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PubMed1999

Mercaptopyridine-N-oxide, an NADH-fumarate reductase inhibitor, blocks Trypanosoma cruzi growth in culture and in infected myoblasts.

The enzyme NADH-fumarate reductase is not found in mammalian cells but it is present in several parasitic protozoa including Trypanosoma cruzi, the parasite that causes Chagas' disease. This study shows that the drug 2-mercaptopyridine-N-oxide (MPNO) inhibits NADH-fumarate reductase purified from T. cruzi (ID50 = 35 microM). When added to intact cells, MPNO inhibited the growth of T. cruzi epimastigotes in culture (ID50 = 0.08 microM) as well as the infection of mammalian myoblasts by T. cruzi trypomastigotes (ID50 = 20 microM). At a concentration of 2.4 microM, MPNO also inhibited the growth of amastigotes (intracellular dividing forms) in cultured mammalian myoblasts. Supplementation of culture media with 5 mM succinate, the product of fumarate reductase, partially protected against the inhibition of the growth of epimastigotes by MPNO. Moreover, MPNO inhibited the accumulation of succinate in cultures of epimastigotes, as measured by high performance liquid chromatography. Although MPNO may have other intracellular targets in addition to fumarate reductase, these results support the hypothesis that compounds which inhibit the enzyme fumarate reductase may be potential chemotherapeutic agents against Chagas' disease.

Animals↗
PubMed1998

Anaerobic expression of Escherichia coli succinate dehydrogenase: functional replacement of fumarate reductase in the respiratory chain during anaerobic growth.

Succinate-ubiquinone oxidoreductase (SQR) from Escherichia coli is expressed maximally during aerobic growth, when it catalyzes the oxidation of succinate to fumarate in the tricarboxylic acid cycle and reduces ubiquinone in the membrane. The enzyme is similar in structure and function to fumarate reductase (menaquinol-fumarate oxidoreductase [QFR]), which participates in anaerobic respiration by E. coli. Fumarate reductase, which is proficient in succinate oxidation, is able to functionally replace SQR in aerobic respiration when conditions are used to allow the expression of the frdABCD operon aerobically. SQR has not previously been shown to be capable of supporting anaerobic growth of E. coli because expression of the enzyme complex is largely repressed by anaerobic conditions. In order to obtain expression of SQR anaerobically, plasmids which utilize the PFRD promoter of the frdABCD operon fused to the sdhCDAB genes to drive expression were constructed. It was found that, under anaerobic growth conditions where fumarate is utilized as the terminal electron acceptor, SQR would function to support anaerobic growth of E. coli. The levels of amplification of SQR and QFR were similar under anaerobic growth conditions. The catalytic properties of SQR isolated from anaerobically grown cells were measured and found to be identical to those of enzyme produced aerobically. The anaerobic expression of SQR gave a greater yield of enzyme complex than was found in the membrane from aerobically grown cells under the conditions tested. In addition, it was found that anaerobic expression of SQR could saturate the capacity of the membrane for incorporation of enzyme complex. As has been seen with the amplified QFR complex, E. coli accommodates the excess SQR produced by increasing the amount of membrane. The excess membrane was found in tubular structures that could be seen in thin-section electron micrographs.

Anaerobiosis↗
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↗
PubMed1996

[Efficacy and safety profile of fumaric acid esters in oral long-term therapy with severe treatment refractory psoriasis vulgaris. A study of 83 patients].

The therapeutic effect and the side of effects fumaric acid derivatives used in treatment of psoriasis vulgaris have been subjects of controversy for more than 30 years. A total of 83 patients with severe psoriasis vulgaris were investigated in a single-centre, long-term open (12 months) clinical trial to evaluate the efficacy and safety profile of the fumaric acid ester preparations Fumaderm initial and Fumaderm. The antipsoriatic effect of the fumaric acid derivatives was clear, with a mean reduction of 76% in PASI. Adverse events in were noted in 62% of the patients (mainly flushing and gastrointestinal complaints). These were dose-dependent and decreased in frequency in the course of the study. No severe adverse events occurred. We believe that of fumaric acid derivatives are indicated in cases of severe therapy-resistant psoriasis to and can be used even for long-term application.

Administration, Oral↗
PubMed1996

The effect of fumaric acid esters and dithranol on acanthosis and hyperproliferation in psoriasis vulgaris.

In this study we investigated the histological changes, regression of acanthosis and rate of proliferation, that accompany the healing of psoriatic lesions after fumaric acid esters and dithranol treatment. Biopsies were taken before and during therapy as well as from neighbouring untreated, clinically uninvolved skin and healthy, non-psoriatic volunteers. Specimens were assessed using computer-supported image analysis and immunohistology. The parameters primarily examined were the height of the rete pegs and of the epithelium above the papillary body, the rate of proliferation, the actual number of cells in the two epidermal compartments and the cellular density in the epidermis. Both fumaric acid esters and dithranol reduce the degree of acanthosis; however, the mechanism and the rate of the reduction differ. While under fumaric acid esters the reduction is more rapid at first but subsequently slows down, dithranol leads to a slow but steady decrease of epidermal thickness, so that at the end of our study the degree of acanthosis was less under dithranol. As an underlying mechanism of action, we found that fumaric acid esters reduce the rate of proliferation and thereby decrease the number of cells per rete peg as well as the size of the individual keratinocytes. Dithranol in contrast does not reduce cell renewal. The decrease of the number of cells in the rete pegs might be caused by an increased differentiation time.

Administration, Topical↗
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↗
PubMed2001

Characteristics and glycerol metabolism of fumarate-reducing Enterococcus faecalis RKY1.

Enterococcus faecalis RKY1, which converts fumarate to succinate with a high yield, was identified on the basis of a phylogenetic analysis of the 16S rDNA gene sequence. The strain was incubated at 38 degrees C for 18 h to examine the possible diversion of glucose or glycerol fermentation by fumarate. The products of glucose and glycerol fermentation with fumarate were quite different from those of normal fermentation, which ultimately produces lactate, in that mainly succinate is produced. Metabolic pathway stoichiometry was used to analyze the oxidation of glycerol to succinate by Enterococcus faecalis RKY1. The stoichiometric relationship between glycerol and fumarate was used as a guideline to accumulate succinate more efficiently.

DNA, Ribosomal↗
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↗
PubMed1998

Fumarate permeation in normal and acidotic rat kidney mitochondria: fumarate/malate and fumarate/aspartate translocators.

In order to gain some insight into the fate of fumarate synthesised in the cytosol in the purine nucleotide cycle and in amino acid catabolism, the capability of both rat kidney mitochondria and acidotic rat kidney mitochondria to take up either externally synthesised, via adenylsuccinate lyase, or added fumarate in exchange with intramitochondrial malate or aspartate was tested by means of both spectrophotometric and isotopic techniques. The appearance of either malate or aspartate caused by the presence of fumarate was revealed outside normal and acidotic mitochondria by using specific substrate detecting systems. Consistently, externally added fumarate was found to cause efflux of either [14C]-malate or [14C]-aspartate from loaded mitochondria. The occurrence in rat kidney mitochondria of two separate translocators, i.e., fumarate/malate and fumarate/aspartate carriers, is shown in the light of saturation kinetics and the different inhibitor sensitivity. The fumarate/aspartate antiporters found in normal and acidotic mitochondria appear to differ from each other.

Acidosis↗
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↗
PubMed1994

Fumarate-enriched blood cardioplegia results in complete functional recovery of immature myocardium.

Amino acid enrichment of cardioplegic solutions has been shown to improve both the metabolic and functional recovery of ischemic myocardium. However, because of the marked systemic vasodilatation involved, use of amino acid enrichment is limited to the periods of induction and reperfusion. Fumarate is a Krebs' cycle intermediate whose conversion to succinate is responsible for the generation of adenosone triphosphate and the oxidation of the reduced form of nicotinamide-adenine nucleotide which is the pathway by which aspartate exerts its effect. Fumarate may also function as a free-radical scavenger and is involved in calcium transport. To determine if fumarate-enriched blood cardioplegia would improve the functional recovery of the neonatal heart, 14 neonatal piglet hearts were isolated and placed on a blood-perfused working heart circuit. After the baseline functional and metabolic assessment was done, cold ischemic arrest was initiated with either standard blood cardioplegic solution (group I; N = 7) or fumarate-enriched (13 mmol/L) blood cardioplegic solution (group II; N = 7). Cardioplegic solution was given at a pressure of 40 mm Hg every 20 minutes for 2 hours, and topical hypothermia was used. Sixty minutes after warm whole blood reperfusion, the functional recovery at left atrial pressures of 3, 6, 9, and 12 mm Hg was 70%, 66%, 66%, and 65%, respectively, in group I, versus 102%, 106%, 105%, and 109%, respectively, in group II (p < 0.05). The tissue creatinine phosphate levels after reperfusion were significantly higher in group II hearts (15.0 +/- 1.2 mumol/g dry heart tissue) than in group I hearts (9.2 +/- 1.9 mumol/g dry heart tissue), although the adenosine triphosphate levels were not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)

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↗
PubMed1985

Intramitochondrial localization of fumarate reductase, NADPH----NAD transhydrogenase, 'malic' enzyme and fumarase in adult Hymenolepis diminuta.

The intramitochondrial localization of the fumarate reductase, NADPH----NAD transhydrogenase, 'malic' enzyme and fumarase was determined in adult Hymenolepis diminuta. The distribution of marker enzymes for the inner membrane, matrix, intermembrane space and outer membrane of H. diminuta mitochondria simulated that of the corresponding ascarid and mammalian organelles. The electron transport-coupled fumarate reductase and the NADPH----NAD transhydrogenase were components of the inner membrane whereas the 'malic' enzyme and fumarase were in the matrix soluble compartment. Assessments of NADH utilization, malate-dependent NADP reduction and NADPH----NAD transhydrogenation by presumedly intact and disrupted mitochondria supported the localization data. The findings presented indicate that in H. diminuta mitochondria (a) NADPH and fumarate are accumulated within the matrix compartment; (b) transhydrogenation between NADPH and NAD is an event associated with the matrix side of the inner membrane; and (c) electron transport-dependent NADH oxidation and fumarate reduction occur at sites on the matrix side of the inner membrane.

Animals↗