative to ketogenesis. The origin of the acetate released was confirmed employing [1-14C]dodecanedioic acid. Thus, the activity of peroxisomes might contribute significantly to the free acetate generation known to occur during fatty acid oxidation in rats and possibly also in humans.

Acetates↗

Inhibitory effect of fumaric acid and dicarboxylic acids on gastric ulceration in rats.

Production of gastric ulcerations in rats by pyloric ligation was found to be inhibited by either intraperitoneal or oral administration of fumaric acid in a dose of 50 mg per kg. The antiulcer action was also exhibited by the four-carbon dicarboxylic acids, maleic acid, oxalacetic acid, succinic acid and malic acid. The studies on fumaric acid indicated that the acid's antiulcer action was based on its ability to inhibit the gastric juice secretion and to dilate the stomach muscle.

Animals↗

Urinary dicarboxylic acids in Reye syndrome.

Urine from 12 patients with Reye syndrome was examined by gas-liquid chromatography for identification of organic acids. Large amounts of lactic acid, dicarboxylic acids (adipic, suberic, and sebacic), and 3-OH butyric acid were noted. The mean (+/- SD) total dicarboxylic acid concentration was 0.98 +/- 0.24 mg/mg creatinine, compared with 0.006 +/- 0.010 mg/mg creatinine in controls, n = 140; the mean in patients with Reye syndrome was higher (1.40 +/- 0.26 mg/mg creatinine, n = 8) when the samples were obtained prior to initiation of therapy, but declined rapidly after administration of hypertonic glucose, exchange transfusion, and osmotic diuretics. The total urine excretion of dicarboxylic acids plus urine ketones at the time of presentation correlated well with the plasma lactate (r2 = 0.9676) and peak blood ammonia (r2 = 0.9216) levels. Our results document the occurrence of significant dicarboxylic aciduria in Reye syndrome and indicate that fatty acid metabolism is more impaired in this disorder than previously appreciated.

Ammonia↗

Repression of fatty-acyl-CoA oxidase-encoding gene expression is not necessarily a determinant of high-level production of dicarboxylic acids in industrial dicarboxylic-acid-producing Candida tropicalis.

The synthesis of dicarboxylic acids (DCAs) in Candida tropicalis is thought to be induced by a decrease in fatty acyl-CoA-oxidase activity. However, in the present study we demonstrate that repression of the POX4 gene, encoding fatty acyl-CoA oxidase, does not directly lead to high-level production of DCAs. No fatty acyl-CoA-oxidase activity was detected if the POX4 gene of C. tropicalis strain 1098 (wild-type strain) was disrupted. Furthermore, introduction of the POX4 gene from C. tropicalis strain M1210A3, which is a mutant derived from strain 1098 and is used as an industrial DCA-producing strain, still exhibited low-level fatty acyl-CoA-oxidase activity. Nevertheless, production of DCA was not observed in either case. Furthermore, the increase in acyl-CoA-oxidase activity by expression of the POX4 gene in strain M1210A3 did not reduce high-level production of DCA. These results suggest that alterations in acyl-CoA-oxidase activity are not necessarily related to production of DCA in industrial DCA-producing C. tropicalis M1210A3.

Acyl-CoA Oxidase↗

Quantitation of methylmalonic acid and other dicarboxylic acids in normal serum and urine using capillary gas chromatography-mass spectrometry.

Methylmalonic acid, succinic acid, and other dicarboxylic acids have been extracted and partially purified from serum and urine using ether extraction and high-performance liquid chromatography. The t-butyldimethylsilyl derivatives were prepared and analyzed using capillary gas chromatography-mass spectrometry with selected ion monitoring. The addition of [methyl-2H3]methylmalonic acid and [1,4-13C2]succinic acid to the starting samples made it possible to quantitate these two dicarboxylic acids. Normal ranges for methylmalonic acid and succinic acid were determined in human and rat serum and in human urine. The utilization of other internal standards would make it possible to quantitate malonic, dimethylmalonic, ethylmalonic, methylsuccinic, glutaric, and other dicarboxylic acids.

Animals↗

Hexahydro-1,4-thiazepine-3,5-dicarboxylic acid and thiomorpholine-3,5-dicarboxylic acid are present in normal human urine.

Hexahydro-1,4-thiazepine-3,5-dicarboxylic acid and thiomorpholine-3,5-dicarboxylic acid, simply referred to as cyclothionine and TMDA, respectively, are two cyclic sulfur-containing imino acids detected in bovine brain. Human urine has been investigated to establish the occurrence of these imino acids as common constituents under normal conditions. The morning urine of healthy subjects has been analyzed for enrichment of these compounds by using an ion-exchange procedure. Gas/liquid chromatography of the final extracts revealed the presence of peaks coeluting with authentic cyclothionine and TMDA. The latter compound eluted very close to an unknown sulfur-containing compound. A resolved peak of TMDA has been obtained by high-performance liquid chromatography of the final extracts derivatized with phenylisothiocyanate. Selected ion monitoring with multiple-ion detection applied to the compounds separated by gas chromatography revealed the presence of the respective molecular ions and of the decarboxylated fragments, thus confirming the identification of cyclothionine and TMDA in human urine.

Adult↗

Synthesis and characterization of metal-organic frameworks based on 4-hydroxypyridine-2,6-dicarboxylic acid and pyridine-2,6-dicarboxylic acid ligands.

The self-assembly of 4-hydroxypyridine-2,6-dicarboxylic acid (H(3)CAM) and pyridine-2,6-dicarboxylic acid (H2PDA) with Zn(II) salts under hydrothermal conditions gave two novel coordination polymers {[Zn(HCAM)].H2O}n (1) and {[Zn(PDA)(H2O)(1.5)]}n (1a). 1 and 1a comprise of a 2D (4,4) net and a 1D zigzag chain, respectively, in which a new coordination mode of PDA is found. The reactions of H(3)CAM and H2PDA with Nd2O3 in the M/L ratio 2:3 gave {[Nd2(HCAM)3(H2O)4].2H2O}n (2) and {[Nd(2)(PDA)3(H2O)(3)].0.5H2O}n (2a). In 2, a square motif as a building block constructed by four Nd(III) ions was further assembled into a highly ordered 2D (4,4) grid. 2a is a 3D microporous coordination polymer. It is interesting to note that, when Ln(III) salts rather than oxides were employed, the reaction produced {[Ln(CAM)(H2O)3].H2O}n (Ln = Gd, 3; Dy, 4; Er, 5) for H(3)CAM and {[Gd2(PDA)3(H2O)3].H2O}n (3a) for H2PDA. 3-5 are 2D coordination polymers with a 3(3)4(2) uniform net, where hydroxyl groups of H3CAM coordinate with metal ions. The reaction of H3CAM and Er2O3 instead of Er(ClO4)3 produced {[Er2(HCAM)3(H2O)4].2H2O}n (6). The compounds 2a and 3a, 2 and 6 are isomorphous. The stereochemical and supramolecular effects of hydroxyl groups result in the dramatic structural changes from 1D (1a) to 2D (1) and from 2D (2) to 3D (2a). When Ln(III) salts instead of Ln2O3 were employed in the hydrothermal reactions with H(3)CAM, different self-assembly processes gave the products of different metal/ligand ratio with reactants (3-5).

Journal Article↗

Conformations, energies, and intramolecular hydrogen bonds in dicarboxylic acids: implications for the design of synthetic dicarboxylic acid receptors.

The various conformers of the dicarboxylic acids HO2C--(CH2)n--CO2H, n = 1-4, were obtained using density functional methods (DFT), both in the gas phase and in the aqueous phase using a polarized continuum model (PCM). Several new conformers were identified, particularly for the two larger molecules glutaric (n = 3) and adipic acid (n =4). The PCM results show that the stability of most conformers were affected, many becoming unstable in the aqueous phase; and the energy ordering of conformers is also different. The results suggest that conformational preferences could be important in determining the design and stability of appropriate synthetic receptors for glutaric and adipic acid. Geometry changes between gas and aqueous phases were most marked in those conformers containing an intramolecular hydrogen bond. Additional calculations have probed the strength of intramolecular hydrogen bonds in these dicarboxylic acids. In the cases of glutaric and adipic acid, the strength of the intramolecular hydrogen bond were estimated to be around 28-29 kJ/mol, without any vibrational energy correction. The intramolecular hydrogen bond energies in malonic and succinic acid were also estimated from the calculated H-bond distances using an empirical relationship. Intramolecular H-bond redshifts of 170-250 cm(-1) have been estimated from the results of the harmonic frequency analyses.

Adipates↗

Binding of straight-chain saturated dicarboxylic acids to albumin.

Dicarboxylic acids are prominent features of several diseases, including Reye's syndrome. Long-chain dicarboxylic acids have profound effects on the function and structure of isolated mitochondria, suggesting that they could contribute to the mitochondrial dysfunction in Reye's syndrome. Binding of fatty acids to albumin and the intracellular fatty acid-binding proteins is important in regulating the transport and metabolism of fatty acids and protects against the toxic effects of unbound fatty acids. We studied the binding of dicarboxylic acids to defatted albumin using equilibrium dialysis to assess to what extent dicarboxylic acids are likely to be bound in the plasma of patients. Dicarboxylic acids bind weakly to albumin in a molar ratio of 3.8, 4.2, 1.6, 0.8, and 0.7 to 1 for octadecanedioic, hexadecanedioic, tetradecanedioic, dodecanedioic, and decanedioic acid, respectively. The dissociation constants for long-chain dicarboxylic acids are 100-1,000-fold larger than those of comparable monocarboxylic acids. Oleate competes with dicarboxylic acid and reduces the moles of dicarboxylic acid bound per mol of albumin to less than 1. Octanoate inhibits dicarboxylic acid binding. Our observations indicate that in Reye's syndrome, substantial concentrations of dicarboxylic acids of patients may be free and potentially toxic to mitochondria and other cellular processes.

Albumins↗

Metabolic origin of urinary 3-hydroxy dicarboxylic acids.

3-Hydroxy dicarboxylic acids with chain lengths ranging from 6 to 14 carbons are excreted in human urine. The urinary excretion of these acids is increased in conditions of increased mobilization of fatty acids or inhibited fatty acid oxidation. Similar urinary profiles of 3-hydroxy dicarboxylic acids were also observed in fasting rats. The metabolic genesis of these urinary 3-hydroxy dicarboxylic acids was investigated in vitro with rat liver postmitochondrial and mitochondrial fractions. 3-Hydroxy monocarboxylic acids ranging from 3-hydroxyhexanoic acid to 3-hydroxyhexadecanoic acid were synthesized. In the rat liver postmitochondrial fraction fortified with NADPH, these 3-hydroxy fatty acids with carbon chains equal to or longer than 10 were oxidized to (omega - 1)- and omega-hydroxy metabolites as well as to the corresponding 3-hydroxy dicarboxylic acids. 3-Hydroxyhexanoic (3OHMC6) and 3-hydroxyoctanoic (3OHMC8) acids were not metabolized. Upon the addition of mitochondria together with ATP, CoA, carnitine, and MgCl2, the 3-hydroxy dicarboxylic acids were converted to 3-hydroxyoctanedioic, trans-2-hexenedioic, suberic, and adipic acids. In the urine of children with elevated 3-hydroxy dicarboxylic acid levels, 3OHMC6, 3OHMC8, 3-hydroxydecanoic, 3,10-dihydroxydecanoic, 3,9-dihydroxydecanoic, and 3,11-dihydroxydodecanoic acids were identified. On the basis of these data, we propose that the urinary 3-hydroxy dicarboxylic acids are derived from the omega-oxidation of 3-hydroxy fatty acids and the subsequent beta-oxidation of longer chain 3-hydroxy dicarboxylic acids. These urinary 3-hydroxy dicarboxylic acids are not derived from the beta-oxidation of unsubstituted dicarboxylic acids.

Animals↗

Determination of malic acid and other C4 dicarboxylic acids in atmospheric aerosol samples.

An ion chromatographic method was developed which is able to separate five unsubstituted and hydroxy C4 dicarboxylic acids, succinic, malic, tartaric, maleic and fumaric acid, besides the other unsubstituted C2-C5 dicarboxylic acids, oxalic, malonic and glutaric acids, as well as inorganic ions in samples extracted from atmospheric particulate matter. By the application of this method it was found for both rural and urban sites and for various types of air masses that in the summer-time malic acid is the most prominent C4 diacid (64 ng m(-3) by average), exceeding succinic acid concentration (28 ng m(-3) by average) considerably. In winter-time considerably less, a factor of 4-15, C4 acids occurred and succinic acid was more concentrated than malic acid. Tartaric, fumaric and maleic acids were less concentrated (5.1, 5.0 and 4.5 ng m(-3) by average, respectively). Tartaric acid was observed for the first time in ambient air. The results indicate that in particular anthropogenic sources are important for the precursors of succinic, maleic and fumaric acids. Biogenic sources seem to influence the occurrence of malic acid significantly.

Aerosols↗