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PubMed1999

Crystallization and preliminary X-ray crystallographic analysis of a periplasmic tetrahaem flavocytochrome c3 from Shewanella frigidimarina NCIMB400 which has fumarate reductase activity.

The fumarate reductase of Escherichia coli and other bacteria is a membrane-bound enzyme consisting of four subunits. A soluble periplasmic 64 kDa tetrahaem flavocytochrome c3 from Shewanella frigidimarina NCIMB400 which possesses a catalytic fumarate reductase activity has been crystallized. The crystals belong to space group P212121 with unit-cell parameters a = 72.4, b = 110.1, c = 230.2 A. Assuming a molecular dimer in the asymmetric unit, the crystals contain 65% solvent and, when cryocooled to 100 K, the crystals diffract to at least 3.0 A resolution. The crystals, however, display an inherent lack of isomorphism and the plausibility of a MAD phasing experiment has therefore been investigated by measuring the iron K absorption edge from a single crystal.

Crystallization↗
PubMed1990

Wolinella succinogenes fumarate reductase contains a dihaem cytochrome b.

The fumarate reductase operon of Wolinella succinogenes is made up of three structural genes (frd-CAB). The frdC gene was located next to the promoter region and identified as the cytochrome b structural gene encoding 256 amino acid residues. The N-terminal amino acid sequences of seven fragments derived from the cytochrome b moiety of the enzyme all mapped within the frdC gene. This suggested that the enzyme contained only one species of cytochrome b. Re-evaluation of earlier measurements of subunit composition, haem B content and molecular weight led to the conclusion that the enzyme contained one molecule of cytochrome b with two haem B groups. The hydropathy plot of the amino acid sequence predicted five membrane-spanning hydrophobic segments, the first four of which contained a single histidine residue each. These residues could form the axial ligands to the two haem B groups. FrdC was found to be homologous with the cytochrome b (SdhC) of the Bacillus subtilis succinate dehydrogenase, but not with the hydrophobic subunits of the fumarate reductase or succinate dehydrogenase of Escherichia coli.

Amino Acid Sequence↗
PubMed1981

The electrochemical proton gradient generated by the fumarate-reductase system in Escherichia coli and its bioenergetic implications.

Proton translocation, coupled to electron transfer in the fumarate reductase system, generates and electrochemical potential gradient for protons (delta approximately mu H+). The magnitude of this free energy gradient has been determined in the Escherichia coli strains ML 208-225 and AN 283. The measurements were performed in (inverted) membrane particles, right-side out membrane vesicles and EDTA-treated intact cells in external media of various ionic compositions and pH. The maximal values of delta approximately mu H+ in these three systems were +103, -101 and -105 mV, respectively. This implicates that in E. coli, upon transition from oxygen to fumarate as electron acceptor, the magnitude of the delta approximately mu H+ decreases considerably. This change of delta approximately mu H+ has substantial consequences for the cellular metabolism.

Cell Membrane↗
PubMed1982

Nucleotide sequence coding for the flavoprotein subunit of the fumarate reductase of Escherichia coli.

The nucleotide sequence of the frdA gene, which encodes the flavoprotein subunit of the fumarate reductase, of Escherichia coli, has been determined. A polypeptide of Mr = 66,052, containing 602 amino acid residues, is predicted. In composition the FrdA protein strongly resembles the flavoprotein subunits of two succinate dehydrogenases. Moreover, a sequence of nine consecutive residues is common to the flavoprotein subunits from fumarate reductase and the beef heart succinate dehydrogenase. This sequence contains a histidyl residue which probably services as the site for attachment of the FAD cofactor to the reductase.

Amino Acid Sequence↗
PubMed1998

Soluble fumarate reductase isoenzymes from Saccharomyces cerevisiae are required for anaerobic growth.

In Saccharomyces cerevisiae, the cytosolic and promitochondrial isoenzymes of fumarate reductase are encoded by the FRDS and OSM1 genes, respectively. The product of the OSM1 gene is reported to be required for growth in hypertonic medium. Simultaneous disruption of the FRDS and OSM1 genes resulted in the inability of the yeasts to grow anaerobically on glucose as a carbon source, and disruption of the OSM1 gene caused poor growth under anaerobic conditions. However, the disruption of both the FRDS and/or OSM1 genes had no effect on aerobic growth or growth under hypertonic conditions. These results suggest that the fumarate reductase isoenzymes in Saccharomyces cerevisiae are essential for anaerobic growth but not for growth under hypertonic conditions.

Anaerobiosis↗
PubMed2002

Physiological role of soluble fumarate reductase in redox balancing during anaerobiosis in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, there are two isoenzymes of fumarate reductase (FRDS1 and FRDS2), encoded by the FRDS and OSM1 genes, respectively. Simultaneous disruption of these two genes results in a growth defect of the yeast under anaerobic conditions, while disruption of the OSM1 gene causes slow growth. However, the metabolic role of these isoenzymes has been unclear until now. In the present study, we found that the anaerobic growth of the strain disrupted for both the FRDS and OSM1 genes was fully restored by adding the oxidized form of methylene blue or phenazine methosulfate, which non-enzymatically oxidize cellular NADH to NAD(+). When methylene blue was added at growth-limiting concentrations, growth was completely arrested after exhaustion of oxidized methylene blue. In the double-disrupted strain, the accumulation of succinate in the supernatant was markedly decreased during anaerobic growth in the presence of methylene blue. These results suggest that fumarate reductase isoenzymes are required for the reoxidation of intracellular NADH under anaerobic conditions, but not aerobic conditions.

Anaerobiosis↗
PubMed2006

Multi-micronutrient Sprinkles including a low dose of iron provided as microencapsulated ferrous fumarate improves haematologic indices in anaemic children: a randomized clinical trial.

Home-fortification of complementary foods with micronutrients (including iron) as Sprinkles is a new strategy to control iron deficiency and anaemia in developing countries. However, the most effective dose and form of iron is not known. The purpose of this study was to compare the efficacy of various doses (12.5, 20 or 30 mg) and treatment methods (multi-micronutrient Sprinkles vs. ferrous sulphate drops) on haemoglobin (Hb) concentration after 8 weeks of treatment in anaemic children. In total, 133 anaemic Ghanaian children (Hb 70-99 g L(-1)) aged 6-18 months were randomly assigned to one of five daily interventions for 8 weeks. Out of the five interventions, four used Sprinkles, and one used iron drops. Of the four Sprinkles groups, three included 12.5, 20 or 30 mg of iron as ferrous fumarate, and one included 20 mg of iron as ferric pyrophosphate. The iron drops group included 12.5 mg of iron as liquid ferrous sulphate. Hb concentrations were measured at baseline, week 3 and week 8. The primary outcome measure was Hb concentration at 8 weeks after treatment. We compared differences in Hb and ferritin concentrations and prevalence of iron deficiency anaemia (Hb < 100 g L(-1) and soluble transferrin receptor concentrations >8.5 mg L(-1)) from baseline to 8 weeks within and between groups. Adherence and reporting of side effects (staining of the teeth, ease of use, diarrhoea and darkening of stools) were compared between groups. Mean change in Hb was 1.4 g L(-1) (SD = 1.8) (P = 0.0001). Change in Hb concentrations from baseline to 8 weeks was significant in all groups (P = 0.0001-0.0007), with no differences across groups. Geometric means of serum ferritin varied from 18.6 to 44.0 microg L(-1) at baseline. At week 8, these means were in the interval of 48.0-78.3 microg L(-1), with no group differences. Prevalence of iron deficiency anaemia decreased significantly from baseline to 8 weeks in all groups with the exception of the iron drops group, with no group differences. Adherence was lower in the drops group (64%) as compared with Sprinkles groups (84%). Greater staining of the teeth and less ease of use were reported in the drops group as compared with Sprinkles groups. A dose as low as 12.5 mg of iron as ferrous fumarate when provided as Sprinkles may be effective in anaemic children.

Administration, Oral↗
PubMed2005

Defining the Q-site of Escherichia coli fumarate reductase by site-directed mutagenesis, fluorescence quench titrations and EPR spectroscopy.

We have used fluorescence quench titrations, EPR spectroscopy and steady-state kinetics to study the effects of site-directed mutants of FrdB, FrdC and FrdD on the proximal menaquinol (MQH(2)) binding site (Q(P)) of Escherichia coli fumarate reductase (FrdABCD) in cytoplasmic membrane preparations. Fluorescence quench (FQ) titrations with the fluorophore and MQH(2) analog 2-n-heptyl-4-hydroxyquinoline-N-oxide (HOQNO) indicate that the Q(P) site is defined by residues from FrdB, FrdC and FrdD. In FQ titrations, wild-type FrdABCD binds HOQNO with an apparent K(d) of 2.5 nM, and the following mutations significantly increase this value: FrdB-T205H (K(d) = 39 nM); FrdB-V207C (K(d) = 20 nM); FrdC-E29L (K(d) = 25 nM); FrdC-W86R (no detectable binding); and FrdD-H80K (K(d) = 20 nM). In all titrations performed, data were fitted to a monophasic binding equation, indicating that no additional high-affinity HOQNO binding sites exist in FrdABCD. In all cases where HOQNO binding is detectable by FQ titration, it can also be observed by EPR spectroscopy. Steady-state kinetic studies of fumarate-dependent quinol oxidation indicate that there is a correlation between effects on HOQNO binding and effects on the observed K(m) and k(cat) values, except in the FrdC-E29L mutant, in which HOQNO binding is observed, but no enzyme turnover is detected. In this case, EPR studies indicate that the lack of activity arises because the enzyme can only remove one electron from reduced MQH(2), resulting in it being trapped in a form with a bound menasemiquinone radical anion. Overall, the data support a model for FrdABCD in which there is a single redox-active and dissociable Q-site.

Binding Sites↗
PubMed1987

Molybdenum effector of fumarate reductase repression and nitrate reductase induction in Escherichia coli.

In Escherichia coli the presence of nitrate prevents the utilization of fumarate as an anaerobic electron acceptor. The induction of the narC operon encoding the nitrate reductase is coupled to the repression of the frd operon encoding the fumarate reductase. This coupling is mediated by nitrate as an effector and the narL product as the regulatory protein (S. Iuchi and E. C. C. Lin, Proc. Natl. Acad. Sci. USA 84:3901-3905, 1987). The protein-ligand complex appears to control narC positively but frd negatively. In the present study we found that a molybdenum coeffector acted synergistically with nitrate in the regulation of frd and narC. In chlD mutants believed to be impaired in molybdate transport (or processing), full repression of phi(frd-lac) and full induction of phi(narC-lac) by nitrate did not occur unless the growth medium was directly supplemented with molybdate (1 microM). This requirement was not clearly manifested in wild-type cells, apparently because it was met by the trace quantities of molybdate present as a contaminant in the mineral medium. In chlB mutants, which are known to accumulate the Mo cofactor because of its failure to be inserted as a prosthetic group into proteins such as nitrate reductase, nitrate repression of frd and induction of narC were also intensified by molybdate supplementation. In this case a deficiency of the molybdenum coeffector might have resulted from enhanced feedback inhibition of molybdate transport (or processing) by the elevated level of the unutilized Mo cofactor. In addition, mutations in chlE, which are known to block the synthesis of the organic moiety of the Mo cofactor, lowered the threshold concentration of nitrate (< 1 micromole) necessary for frd repression and narC induction. These changes could be explained simply by the higher intracellular nitrate attainable in cells lacking the ability to destroy the effector.

Chlorates↗
PubMed1988

Structural and functional changes in lung tissue of mice fed with beta-aminopropionitrile fumarate, L-3-cis-hydroxyproline, and L-4-cis-hydroxyproline.

Structural and functional changes in lung tissue of mice fed with beta-aminopropionitrile fumarate, L-3-cis-hydroxyproline, and L-4-cis-hydroxyproline. We fed 0.1% solutions of 3-cis-hydroxyproline (3cisHP), 4-cis-hydroxyproline (4cisHP) or beta-aminopropionitrile fumarate (beta APN) to 5-week-old mice for 1 month and studied the effect of each of these substances on the lung function and structure. Compared to control animals the compliance of the respiratory system in the mean was increased by 3-15% in the mice fed beta APN or 3cisHP, and decreased by 2-8% in the mice fed 4cisHP. On electron microscopial examination no overt morphological changes were detectable although as proven by biochemical analysis 3cisHP and 4cisHP were incorporated into the collagen of the mice who received these substances. We conclude that the effect of substances interfering with the normal production of collagen molecules depends on the kind of collagen affected and on the rate of collagen turnover.

Aminopropionitrile↗
PubMed1999

Efficacy and safety of ibutilide fumarate for the conversion of atrial arrhythmias after cardiac surgery.

BACKGROUND: Atrial arrhythmias occur commonly after cardiac surgery and are a cause of significant morbidity and increased hospital costs, yet there is no well-studied treatment strategy to deal with them expeditiously. The purpose of this study was to determine the efficacy and safety of ibutilide fumarate, an approved drug for the rapid conversion of atrial fibrillation and flutter, in patients after cardiac surgery. METHODS AND RESULTS: Patients with atrial fibrillation or flutter occurring 1 to 7 days after surgery and lasting 1 hour to 3 days were randomized to receive two 10-minute blinded infusions of placebo or 0.25, 0.5, or 1.0 mg of ibutilide fumarate. Treatment was considered successful if sinus rhythm was restored for any period of time by hour 1.5. A total of 302 patients were randomized, 201 with fibrillation and 101 with flutter. Treatment with ibutilide resulted in significantly higher conversion rates than placebo, and efficacy was dose related (placebo 15%; ibutilide 0.25 mg 40%, 0.5 mg 47%, and 1.0 mg 57%). Conversion rates at all doses were higher for atrial flutter than for atrial fibrillation. Mean time to conversion decreased as the dose was increased. Polymorphic ventricular tachycardia was the most serious adverse effect and occurred in 1.8% of the ibutilide-treated patients compared with 1.2% of patients who received placebo. CONCLUSIONS: Ibutilide is a useful and safe treatment alternative for the atrial arrhythmias that occur after cardiac surgery.

Adult↗
PubMed2000

Developing porosity of poly(propylene glycol-co-fumaric acid) bone graft substitutes and the effect on osteointegration: a preliminary histology study in rats.

Bioresorbable bone graft substitutes could eliminate disadvantages associated with the use of autografts, allografts and other synthetic materials. We investigated a bioresorbable bone graft substitute made from the unsaturated polyester poly(propylene fumarate) which is crosslinked in the presence of soluble and insoluble calcium filler salts. This compact bone graft substitute material develops porosity in vivo by leaching of the soluble filler salts. In attempt to develop materials whose in vivo porosity can be designed such that implant degradation would occur at a rate that remains supportive of the overall structural integrity of the repairing defect site, we studied the early tissue response upon implantation in a bony defect. Three grout formulations of varying solubilities using slightly soluble hydroxyapatite (HA) and soluble calcium acetate (CA) were evaluated in 3 mm holes made in the anteromedial tibial metaphysis of 200 g Sprague Dawley rats (n = 16 per formulation for a total of 48 animals). Grout formulations cured in situ. Animals from each formulation were sacrificed in groups of 8 at 4 days and 3 weeks postoperatively. Histologic analysis of the healing process revealed improved in vivo osteointegration of bone graft substitutes when a higher loading of calcium acetate was employed. All formulations maintained implant integrity and did not provoke sustained inflammatory responses. This study suggested that the presence of a soluble salt permits in vivo development of porosity of a poly(propylene fumarate) based bone graft substitute material.

Acetates↗
PubMed1998

Preparation and characterization of poly(propylene fumarate-co-ethylene glycol) hydrogels.

We describe the preparation and bulk characterization of a cross-linked poly(propylene fumarate-co-ethylene glycol), p(PF-co-EG), hydrogel. Eight block copolymer formulations were made varying four different design parameters including: poly(ethylene glycol) (PEG) molecular weight, poly(propylene fumarate) (PPF) molecular weight, copolymer molecular weight, and ratio of PEG to PPF. Two different cross-linking formulations were also tested, one with a cross-linking monomer and one without. The extent of the cross-linking reaction and the degree of swelling in aqueous solution were determined on copolymer formulations made without a cross-linking monomer. The values of molecular weight between cross-links, Mc ranged from 300 +/- 120 to 1190 +/- 320 as determined from swelling data (n = 3). The equilibrium volume swelling ratios, Q, varied from 1.5 +/- 0.1 to 3.0 +/- 0.1. This ratio was found to increase with increasing PEG content in the copolymer and decrease with increasing PPF molecular weight. The values for complex dynamic elastic moduli magnitudes of E*, ranged from 0.9 +/- 0.2 to 13.1 +/- 1.1 MPa for the formulations with the cross-linking monomer, N-vinyl pyrrolidinone (VP) (n = 3). The ultimate tensile stresses on the formulations made with VP ranged from 0.15 +/- 0.03 to 1.44 +/- 1.06 MPa, and tensile moduli ranged from 1.11 +/- 0.20 to 20.66 +/- 2.42 MPa (n = 5). All of the mechanical properties increased with increasing PPF molecular weight and decreased with increasing PEG content in the copolymer. These data show that the physical properties of p(PF-co-EG) hydrogels can be tailored for specific applications by altering the material composition.

Biocompatible Materials↗
PubMed1993

[Inhibitory effect of bithionol on NADH-fumarate reductase in ascarides].

To elucidate the mechanism of anthelmintic action of bithionol, the inhibitory effect of the drug on NADH-fumarate reductase (NADH-FR) of Ascaris lumbricoides suum was examined. NADH-FR, an enzyme of anaerobic carbohydrate metabolic pathway was solubilized from the mitochondria of the worm's muscle with deoxycholate, and then partially purified with the monoethanolamine-Sepharose 4B column chromatography. Rhodoquinone (RQ), which is required for the electron transfer from NADH to fumarate, was separated from the enzyme protein and phospholipids. Although the enzyme protein fraction eluted from the above column did not show NADH-FR activity, this enzyme was reactivated by the addition of purified RQ and phosphatidylcholine. The IC50 value of bithionol for reconstituted NADH-FR was 18 +/- 2 microM. The inhibition type was competitive to RQ. Bithionol inhibited at most 30% NADH-ferricyanide reductase, which did not require RQ, even at high concentration of 150 microM. These results suggest that the pharmacological action of bithionol, a phenolic anthelmintic, depends on the inhibition of the electron transport system by the competition with RQ.

Animals↗
PubMed2006

Use of tenofovir disoproxil fumarate and emtricitabine combination in HIV-infected patients.

With the continuing spread of HIV infection, particularly in developing countries, cost-effective treatment for its management is a high priority. Truvada (Gilead Sciences) is a single combination pill of the nucleotide reverse transcriptase inhibitors tenofovir disoproxil fumarate and emtricitabine, which is used once daily. It is anticipated to be a clinically potent combination that is free of short-term irritating toxicity. The drug has recently been licensed but there are currently little clinical efficacy data regarding its use. The limited published data have indicated that emtricitabine and lamivudine have equivalent potency, and randomised controlled trials have produced evidence of the efficacy of lamivudine combined with tenofovir disoproxil fumarate in a regimen containing either the non-nucleoside reverse transcriptase inhibitor efavirenz or a protease inhibitor lopinavir/ritonavir. In these trials, long-term durability data are available for < or = 96 weeks.

Adenine↗
PubMed2006

Tenofovir disoproxil fumarate for the treatment of HIV infection.

Tenofovir disoproxil fumarate is a nucleotide analogue reverse transcriptase inhibitor approved by the FDA for the treatment of HIV infection. It is a potent agent with a long intracellular half-life that allows for once-daily dosing. It has been well tolerated in clinical trials, without evidence of the mitochondrial toxicity that has been associated with long-term treatment of some of the nucleoside analogue reverse transcriptase inhibitors. Because of its demonstrated efficacy and favourable safety profile, tenofovir disoproxil fumarate has quickly become a favoured nucleoside component of antiretroviral regimens for both treatment-naive and -experienced patients.

Adenine↗
PubMed2004

Calculated coupling of transmembrane electron and proton transfer in dihemic quinol:fumarate reductase.

The quinol:fumarate reductase of Wolinella succinogenes binds a low- and a high-potential heme b group in its transmembrane subunit C. Both hemes are part of the electron transport chain between the two catalytic sites of this redox enzyme. The oxidation-reduction midpoint potentials of the hemes are well established but their assignment in the structure has not yet been determined. By simulating redox titrations, using continuum electrostatics calculations, it was possible to achieve an unequivocal assignment of the low- and high-potential hemes to the distal and proximal positions in the structure, respectively. Prominent features governing the differences in midpoint potential between the two hemes are the higher loss of reaction field energy for the proximal heme and the stronger destabilization of the oxidized form of the proximal heme due to several buried Arg and Lys residues. According to the so-called "E-pathway hypothesis", quinol:fumarate reductase has previously been postulated to exhibit a novel coupling of transmembrane electron and proton transfer. Simulation of heme b reduction indicates that the protonation state of the conserved residue Glu C180, predicted to play a key role in this process, indeed depends on the redox state of the hemes. This result clearly supports the E-pathway hypothesis.

Cell Membrane↗
PubMed2004

Comparison of a combination ferrous fumarate product and a polysaccharide iron complex as oral treatments of iron deficiency anemia: a Taiwanese study.

Despite efforts to improve iron supplements for iron deficiency anemia, there is no consensus on products that balance efficacy, safety and tolerability, and cost. Ferrous products are effective, but they are associated with more gastrointestinal side effects than ferric products. Ferric products tend to have lower absorption. We present results from a 12-week study that randomized 72 people with uncomplicated iron deficiency anemia to receive a ferrous iron supplement (Ferall, a combination of ferrous fumarate with ascorbic acid, folic acid, and cyanocobalamin) or a ferric iron polysaccharide complex (Niferex, ferro-glycine sulfate) plus ascorbic acid. The ferrous product was significantly more effective, the primary and secondary endpoints including changes in levels of hemoglobin and serum ferritin. There was a slightly higher frequency of gastrointestinal side effects in patients taking the ferrous product, but both supplements were well tolerated. No participant withdrew from the study because of side effects. We concluded that the ferrous product is safe and effective for use in uncomplicated iron deficiency anemia. The lack of direct comparison between single-agent ferrous fumarate and the combination ferrous product limited interpretation of results in terms of possible effects due to other components, such as ascorbic acid.

Administration, Oral↗