fumarates and malonic-acid

ST segment elevation myocardial infarction (STEMI) is one of the most common global causes of cardiovascular disease-related death. Several metabolites may change during STEMI. Hence, analysis of metabolites in body fluid may be considered as a rapid and accurate test for initial diagnosis. This study has therefore attempted to determine the variation in metabolites identified in the serum of STEMI patients (n = 20) and 15 controls. Samples collected from the Cardiology Department, Medical Faculty, Ataturk University, were extracted by liquid-liquid extraction and analysed using liquid chromatography quadrupole time-of-flight mass spectrometry. The METLIN database was used for the identification and characterization of metabolites. According to Q-TOF/MS measurements, 231 m/z values, which were significantly different between groups (P < 0.01 and fold analysis >1.5) were detected. Metabolite identification was achieved via the Human Metabolome database. According to the multivariate data analysis, leucine, isoleucine, l-proline, l-alanine, glycine, fumaric acid, citrate, succinate and carnitine levels were decreased, whereas levels of propionic acid, maleic acid, butyric acid, urea, oleic acid, palmitic acid, lysoPC [18:2(9Z)], glycerol, phoshpatidylethanolamine, caffeine and l-lactic acid were increased in STEMI patients compared with controls. In conclusion, malonic acid, maleic acid, fumaric acid and palmitic acid can be used as biomarkers for early risk stratification of patients with STEMI.

Topics: Amino Acids; Chromatography, Liquid; Female; Fumarates; Humans; Male; Maleates; Malonates; Mass Spectrometry; Metabolome; Metabolomics; Middle Aged; ST Elevation Myocardial Infarction

Cocrystallization and salt formation were used to produce new multicomponent forms of a novel antimalarial imidazopyridazine drug lead (MMV652103) that displayed improved physicochemical properties. The drug lead had earlier shown good in vitro potency against multidrug resistant (K1) and sensitive (NF54) strains of the human malaria parasite Plasmodium falciparum, and high in vivo efficacy in both Plasmodium berghei and Plasmodium falciparum mouse models. A major drawback of MMV652103 is its limited aqueous solubility. Various new supramolecular products, including several multicomponent solid forms, are reported here, namely 3 cocrystal forms with the dicarboxylic acid coformers adipic acid, glutaric acid, and fumaric acid, and a salt form with malonic acid. These were characterized by thermal methods and their structures elucidated by single-crystal X-ray diffraction. A customized solubility experiment was performed in fasted-state simulated intestinal fluid for comparison of the solubility behavior of each new form of the drug lead with that of the untreated starting material. All of the multicomponent forms showed an improvement in the maximum concentrations (C

Topics: Adipates; Antimalarials; Crystallization; Crystallography, X-Ray; Dicarboxylic Acids; Fumarates; Glutarates; Imidazoles; Malonates; Powder Diffraction; Pyridines; Sodium Chloride; Solubility; X-Ray Diffraction

Cocrystal forming ability of antiviral drug acyclovir (ACV) with different coformers was studied. Three cocrystals containing ACV with fumaric acid, malonic acid, and DL-tartaric acid were isolated. Methods of cocrystallization included grinding with dropwise solvent addition and solvent evaporation. The cocrystals were characterized by powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. The crystal structure of the cocrystal with fumaric acid as conformer was determined by single crystal X-ray diffraction. Formation of supramolecular synthon was observed in the cocrystal. Stability with respect to relative humidity for the three cocrystals was evaluated. The aqueous solubility of the ACV-cocrystal materials was significantly improved with a maximum of malonic acid cocrystal, which was about six times more soluble at 35°C compared with that of parent ACV. The dissolution profile indicates that at any particular dissolution time, the concentration of cocrystals in the solution was higher than that of the parent ACV, and malonic acid cocrystals had a maximum release of about twice than the hydrated ACV.

Topics: Acyclovir; Antiviral Agents; Calorimetry, Differential Scanning; Chemical Phenomena; Crystallization; Crystallography, X-Ray; Dicarboxylic Acids; Drug Compounding; Drug Stability; Fumarates; Hydrogen Bonding; Kinetics; Malonates; Models, Molecular; Molecular Conformation; Pharmaceutic Aids; Powder Diffraction; Solubility; Tartrates; Thermogravimetry

The properties of nitrogen centres acting either as hydrogen-bond or Brønsted acceptors in solid molecular acid-base complexes have been probed by N 1s X-ray photoelectron spectroscopy (XPS) as well as (15)N solid-state nuclear magnetic resonance (ssNMR) spectroscopy and are interpreted with reference to local crystallographic structure information provided by X-ray diffraction (XRD). We have previously shown that the strong chemical shift of the N 1s binding energy associated with the protonation of nitrogen centres unequivocally distinguishes protonated (salt) from hydrogen-bonded (co-crystal) nitrogen species. This result is further supported by significant ssNMR shifts to low frequency, which occur with proton transfer from the acid to the base component. Generally, only minor chemical shifts occur upon co-crystal formation, unless a strong hydrogen bond is formed. CASTEP density functional theory (DFT) calculations of (15)N ssNMR isotropic chemical shifts correlate well with the experimental data, confirming that computational predictions of H-bond strengths and associated ssNMR chemical shifts allow the identification of salt and co-crystal structures (NMR crystallography). The excellent agreement between the conclusions drawn by XPS and the combined CASTEP/ssNMR investigations opens up a reliable avenue for local structure characterization in molecular systems even in the absence of crystal structure information, for example for non-crystalline or amorphous matter. The range of 17 different systems investigated in this study demonstrates the generic nature of this approach, which will be applicable to many other molecular materials in organic, physical, and materials chemistry.

Topics: Benzenesulfonates; Benzoates; Citric Acid; Crystallography, X-Ray; Fumarates; Glutarates; Hydrochloric Acid; Hydrogen Bonding; Malonates; Models, Molecular; Molecular Structure; Oxalic Acid; Protons; Quantum Theory; Salicylates; Spectrophotometry; X-Rays

We investigated the effect of Al (400μM) on organic acids secretion, accumulation and metabolism in Plantago almogravensis Franco and Plantago algarbiensis Samp. Al induced a significant reduction on root elongation only in P. algarbiensis. Both species accumulated considerable amounts of Al (>120μgg(-1)) in their tissues, roots exhibiting the highest contents (>900μgg(-1)). Al stimulated malonic acid secretion in P. algarbiensis, while citric, succinic and malic acids were secreted by P. almogravensis. Moreover, Al uptake was accompanied by substantial increases of citric, oxalic, malonic and fumaric acids contents in the plantlets of either species. Overall, the acid metabolizing enzymes were not directly involved in the Al induced organic acid secretion and accumulation. Our data suggest that Al detoxification in P. almogravensis implies both secretion of organic acids from roots and tolerance to high Al tissue concentrations, while in P. algarbiensis only the tolerance mechanism seems to be involved.

Topics: Adaptation, Physiological; Aluminum; Biological Transport; Carboxylic Acids; Citric Acid; Fumarates; Inactivation, Metabolic; Malates; Malonates; Oxalic Acid; Plant Growth Regulators; Plant Roots; Plantago; Stress, Physiological; Succinic Acid

Two main entry points for electrons into the mitochondrial respiratory chain are NADH:ubiquinone oxidoreductase (complex I) and succinate:ubiquinone oxidoreductase (complex II). Metabolic regulation of these two respiratory complexes is not understood in detail. It has been suggested that the Krebs cycle metabolic intermediate oxaloacetate (OAA) inhibits complex II in vivo, whereas complex I undergoes a reversible active/de-active transition. In normoxic and anoxic hearts it has been shown that the proportion of complex I in the active and de-active states is different suggesting a possible mode of regulation of the enzyme by oxygen concentration. In the current studies rapid isolation of mitochondrial membranes in a state that preserves the activity of both complex I and complex II has been achieved using Langendorff perfused rat hearts. The findings indicate that the state of activation of complex I is controlled by the oxygen saturation in the perfusate. In addition, these studies show that complex II is fully active in the mitochondrion and not inhibited by OAA regardless of the oxygen concentration.

Topics: Animals; Electron Transport Complex I; Electron Transport Complex II; Fumarates; Heart; Hypoxia; In Vitro Techniques; Intracellular Membranes; Male; Malonates; Mitochondria, Heart; Multienzyme Complexes; Myocardium; NADH, NADPH Oxidoreductases; Oxaloacetic Acid; Oxygen; Perfusion; Potassium Cyanide; Rats; Rats, Sprague-Dawley; Succinate Dehydrogenase

Twelve compounds containing two quadruply bonded Mo(2)(DAniF)(3) (DAniF = N,N'-di-p-anisylformamidinate) units linked by dicarboxylate anions have been prepared in high purity and good yields. All of these compounds have been characterized by crystallography and NMR. The dinuclear pairs display electrochemical behavior which is controlled by the nature of the bridging dicarboxylate group. As described by the linkers, the compounds are oxalate, 1; acetylene dicarboxylate, 2; fumarate, 3; tetrafluorophthalate, 4; carborane dicarboxylate, 5; ferrocene dicarboxylate, 6; malonate, 7; succinate, 8; propane-1,3-dicarboxylate, 9; tetrafluorosuccinate, 10; bicyclo[1.1.1]pentane-1,3-dicarboxylate, 11; and trans-1,4-cyclohexanedicarboxylate, 12.

Topics: Acetylene; Dicarboxylic Acids; Electrochemistry; Fumarates; Malonates; Models, Molecular; Molecular Structure; Molybdenum; Organometallic Compounds; Oxalates; Phthalic Acids; Propane; Spectrometry, X-Ray Emission; Succinates

Analysis of the content and distribution of organic acids in chickpea plants (Cicer arietinum L.) showed that malonate was the most abundant acid in roots and nodules, whereas malate was the main acid in leaves and stems. The highest concentration of malonate in roots was in the apices. Malonate metabolism did not appear to be directly related to abiotic stress. We suggest that malonate has a role as a defensive chemical in roots and nodules of chickpeas.

Topics: Fabaceae; Fumarates; Malates; Malonates; Nitrogenase; Plant Roots; Plant Shoots; Plants, Medicinal; Succinates

The Saccharomyces cerevisiae succinate-ubiquinone reductase or succinate dehydrogenase (SDH) is a tetramer of non-equivalent subunits encoded by the SDH1, SDH2, SDH3, and SDH4 genes. In most organisms, SDH contains one or two endogenous b-type hemes. However, it is widely believed that the yeast SDH does not contain heme. In this report, we demonstrate the presence of a stoichiometric amount of cytochrome b562 in the yeast SDH. The cytochrome is detected as a peak present in fumarate-oxidized, dithionite-reduced mitochondria. The peak is centered at 562 nm and is present at a heme:covalent FAD molar ratio of 0.92+/-0.11. The cytochrome is not detectable in mitochondria isolated from SDH3 and SDH4 deletion strains. These observations strongly support our conclusion that cytochrome b562 is a component of the yeast SDH.

Topics: Animals; Cytochrome b Group; Dithionite; Electron Transport Complex II; Escherichia coli Proteins; Flavin-Adenine Dinucleotide; Fumarates; Fungal Proteins; Gene Deletion; Intracellular Membranes; Lactic Acid; Malonates; Mice; Mitochondria; Multienzyme Complexes; Oxidation-Reduction; Oxidoreductases; Saccharomyces cerevisiae; Spectrum Analysis; Succinate Dehydrogenase

The 1H magic-angle spinning (MAS) spectrum for a typical powdered solid is composed of a high resolution component and a broadline component. The high resolution component can be well isolated from the broadline component by the Hahn echo sequence with a long echo time. Compared with CRAMPS experiment, which measures the proton system as a whole, the high resolution echo-MAS method measures only a fraction of the solid, which is usually small at room temperature and quite different from the majority of the solid in both molecular motion and chemical environment. It is shown that for a sample of fumaric acid monoethyl ester, the chemical shifts of the high resolution component are apparently distinguishable from the isotropic chemical shifts of the broadline component in the CRAMPS spectrum as the temperature approaches the melting point. In addition, for a sample of malonic acid, the echo-MAS spectrum is sensitive to moisture and temperature, while its corresponding CRAMPS spectrum is not. It is suggested that the molecules which produce the high resolution component are related to the lattice defects in a solid, including the surface disorder of the polycrystallites, while the molecules that generate the broadline component are located on the rigid lattice of the solid.

Topics: Chemical Phenomena; Chemistry, Physical; Crystallization; Crystallography; Fumarates; Hot Temperature; Hydrogen; Magnetic Resonance Spectroscopy; Malonates; Molecular Structure; Protons; Temperature; Water

The fumarate reductase (FR) and succinate dehydrogenase (SDH) activities of isolated submitochondrial particles (SMPs) prepared from axenised L3 larvae of S. ratti were characterised with respect to their response to a selected range of inhibitors. Rotenone (a specific inhibitor of electron transport Complex I) inhibited the S. ratti FR (EC50 = 3.0 x 10(-7) M) but not SDH. This strongly suggests that the S. ratti FR is functionally linked with the S. ratti ET-Complex I. 2-Thenoyltrifluoroacetone (TTFA, an inhibitor of ET-Complex II) inhibited FR (EC50 = 2.6 x 10(-5) M) and SDH (EC50 = 2.8 x 10(-5) M) with similar effectiveness. Sodium malonate (substrate analogue of succinate) had a greater affinity for SDH (EC50 = 6.8 x 10(-4) M), than FR (EC50 = 1.9 x 10(-2) M). Sodium fumarate was ca. 8-fold more effective in inhibiting the S. ratti FR (EC50 = 6.0 x 10(-4) M) than SDH (EC50 = 4.8 x 10(-3) M). The S. ratti FR was more sensitive to inhibition by thiabendazole (TBZ; EC50 = 4.6 x 10(-4) M) than SDH (EC50 > 1.0 x 10(-3) M), suggesting that one of the sites-of-action of TBZ to be the FR of S. ratti mitochondria. More potent inhibitors of S. ratti FR, if developed, may prove to be effective chemotherapeutic agents in the management of human strongloidiasis.

Topics: Animals; Electron Transport; Female; Fumarates; Kinetics; Larva; Malonates; Rats; Rats, Sprague-Dawley; Rotenone; Sensitivity and Specificity; Strongyloides ratti; Submitochondrial Particles; Succinate Dehydrogenase; Thenoyltrifluoroacetone; Thiabendazole

Topics: Bacteroides fragilis; Carboxylic Acids; Chromatography, Gas; Fumarates; Lactates; Lactic Acid; Malonates; Methylmalonic Acid; Oxalates; Oxalic Acid; Pyruvates; Pyruvic Acid; Succinates; Succinic Acid

The protective effect of dicarboxylates on the active-site-directed inhibition of the membrane-bound succinate dehydrogenase by N-ethylmaleimide, steady-state kinetics methods for Ki and Ks determinations, and equilibrium studies were employed to quantitate the relative affinities of succinate, fumarate, malonate and oxaloacetate to the reduced and oxidized species of the enzyme. A more than 10-fold difference in the relative affinities of the reduced and oxidized succinate dehydrogenase to succinate, fumarate and oxaloacetate is found, whereas the reactivity of the active-site sulphydryl group does not depend on the redox state of the enzyme. The redox-state-dependent changes in the affinity of the membrane-bound succinate dehydrogenase to oxaloacetate can be quantitatively accounted for by a 10-fold increase in the rate of dissociation of the enzyme-inhibitor complex which occurs upon reduction of the enzyme. The data obtained give no support for either the existence of a sulphydryl group other than the active-site one important for the catalysis or for the presence of a separate dicarboxylate-specific regulatory site in the succinate dehydrogenase molecule.

Topics: Animals; Binding Sites; Binding, Competitive; Enzyme Inhibitors; Ethylmaleimide; Fumarates; Kinetics; Malonates; Succinate Dehydrogenase; Succinates; Succinic Acid

1. The rate and stability to aging of the metabolism of propionate by sheep-liver slices and sucrose homogenates were examined. Aging for up to 20min. at 37 degrees in the absence of added substrate had little effect with slices, whole homogenates or homogenates without the nuclear fraction. 2. Metabolism of propionate by sucrose homogenates was confined to the mitochondrial fraction, but the mitochondrial supernatant (microsomes plus cell sap) stimulated propionate removal. 3. The rate of propionate metabolism by liver slices was higher in a high potassium phosphate-bicarbonate medium [0.88(+/-s.e.m. 0.16)mumole/mg. of N/hr.] than in Krebs-Ringer bicarbonate medium [0.44(+/-s.e.m. 0.13)mumole/mg. of N/hr.]. 4. Metabolism of propionate by sucrose homogenates freed from nuclei was dependent on the presence of oxygen, carbon dioxide and ATP. Propionate removal was stimulated 250% by Mg(2+) ions and 670% by cytochrome c. 5. In the complete medium 2.39(+/-s.e.m. 0.15)mumoles of propionate were consumed/mg. of N/hr. 6. The ratio of oxygen consumption to propionate utilization was sufficient to account for the complete oxidation of half the propionate consumed. 7. The only products detected under these conditions were succinate, fumarate and malate. Propionate had no effect on the production of lactate from endogenous sources and did not itself give rise to lactate. 8. Methylmalonate did not accumulate when propionate was metabolized and was not oxidized. It was detected as an intermediate in the conversion of propionyl-CoA into succinate. The rate of this reaction sequence was adequate to account for the rate of propionate metabolism by sucrose homogenates or slices, provided that the rate of formation of propionyl-CoA was not limiting. 9. The methylmalonate pathway was predominantly a mitochondrial function. 10. The metabolism of propionate appeared to be dependent on active oxidative phosphorylation.

Topics: Acyl Coenzyme A; Adenosine Triphosphate; Animals; Bicarbonates; Carbon Dioxide; Chromatography; Coenzyme A; Dinitrophenols; Fatty Acids; Fumarates; Lipid Metabolism; Liver; Malates; Malonates; Manometry; Mitochondria; Oxidation-Reduction; Oxidative Phosphorylation; Pharmacology; Potassium Compounds; Propionates; Research; Sheep; Sheep, Domestic; Succinates

Topics: Anti-Bacterial Agents; Coenzyme A; Dermatologic Agents; Erythromycin; Fumarates; Glycosides; Lactones; Malonates; Metabolism; Propionates; Research; Streptomyces; Succinates

Topics: 3-Hydroxybutyric Acid; Acetoacetates; Adenosine Triphosphate; Animals; Coenzyme A; Cytoplasmic Granules; Dinitrophenols; Fatty Acids; Female; Fumarates; Hexokinase; Humans; Hydroxybutyrates; Liver; Malonates; Metabolism; Mitochondria; Mitochondria, Muscle; Muscle, Smooth; Myocardium; NAD; Pharmacology; Research; Swine; Uterus