Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Fumarates”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed1986

Fumaric acid enhances DNA synthesis of rat hepatocytes by counteracting the toxicities of mitomycin C and aflatoxin B1.

The effect of fumaric acid was examined on DNA synthesis in hepatocytes or hepatoma cells from rats treated with toxic agents. Male Donryu rats were injected with mitomycin C or aflatoxin B1, singly or in combination with fumaric acid. After a specified period, hepatocytes were isolated from the liver by the collagenase perfusion method and placed in culture, and their activities for DNA synthesis were measured. The iv injection of rats with mitomycin C (0.5 mg/kg) reduced the semiconservative DNA synthesis of the hepatocytes, but simultaneous dosing of fumaric acid (40 mg/kg) enhanced the recovery of the DNA synthesis. The DNA synthesis of hepatoma cells, a 3'-methyl-4-(dimethylamino)azobenzene-induced transplantable cell line growing in the abdominal ascites of rats, was also reduced by the iv injection of mitomycin C but, in contrast to that of the hepatocytes, was little influenced by the simultaneous dosing of fumaric acid. The ip injection of fumaric acid also reduced the toxicity of aflatoxin B1 (0.25 mg/kg, ip), preventing the reduction of DNA synthesis as well as the occurrence of nuclear degenerative changes in the aflatoxin B1-exposed hepatocytes.

Aflatoxin B1↗
PubMed1987

[Peroral long-term treatment of psoriasis using fumaric acid derivatives].

Oral treatment of psoriasis on an outpatient basis, using a preparation containing fumaric acid derivatives, was evaluated as initial monotherapy (3 months) and as long-term basic therapy (12-14 months) in 13 and 11 patients, respectively. The course of the disease was analysed in each individual case. After completion of both parts of the trial, half of the patients that had only responded poorly to conventional antipsoriatic therapy showed a significant improvement which occurred after several weeks of treatment. In 4 patients the medication had to be stopped because of abdominal pain. No severe side effects, particularly of a renal, hepatic or haematological nature, could be established. Studies in mice and rats disclosed only a low acute toxicity of the fumaric acid derivatives used. In additional analyses, hypotheses were dealt with concerning the mechanism of action of fumaric acid in psoriasis. To establish fumaric acid derivatives in the treatment of psoriasis, studies on chronic toxicity and pharmacokinetics will have to be conducted. Further clinical trials should evaluate a single fumaric acid derivative instead of mixtures.

Animals↗
PubMed1985

Fumarate is the cause of the apparent ping-pong kinetics of dopamine beta-hydroxylase.

The kinetic mechanism of dopamine beta-hydroxylase (dopamine beta-monooxygenase EC 1.14.17.1) was studied either in the absence or the presence of the nonessential activator fumarate. In the absence of fumarate, intersecting initial velocity patterns were obtained, consistent with a sequential mechanism. In the presence of saturating concentrations of fumarate, initial velocity patterns became parallel. Other activating anions, such as acetate and chloride, could replicate the effects of fumarate. Since previous initial rate studies of dopamine beta-hydroxylase have been performed in the presence of saturating concentrations of fumarate, the present results may explain why parallel initial velocity patterns, apparently consistent with a ping-pong mechanism, have been so far observed. As a plausible mechanism of the anion effect it is proposed that activating anions induce saturation of the enzyme with oxygen.

Adrenal Glands↗
PubMed1988

Electron-transfer complexes of Ascaris suum muscle mitochondria. III. Composition and fumarate reductase activity of complex II.

Complex II of the anaerobic respiratory chain in Ascaris muscle mitochondria showed a high fumarate reductase activity when reduced methyl viologen was used as the electron donor. The maximum activity was 49 mumol/min per mg protein, which is much higher than that of the mammalian counterpart. The mitochondria of Ascaris-fertilized eggs, which require oxygen for its development, also showed fumarate reductase activity with a specific activity intermediate between those of adult Ascaris and mammals. Antibody against the Ascaris flavoprotein subunit reacted with the mammalian counterparts, whereas those against the Ascaris iron-sulfur protein subunit did not crossreact, although the amino acid compositions of the subunits in Ascaris and bovine heart were quite similar. Cytochrome b-558 of Ascaris complex II was separated from flavoprotein and iron-sulphur protein subunits by high performance liquid chromatography with a gel permeation system in the presence of Sarkosyl. Isolated cytochrome b-558 is composed of two hydrophobic polypeptides with molecular masses of 17.2 and 12.5 kDa determined by gradient gel, which correspond to the two small subunits of complex II. Amino acid compositions of these small subunits showed little similarity with those of cytochrome b-560 of bovine heart complex II. NADH-fumarate reductase, which is the final enzyme complex in the anaerobic respiratory chain in Ascaris, was reconstituted with bovine heart complex I, Ascaris complex II and phospholipids. The maximum activity was 430 nmol/min per mg protein of complex II. Rhodoquinone was essential for this reconstitution, whereas ubiquinone showed no effect. The results clearly indicate the unique role of Ascaris complex II as fumarate reductase and the indispensability of rhodoquinone as the low-potential electron carrier in the NADH-fumarate reductase system.

Amino Acid Sequence↗
PubMed1992

Fumarate reductase system of filarial parasite Setaria digitata.

In the cattle filarial parasite Setaria digitata the mitochondria like particles have been shown to possess NADH dependent fumarate reduction coupled with site I electron transport associated phosphorylation. This reduction is catalysed by the fumarate reductase system. The Km for fumarate is 1.47 mM and that for NADH is 0.33 mM. This activity is sensitive to rotenone, antimycin A and o-Hydroxy diphenyl. One ATP is produced for each pair of electrons transferred to fumarate. The fumarate reductase system consisting of NADH-coenzyme Q reductase, cytochrome b like component(s) and succinate dehydrogenase/fumarate reductase is thus very important and hence specific inhibitors of the system may prove useful in the effective control of filariasis.

Animals↗
PubMed1986

Oxidation of reduced menaquinone by the fumarate reductase complex in Escherichia coli requires the hydrophobic FrdD peptide.

Plasmids carrying cloned segments of the frd operon of Escherichia coli have been used in genetic complementation studies to identify two independent mutants defective in the frdD gene, which encodes the hydrophobic FrdD polypeptide of the fumarate reductase complex. Mutations in the frdA and frdB genes have also been mapped by this technique. One of the FrdD peptide mutants, DW109 (frdD-109), showed that fumarate reductase was not as tightly bound to the membrane in this mutant. In addition, the mutation in the FrdD peptide caused an almost total loss of the ability of the enzyme to oxidize either menaquinol-6, a physiological donor for fumarate reduction, or reduced benzyl viologen. However, the mutation did not impair the ability of the membrane-bound fumarate reductase complex to function with succinate as substrate, as evidenced by unchanged turnover numbers for phenazine methosulfate and 2,3-dimethoxy-5-methyl-6-pentyl-1,4-benzoquinone (a quinone analogue) reductase activities. These data establish the essential role of the FrdD polypeptide both in the interaction of the enzyme with reduced menaquinone and thus in anaerobic respiration with fumarate as electron acceptor, and in binding the enzyme to the membrane.

Benzoquinones↗
PubMed1988

Fumarate reductase of Escherichia coli: an investigation of function and assembly using in vivo complementation.

Recombinant plasmids which carried portions of the Escherichia coli frd operon were constructed and their expression examined by in vivo complementation of E. coli MI1443. This strain lacked a chromosomal frd operon and was unable to grow anaerobically on glycerol and fumarate. Introduction of all four fumarate reductase subunits into E. coli MI1443 was essential for the restoration of growth. The FRD A, FRD B dimer (but neither subunit alone) was active in the benzyl viologen oxidase assay. Both FRD C and FRD D were required for membrane association of fumarate reductase and for the oxidation of reduced quinone analogues. Introduction into E. coli MI1443 of the frdABC and frdD genes on two separate plasmid vectors failed to restore anaerobic growth on glycerol and fumarate. Thus separation of the DNA coding for the FRD C and FRD D proteins affected the ability of fumarate reductase to assemble into a functional complex.

Anaerobiosis↗
PubMedDate not supplied

A soluble fumarate reductase in Trypanosoma brucei procyclic trypomastigotes.

The enzyme NADH-fumarate reductase associated with the membrane fraction of Trypanosoma brucei procyclic trypomastigotes, can be solubilized by more than 50% when increasing the ionic strength to the equivalent of 150 mM KCl. The apparent KMs for NADH (125 microM) and fumarate (50 microM) remain close to those previously reported for the membrane-bound form of this enzyme. Other electron acceptors (i.e. oxygen or cytochrome c) appear to accept electrons in the absence of fumarate (KM for cytochrome c = 50 microM). The drug L-092,201 (Merck, Sharp and Dohme Research Laboratories, Rahway, NJ), an inhibitor of the membrane-bound fumarate reductase, also blocked the solubilized enzyme. Given the relatively high ionic strength of the intracellular environment we propose that, in vivo, the enzyme fumarate reductase is in the mitochondrial matrix or in the soluble fraction of another intracellular compartment.

Animals↗
PubMed1981

Cloning and expression of fumarate reductase gene of Escherichia coli.

Mutants of Escherichia coli deficient in fumarate reductase activity and therefore unable to grow anaerobically with fumarate as an electron acceptor have been isolated. By F+-mediated conjugation and complementation with the mutant host, two E. coli: Col E1 recombinant DNA plasmids have been identified from the Clarke and Carbon Colony Bank which carry the structural genes for fumarate reductase. Bacteria harboring either of these plasmids express about ten times the normal level of fumarate reductase. Enzyme purified from the two sources, plasmid-carrying and plasmidless E. coli, have identical physical and kinetic properties indicating that both the 69 000 and 25 000 dalton polypeptides are amplified. Regulation of plasmid-encoded enzyme, like the chromosomally encoded enzyme, is dependent upon the presence of fumarate and anaerobiosis.

Anaerobiosis↗
PubMed1992

[Drug induced cystitis due to ketotifen fumarate--a case report].

Tranilast, an antiallergic drug, is well known as a causal drug of cystitis, and a report is made here of our experience of 1 case of drug-induced cystitis ascribable to ketotifen fumarate. A 13-year-old female had been taking anti-asthmatic drugs orally since the onset of athmatoid attacks, from age of 5. The attacks intensified from the age of 12, because of this she began to take various anti-asthmatic drugs orally. She visited another hospital, due to pollakisuria, in November, 1990, and received treatment for cystitis. However, the symptoms were not alleviated, and she visited our department on January 9, 1991. By urinalysis, large counts of leukocytes and erythrocytes were observed in a visual field of the sediment. Remarkable reddening was observed over the urinary bladder in the patient's cystoscopic findings. Treatment was given at our department, on an outpatient basis, with various antibacterial drugs for approximately one month, but her symptoms were not alleviated, pollakisuria and aseptic pyuria persisted. The patient had never taken tranilast; oral intake of ketotifen fumarate and saibokutou was discontinued on February 13, due to a suspicion of drug-induced cystitis, and her symptoms subsequently disappeared. On February 22, she took ketotifen fumarate orally again, on her own, due to asthmatoid attack, and her symptoms returned. The oral intake of ketotifen fumarate was again discontinued, and alleviation of the symptoms and normalization of the urinary findings were again observed. As a result, lymphocyte stimulation tests on all the drugs the patient had ever taken, only ketotifen fumarate turned out to be positive.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Identification of active site residues of Escherichia coli fumarate reductase by site-directed mutagenesis.

Menaquinol-fumarate oxidoreductase of Escherichia coli is a four-subunit membrane-bound complex that catalyzes the final step in anaerobic respiration when fumarate is the terminal electron acceptor. The enzyme is structurally and catalytically similar to succinate dehydrogenase (succinate-ubiquinone oxidoreductase) from both procaryotes and eucaryotes. Both enzymes have been proposed to contain an essential cysteine residue at the active site based on studies with thiol-specific reagents. Chemical modification studies have also suggested roles for essential histidine and arginine residues in catalysis by succinate dehydrogenase. In the present study, a combination of site-directed mutagenesis and chemical modification techniques have been used to investigate the role(s) of the conserved histidine 232, cysteine 247, and arginine 248 residues of the flavorprotein subunit (FrdA) in active site function. A role for His-232 and Arg-248 of FrdA is shown by loss of both fumarate reductase and succino-oxidase activities following site-directed substitution of these particular amino acids. Evidence is also presented that suggests a second arginine residue may form part of the active site. Potential catalytic and substrate-binding roles for arginine are discussed. The effects of removing histidine-232 of FrdA are consistent with its proposed role as a general acid-base catalyst. The fact that succinate oxidation but not fumarate reduction was completely lost, however, might suggest that alternate proton donors substitute for His-232. The data confirm that cysteine 247 of FrdA is responsible for the N-ethylmaleimide sensitivity shown by fumarate reductase but is not required for catalytic activity or the tight-binding of oxalacetate, as previously thought.

Amino Acid Sequence↗
PubMed1995

A metabolic enzyme that rapidly produces superoxide, fumarate reductase of Escherichia coli.

Aerobic organisms synthesize superoxide dismutases in order to escape injury from endogenous superoxide. An earlier study of Escherichia coli indicated that intracellular superoxide is formed primarily by autoxidation of components of the respiratory chain. In order to identify those components, inverted respiratory vesicles were incubated with five respiratory substrates. In most cases, essentially all of the superoxide was formed through autoxidation of fumarate reductase, despite the paucity of this anaerobic terminal oxidase in the aerobic cells from which the vesicles were prepared. In contrast, most dehydrogenases, the respiratory quinones, and the cytochrome oxidases did not produce any detectable superoxide. The propensity of fumarate reductase to generate superoxide could conceivably deluge cells with superoxide when anaerobic cells, which contain abundant fumarate reductase, enter an aerobic habitat. In fact, deletion or overexpression of the frd structural genes improved and retarded, respectively, the outgrowth of superoxide dismutase-attenuated cells when they were abruptly aerated, suggesting that fumarate reductase is a major source of superoxide in vivo. Steric inhibitors that bind adjacent to the flavin completely blocked superoxide production, indicating that the flavin, rather than an iron-sulfur cluster, is the direct electron donor to oxygen. Since the turnover numbers for superoxide formation by other flavoenzymes are orders of magnitude lower than that of fumarate reductase (1600 min-1), additional steric or electronic factors must accelerate its autoxidation.

Binding Sites↗
PubMedDate not supplied

[Enzymatic synthesis of L-malic acid from fumaric acid using immobilized Escherichia coli cells].

Optimal conditions were chosen for cultivation of Escherichia coli 85 cells with a rather high fumarate-hydratase activity on a cheap medium containing no edible raw material. An active biocatalyst for the synthesis of L-malic acid from fumaric acid was obtained based on E. coli 85 cells immobilized in carrageenan. The enzymatic synthesis of L-malic acid from potassium fumarate was kinetically studied and optimized. Some thermodynamic parameters of fumaric acid hydration into malic acid were determined. A technique for assaying the reaction mixture was developed that involved high performance liquid chromatography.

Escherichia coli↗
PubMed1995

Fumarate reductase: a target for therapeutic intervention against Helicobacter pylori.

The potential of fumarate reductase as a therapeutic target against the human pathogen Helicobacter pylori was investigated by studying the cytotoxicity of morantel, oxantel, and thiabendazole, known to inhibit the enzyme in parasitic worms. Nuclear magnetic resonance spectroscopy was employed to investigate the effects of the inhibitors on the fumarate reductase activity of laboratory-adapted and wild-type bacterial strains. Production of succinate from fumarate in H. pylori cells was inhibited by morantel, oxantel, and thiabendazole. Cell growth and viability techniques were used to examine the bacteriostatic and bactericidal effects of the three anthelmintics. Each of the antiparasites arrested growth and produced cell death in liquid cultures, although the minimal inhibitory and bactericidal concentrations of these compounds are such that they would not be of therapeutic use. The strength of the effects as measured by minimal inhibitory and bactericidal concentrations was oxantel > thiabendazole > morantel. The findings suggested that fumarate reductase is an essential component of the metabolism of H. pylori and as such constitutes a possible target for therapeutic intervention in the treatment of the bacterium.

Aconitate Hydratase↗
PubMed1990

The specific functions of menaquinone and demethylmenaquinone in anaerobic respiration with fumarate, dimethylsulfoxide, trimethylamine N-oxide and nitrate by Escherichia coli.

The respiratory activities of E. coli with H2 as donor and with nitrate, fumarate, dimethylsulfoxide (DMSO) or trimethylamine N-oxide (TMAO) as acceptor were measured using the membrane fraction of quinone deficient strains. The specific activities of the membrane fraction lacking naphthoquinones with fumarate, DMSO or TMAO amounted to less than or equal to 2% of those measured with the membrane fraction of the wild-type strain. After incorporation of vitamin K1 [instead of menaquinone (MK)] into the membrane fraction deficient of naphthoquinones, the activities with fumarate or DMSO were 92% or 17%, respectively, of the activities which could be theoretically achieved. Incorporation of demethylmenaquinone (DMK) did not lead to a stimulation of the activities of the mutant. In contrast, the electron transport activity with TMAO was stimulated by the incorporation of either vitamin K1 or DMK. Nitrate respiration was fully active in membrane fractions lacking either naphthoquinones or Q, but was less than or equal to 3% of the wild-type activity, when all quinones were missing. Nitrate respiration was stimulated on the incorporation of either vitamin K1 or Q into the membrane fraction lacking quinones, while the incorporation of DMK was without effect. These results suggest that MK is specifically involved in the electron transport chains catalyzing the reduction of fumarate or DMSO, while either MK or DMK serve as mediators in TMAO reduction. Nitrate respiration requires either Q or MK.

Anaerobiosis↗
PubMed1982

Biosynthetic Pathways of Vibrio succinogenes growing with fumarate as terminal electron acceptor and sole carbon source.

1. With fumarate as the terminal electron acceptor and either H2 or formate as donor, Vibrio succinogenes could grow anaerobically in a mineral medium using fumarate as the sole carbon source. Both the growth rate and the cell yield were increased when glutamate was also present in the medium. 2. Glutamate was incorporated only into the amino acids of the glutamate family (glutamate, glutamine, proline and arginine) of the protein. The residual cell constituents were synthesized from fumarate. 3. Pyruvate and phosphoenolpyruvate, as the central intermediates of most of the cell constituents, were formed through the action of malic enzyme and phosphoenolpyruvate synthetase. Fructose-1,6-bisphosphate aldolase was present in the bacterium suggesting that this enzyme is involved in carbohydrate synthesis. 4. In the absence of added glutamate the amino acids of the glutamate family were synthesized from fumarate via citrate. The enzymes involved in glutamate synthesis were present. 5. During growth in the presence of glutamate, net reducing equivalents were needed for cell synthesis. Glutamate and not H2 or formate was used as the source of these reducing equivalents. For this purpose part of the glutamate was oxidized to yield succinate and CO2. 6. The alpha-ketoglutarate dehydrogenase involved in this reaction was found to use ferredoxin as the electron acceptor. The ferredoxin of the bacterium was reoxidized by means of a NADP-ferredoxin oxidoreductase. Enzymes catalyzing the reduction of NAD, NADP or ferredoxin by H2 or formate were not detected in the bacterium.

Electron Transport↗
PubMed1978

Cell yields of Escherichia coli during anaerobic growth on fumarate and molecular hydrogen.

Escherichia coli was grown anaerobically on sodium fumarate and molecular hydrogen or sodium formate in continuous culture. The maximal growth yield and the maintenance coefficient were determined. In a mineral medium a Ymax(fum) value of 6.6 g dry weight per mol fumarate was found. This value increased to 7;5 when casamino acids were present in the medium. From these data and the corresponding Ymax(ATP) values it could be calculated that per mol of fumarate reduced, 0;4 mol of ATP became available for growth. In batch culture a Yfum value of 4.8 g dry weight per mol fumarate was determined.

Adenosine Triphosphate↗
PubMed1976

Nitrate, fumarate, and oxygen as electron acceptors for a late step in microbial heme synthesis.

Nitrate can serve as anaerobic electron acceptor for the oxidation of protoporphyrinogen to protoporphyrin in cell-free extracts of Escherichia coli grown anaerobically in the presence of nitrate. Two kinds of experiments indicated this: anaerobic protoporphyrin formation from protoporphyrinogen, followed spectrophotometrically, was markedly stimulated by addition of nitrate; and anaerobic protoheme formation from protoporphyrinogen, determined by extraction procedures, was markedly stimulated by addition of nitrate. In contrast, anaerobic protoheme formation from protoporphyrin was not dependent upon addition of nitrate. This was the first demonstration of the ability of nitrate to serve as electron acceptor for this late step of heme synthesis. Previous studies with mammalian and yeast mitochondria had indicated an obligatory requirement for molecular oxygen at this step. In confirmation of our previous preliminary report, fumarate was also shown to be an electron acceptor for anaerobic protoporphyrinogen oxidation in extracts of E. coli grown anaerobically on fumarate. For the first time, anaerobic protoheme formation from protoporphyrinogen, but not from protoporphyrin, was shown to be dependent upon the addition of fumarate. The importance of these findings is 2-fold. First, they establish that enzymatic protoporphyrinogen oxidation can occur in the absence of molecular oxygen, in contrast to previous observations using mammalian and yeast mitochondria. Secondly, these findings help explain the ability of some facultative and anaerobic bacteria to form very large amounts of heme compounds, such as cytochrome pigments, when grown anaerobically in the presence of nitrate or fumarate. In fact, denitrifying bacteria are known to form more cytochromes when grown anaerobically than during aerobic growth. An unexpected finding was that extracts of another bacterium, Staphylococcus epidermidis, exhibited very little ability to oxidize protoporphyrinogen to protoporphyrin as compared to E. coli extracts. This finding suggests some fundamental differences in these two organisms in this key step in heme synthesis. It is known that these two facultative organisms also differ in that E. coli synthesizes cytochrome during both aerobic and anaerobic growth, while Staphylococcus only synthesizes cytochromes when grown aerobically.

Cell-Free System↗