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PubMed1990

Mitochondrial hydrogen peroxide formation and the fumarate reductase of Hymenolepis diminuta.

The catalysis of hydrogen peroxide accumulation by the mitochondrial, membrane-associated NADH oxidase and less active succinoxidase of adult Hymenolepis diminuta was confirmed. NADH-dependent peroxide formation by isolated mitochondrial membranes occurred at about half the coincident rates of NADH and oxygen utilization, whereas succinate-dependent peroxide formation accounted for approximately 40% of the oxygen consumed. These findings, coupled with evaluations of the oxidases, indicated that both systems use in common 2 mechanisms for oxygen reduction, 1 of which is peroxide-forming. Neither system was sensitive to cyanide, azide, or antimycin A. Rotenone inhibition of NADH oxidation resulted in equivalent decreases in oxygen consumption by the peroxide-forming and nonperoxide-forming mechanisms. In contrast, malonate inhibition occurred via disruption of the peroxide-forming mechanism. Fumarate stimulated membrane-catalyzed NADH oxidation, despite aerobic conditions, and this fumarate reductase was rotenone-sensitive. NADH- or succinate-dependent peroxide formation virtually was abolished and oxygen consumption was minimal in the presence of fumarate. Malonate also inhibited fumarate-dependent NADH oxidation and succinate-dependent peroxide formation/oxygen consumption. Collectively, these findings clearly indicate that NADH- or succinate-dependent hydrogen peroxide accumulation involves the malonate-sensitive fumarate reductase, in the absence of fumarate. A model of the H. diminuta electron transport system is presented.

Animals↗
PubMed1977

Double-blind, controlled study of clemastine fumarate, chlorpheniramine and placebo in patients with seasonal allergic rhinitis.

A whole body plethysmograph (body box) equipped with a flow meter (see Figure 1) was used for objective quantification of the effects of single doses of clemastine fumarate 2.68 mg, chlorpheniramine 4 mg and placebo in a double-blind study of 48 patients with seasonal allergic rhinitis. This technique offers an objective means of assessing drug effects on nasal congestion and obstruction. Before the development of whole body plethysmography, only subjective assessments of antihistamines' effects on nasal blockage or congestion were available. These subjective reports usually noted that nasal blockage or congestion was refractory to antihistamines or minimally relieved by them. However, in this study, nasal and oral airway resistances, each measured by whole body plethysmography, were lowered by clemastine fumarate and chlorpheniramine. These results were corroborated by the patients' and physician's assessments of changes in symptom severity and the physician's evaluation of intranasal photographs taken for each patient. Oral airway resistance of patients treated with clemastine fumarate was improved to a significantly greater extent than in patients receiving placebo. At two hours post-drug, patients receiving clemastine fumarate usually showed a greater response in most assessments than those receiving chlorpheniramine, and the trend of most comparisons was clearly in favor of clemastine fumarate. Patients in all three treatment groups experienced drowsiness but both incidence and severity were lower with clemastine fumarate.

Airway Resistance↗
PubMed1992

Fumaric acid production from hydrolysates of starch-based substrates.

Fumaric acid production by Rhizopus arrhizus from commercial hydrolysates of corn starch (i.e. glucose molasses) was studied at different initial concentrations of glucose (S) and C:N ratios (R) by performing a 3(2) factorial experiment. By using the response surface methodology and statistical analysis, fumaric acid (YF) and mycelial biomass (YX) yields, as referred to the initial concentration of glucose and fumaric acid productivity (PF), were fitted to the only significant first-order effects of S and R with mean percentage errors ranging from 11 to 15%. The resulting empiric models were used to determine the optimal values of S (100-130 g dm-3) and R (150-210 g-atom C per g-atom N) associated with YF and PF varying in the ranges 40-49% and 7-8.5 g dm-3 day-1, respectively. After establishing the validity of these data at the 95% confidence level, an optimal operating condition (S = 120 g dm-3 and R = 150) was further tested using other substrates (i.e. glucose and acid or enzymatic hydrolysates of cassava, corn and potato flours). Statistically significant improvements in the fumaric acid yield and productivity were determined with respect to the predicted values. Since the highest values of YF and PF were obtained from the acid hydrolysates of the starch-based materials and such values were also found to be insensitive to the substrate used (at a probability level of 0.05), the above operating condition might be further employed to minimise fumaric acid production costs as a function of the feedstock used.

Culture Media↗
PubMed1977

ATP formation associated with fumarate and nitrate reduction in growing cultures of Veillonella alcalescens.

Molar growth yields, fermentation balances and enzyme activities were measured in Veillonella alcalescens grown anaerobically with different substrates in the absence or presence of fumarate or nitrate. The molar growth yields on malate (14.3 g dry wt bacteria/mole substrate) and citrate (19.3) were higher than that on lactate (8.6). The molar growth yield on lactate was increased to 15.5 or 19.8 by the addition of fumarate or nitrate, respectively, to the growth medium, and the molar growth yield on citrate was increased to 25.3 by addition of nitrate. Active growth on pyruvate was only observed in the presence of nitrate, and the molar growth yield was 25.5. From fermentation balances and fermentation systems similar YATP values (g dry wt bacteria/mole ATP) were calculated for all substrates or mixtures of substrates assuming that one mole of ATP is generated at the electron transport from pyruvate, NADH and NADPH to nitrate or fumarate whereas ATP is not produced in the electron transport from lactate to fumarate or nitrate, and, therefore, this assumption was considered to reflect the actual situation. The mean YATP value at a doubling time of 1 h was 16.5 g dry wt bacteria/mole ATP for growth without an added hydrogen acceptor, 14.4 for growth with fumarate, and 14.2 for growth with nitrate.

Adenosine Triphosphate↗
PubMed1976

Fumarate reduction in Proteus mirabilis.

1. Proteus mirabilis formed fumarate reductase under anaerobic growth conditions. The formation of this reductase was repressed under conditions of growth during which electron transport to oxygen or to nitrate is possible. In two of three tested chlorate-resistant mutant strains of the wild type, fumarate reductase appeared to be affected. 2. Cytoplasmic membrane suspensions isolated from anaerobically grown P. mirabilis oxidized formate and NADH with oxygen and with fumarate, too. 3. Spectral investigation of the cytoplasmic membrane preparation revealed the presence of (probably at least two types of) cytochrome b, cytochrome a1 and cytochrome d. Cytochrome b was reduced by NADH as well as by formate to approximately 80%. 4. 2-n-Heptyl-4-hydroxyquinilone-N-oxide and antimycin A inhibited oxidation of both formate and NADH by oxygen and fumarate. Both inhibitors increased the level of the formate/oxygen steady state and the formate/fumarate steady state. 5. The site of inhibition of the respiratory activity by both HQNO and antimycin A was located at the oxidation side of cytochrome b. 6. The effect of ultraviolet-irradiation of cytoplasmic membrane suspensions on oxidation/reduction phenomena suggested that the role of menaquinone is more exclusive in the formate/fumarate pathway than in the electron transport route to oxygen. 7. Finally, the conclusion has been drawn that the preferential route for electron transport from formate and from NADH to fumarate (and to oxygen) includes cytochrome b as a directly involved carrier. A hypothetical scheme for the electron transport in anaerobically grown P. mirabilis is presented.

Anaerobiosis↗
PubMed1975

Reduced nicotinamide adenine dinucleotide dependent reduction of fumarate coupled to membrane energization in a cytochrome deficient mutant of Escherichia coli K12.

Escherichia coli SASX76 does not form cytochromes unless supplemented with 5-aminolevulinic acid. It can grow anaerobically on glycerol and DL-glycerol 3-phosphate in the absence of 5-aminolevulinic acid with fumarate but not with nitrate as the terminal electron acceptor. Cytochrome-independent NADH oxidase, glycerol 3-phosphate- and NADH-fumarate oxidoreductase activities are induced by anaerobic growth on a glycerol-fumarate medium. The pathway of electrons from substrate to fumarate involves menaquinone. The NADH-fumarate oxidoreductase and cytochrome-independent NADH oxidase systems are inhibited by piericidin A, 2-heptyl-4-hydroxyquinoline N-oxide, and iron chelating agents. Both systems can energize the membrane particles as indicated by quenching of atebrin fluorescence.

Aminolevulinic Acid↗
PubMed1985

Fumarate permeation in rat liver mitochondria: fumarate/malate and fumarate/phosphate translocators.

Fumarate permeation in isolated rat liver mitochondria was demonstrated by measuring malate and phosphate efflux caused by fumarate added externally to the mitochondrial suspension. The existence of two specific fumarate translocators, fumarate/malate and fumarate/phosphate, is shown here. These carriers are distinguished in the light of different kinetic parameters (Km values are 50 microM and 150 microM, and Vmax values are 17 and 40 nmoles/min X mg mitochondrial protein, respectively) and of differing sensitivity to non-penetrant compounds. Fumarate was found to cause oxaloacetate efflux from mitochondria by means of an indirect process which involves the cooperation of both fumarate/malate and malate/oxaloacetate translocators. Results are discussed in the light of the physiological role played by fumarate translocation in both ureogenesis and aminoacid metabolism.

Animals↗
PubMed1995

Transhydrogenase activities and malate dismutation linked to fumarate reductase system in the filarial parasite Setaria digitata.

Setaria digitata, a cattle filarial parasite, similar to human filarial parasites, possesses significant activities of the 4 transhydrogenases namely NADH-NAD+, NADPH-NAD+, NADH-NADP+, and NADPH-NADP+ in the sonicated mitochondria like particles. The transhydrogenases appear to regulate the metabolic pathways of the parasite in response to the presence of adenyl nucleotides and are non-energy linked. Observations on the transhydrogenase and fumarate reductase activities show the existence of a protein bound NAD in the MLP and a linkage between the fumarate reductase system and malic enzyme through transhydrogenases. The malate dismutation reaction is the result of malic and fumarase enzyme activities. Fumarase and fumarate reductase activities result in succinate formation under anaerobic conditions showing major energy production at the fumarate reductase site. The existence of acetate kinase, phosphotransacetylase, pyruvate carboxylase, propionyl CoA carboxylase and CoA transferase enzymes in the mitochondrial system shows the presence of other energy producing sites in the parasite. The transhydrogenase system, NAD+/NADP+ malic enzyme, fumarase and fumarate reductase are the key enzymes of, production of reducing power for synthetic reactions and regulation of oxidative and reductive stages of the mitochondrial system. Hence, specific drugs targeted against this interconnected complex enzyme system, will be very effective in the control of filarial parasites.

Adenosine Triphosphate↗
PubMed1983

Mechanism of modulation of dopamine beta-monooxygenase by pH and fumarate as deduced from initial rate and primary deuterium isotope effect studies.

Dopamine beta-monooxygenase catalyzes a reaction in which 2 mol of protons are consumed for each turnover of substrate. Studies of the pH dependence of initial rate parameters (Vmax and Vmax/Km) and their primary hydrogen isotope effects show that at least two ionizable residues are involved in catalysis. One residue (B1, pK = 5.6-5.8) must be protonated prior to the carbon-hydrogen bond cleavage step, implying a role for general-acid catalysis in substrate activation. A second protonated residue (B2, pK = 5.2-5.4) facilitates, but is not required for, product release. Recent measurement of the intrinsic isotope effect for dopamine beta-monoxygenase [Miller, S. M., & Klinman, J. P. (1983) Biochemistry (preceding paper in this issue)] allows an analysis of the pH dependence of rate constant ratios and in selected instances individual rate constants. We demonstrate large changes in the rate-determining step as well as an unprecedented inversion in the kinetic order of substrate release from ternary complex over an interval of 2 pH units. Previously, fumarate has been used in dopamine beta-monooxygenase assays because of its property of enzyme activation. Studies of the pH behavior in the presence of saturating concentrations of fumarate have shown two causes of the activation: (i) fumarate perturbs the pK of B1 to pK = 6.6-6.8 such that the residue remains protonated and the enzyme optimally active over a wider pH range; (ii) fumarate decreases the rate of dopamine release from the ternary enzyme-substrate complex, increasing the equilibrium association constant for dopamine binding. Both effects are consistent with a simple electrostatic stabilization of bound cationic charges by the dianionic form of fumarate.

Animals↗
PubMed1979

Production of a soluble form of fumarate reductase by multiple gene duplication in Escherichia coli K12.

1. Ampicillin-hyperresistant mutants of Escherichia coli K12 bearing multiple gene duplications in the ampC (beta-lactamase) gene region of the chromosome overproduced at least six proteins with molecular weights 97,000, 80,000, 72,000, 49,000, 33,000 and 26,500 during anaerobic growth. All but two of the proteins (80,000-Mr and 49,000-Mr) were also overproduced during aerobic growth. The distribution of the proteins in soluble and particulate cell fractions was investigated. 2. The 33,000-Mr and 72,000-Mr components were identified as beta-lactamase and the amp-linked frdA gene product, fumarate reductase, respectively. Co-sedimentation of the 26,500-Mr component with the fumarate reductase suggested that the smaller protein could be functionally related to the reductase. The lack of correspondence between the amplified proteins and the products of other amp-linked genes, aspA and mop(groE), indicated that these genes are not included in the repetitive sequence. 3. Fumarate reductase activities were amplified up to 32-fold by the multiple gene duplications. Two forms of fumarate reductase were produced: particulate (membrane-bound) and soluble (cytoplasmic). Production of the soluble form occurred when the binding capacity of the membrane was saturated. Both forms of fumarate reductase were enzymically active but the soluble form was readily inactivated under assay conditions.

Centrifugation, Density Gradient↗
PubMed1966

Fumarate reductase in the control of heme biosynthesis.

A drug-induced stimulation of heme biosynthesis in mouse liver was accompanied by altered fumarate metabolism. In liver homogenate, fumarate 1,4-C(14) was incorporated, via succinate and succinyl coenzyme A, into heme at an accelerated rate. This pathway of fumarate utilization was inhibited by acetoacetate but not by beta-hydroxybutyrate. Fumarate reduction to succinate required reduced nicotinamide adenine dinucleotide. The enzyme fumarate reductase is suggested as a link between terminal oxidation and cellular control of the heme biosynthetic pathway.

Acetoacetates↗
PubMed1987

Inhibition of Clostridium botulinum 62A by fumarates and maleates and relationship of activity to some physicochemical constants.

A series of n-monoalkyl maleates and n-mono-, di-, and methyl n-alkyl fumarates were prepared, 18 esters of each, with R = CH3 to C18H37. Their activity against Clostridium botulinum was determined in culture medium. The n-monoalkyl maleates and fumarates possessed significant activity, particularly those esterified with higher C13 to C18 alcohols. Somewhat lower activity was exhibited by methyl n-alkyl fumarates, while symmetrical esters, di-n-alkyl fumarates, were almost inactive. An attempt was made to correlate the activity of n-monoalkyl maleates and fumarates with chain length, solubility in water, apparent dissociation constant (pKa'), and infrared and UV absorption frequencies. The active esters may have potential as preservatives in foods.

Chromatography, High Pressure Liquid↗
PubMed1975

Evidence for cytochrome involvement in fumarate reduction and adenosine 5'-triphosphate synthesis by Bacteroides fragilis grown in the presence of hemin.

Growth of Bacteroides fragilis subsp. fragilis on glucose was very much stimulated by the addition of hemin (2 mg/liter) to the medium. The generation time decreased from 8 to 2 h, and the molar growth yield increased from YM = 17.9 to YM = 47 g (dry weight) of cells per mol of glucose. In the absence of hemin, glucose was fermented to fumarate, lactate, and acetate. The cells did not contain detectable amounts of cytochromes or fumarate reductase. In the presence of hemin, the major products of fermentation were succinate, propionate, and acetate. A b-type cytochrome, possibly a c-type cytochrome, and a very active fumarate reductase were present in the cells. It is concluded from these results that hemin is required by B. fragilis to synthesize a functional fumarate reductase and that the hemin-dependent, enormous increase of the growth yield may be due to adenosine 5'-triphosphate production during reduction of fumarate to succinate.

Acetates↗
PubMed1978

Fermentation of fumarate and L-malate by Clostridium formicoaceticum.

The fermentation of fumarate and L-malate by Clostridium formicoaceticum was investigated. Growing and nongrowing cells degraded fumarate by dismutation to succinate, acetate, and CO2; on the other hand, only small amounts of succinate were detected when the organism was grown on L-malate. This dicarboxylic acid was mainly converted to acetate and CO2. The fermentation balances were modified if bicarbonate or formate were present in the medium. When C. formicoaceticum was grown in the presence of both dicarboxylic acids, fumarate was consumed before L-malate. The latter was mainly converted to acetate, whereas fumarate was fermented to acetate and succinate. Molar growth yields were determined to be 6 g of dry weight per mol of fumarate and 8 g of dry weight per mol of L-malate fermented.

Acetates↗
PubMed1992

Anaerobic fumarate transport in Escherichia coli by an fnr-dependent dicarboxylate uptake system which is different from the aerobic dicarboxylate uptake system.

Escherichia coli grown anaerobically with fumarate as electron acceptor is able to take up C4-dicarboxylates by a specific transport system. The system differs in all tested parameters from the known aerobic C4-dicarboxylate transporter. The anaerobic transport system shows higher transport rates (95 mumol/g [dry weight] per min versus 30 mumol/g/min) and higher Kms (400 versus 30 microM) for fumarate than for the aerobic system. Mutants lacking the aerobic dicarboxylate uptake system are able to grow anaerobically at the expense of fumarate respiration and transport dicarboxylates with wild-type rates after anaerobic but not after aerobic growth. Transport by the anaerobic system is stimulated by preloading the bacteria with dicarboxylates. The anaerobic transport system catalyzes homologous and heterologous antiport of dicarboxylates, whereas the aerobic system operates only in the unidirectional mode. The anaerobic antiport is measurable only in anaerobically grown bacteria with fnr+ backgrounds. Additionally, the system is inhibited by incubation of resting bacteria with physiological electron acceptors such as O2, nitrate, dimethyl sulfoxide, and fumarate. The inhibition is reversed by the presence of reducing agents. It is suggested that the physiological role of the system is a fumarate/succinate antiport under conditions of fumarate respiration.

Aerobiosis↗
PubMed1967

Fumarate reductase activity of Streptococcus faecalis.

Some characteristics of a fumarate reductase from Streptococcus faecalis are described. The enzyme had a pH optimum of 7.4; optimal activity was observed when the ionic strength of the phosphate buffer was adjusted to 0.088. The K(m) value of the enzyme for reduced flavin mononucleotide was 2 x 10(-4)m as determined with a 26-fold preparation. In addition to fumarate, the enzyme reduced maleate and mesaconate. No succinate dehydrogenase activity was detected, but succinate did act as an inhibitor of the fumarate reductase activity. Other inhibitors were malonate, citraconate, and trans-, trans-muconate. Metal-chelating agents did not inhibit the enzyme. A limited inhibition by sulfhydryl-binding agents was observed, and the preparations were sensitive to air oxidation and storage. Glycine, alanine, histidine, and possibly lysine stimulated fumarate reductase activity in the cell-free extracts. However, growth in media supplemented with glycine did not enhance fumarate reductase activity. The enzymatic activity appears to be constitutive.

Amino Acids↗
PubMed1992

[Osteomalacia as an apparently rare side effect of oral fumaric acid therapy. Secondary DeToni-Debré Fanconi syndrome in the adult].

A case of fully reversible tubular toxicity with consecutive metabolic osteopathy following systemic fumaric acid therapy is reported. This secondary effect of oral fumaric acid therapy obviously occurs very rarely, never having been described before. A 46-year-old female patient with a long history of recurrent palmoplantar psoriasis underwent oral treatment with fumaric acid and its esters in accordance with the Schäfer method, preceding attempts at curative treatment with conventional antipsoriatic agents having proved unsatisfactory. Two months later, the patient started to experience arthralgia, back pain in the early hours of the morning and myalgia with increasing frequency, progressing to disablement in moving and walking and, finally, to total immobility. Not until 9 months later was the reason for these severe disabilities found: they stemmed from hypophosphataemic osteomalacia as a result of a complex disturbance of the renal tubular system. The clinical symptoms and the results of laboratory chemistry tests returned to normal as soon as fumaric acid medication was discontinued. Two attempts at reexposure confirmed the causal relationship. Oral fumaric acid medication should never be administered without clinical and chemical controls.

Administration, Oral↗
PubMed1989

Fumarate reductase mutants of Escherichia coli that lack covalently bound flavin.

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 catalytic domain of fumarate reductase consists of the FrdA subunit, which contains the active site, and a FAD prosthetic group covalently attached to His44, plus the FrdB subunit which contains at least two of the three nonidentical iron-sulfur clusters of the enzyme. To examine the role of covalently bound FAD in enzyme activity and electron transfer during anaerobic cell growth, site-directed mutagenesis was used to alter His44 of the FrdA subunit to a Ser, Cys, or Tyr residue. The resulting mutant enzyme complexes that were synthesized associated normally with the cytoplasmic membrane, but had decreased ability (greater than 70%) to reduce fumarate with reduced benzyl viologen, an artificial electron donor of low redox potential (Em = -359 mV; Clark, W. M. (1972) Oxidation-Reduction Potentials of Organic Systems, Robert E. Kreiger Publishing Co., Melbourne, FL). Even lower activities were measured when the higher potential, natural electron donor menaquinol was used, which, however, correlated with the slower growth rates of the different mutant complexes. In contrast to the normal enzyme, the mutant enzyme complexes were unable to oxidize succinate. Substitution of Arg for His44 produced a totally inactive enzyme complex that permitted no cell growth on nonfermentable substrates with fumarate as electron acceptor. All four mutant complexes contained noncovalently bound FAD in stoichiometric amounts. These data indicate a unique role of the 8 alpha-[N(3)-histidyl] FAD linkage in enzyme activity, by raising the redox potential of free FAD to permit reduction by both menaquinol and succinate.

Amino Acid Sequence↗