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PubMed1994

Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients.

BACKGROUND: Psoriasis vulgaris may benefit from treatment with fumaric acid and/or its derivatives; however, because different preparations have been used, results have been contradictory and difficult to interpret. OBJECTIVE: The purpose of this clinical trial was to evaluate the therapeutic value of fumaric acid derivatives. METHODS: A randomized double-blind study was carried out in patients with psoriasis, comparing a well-characterized formulation of fumaric acid derivatives with placebo. RESULTS: The results indicated statistically significant superiority of the fumaric acid derivatives over placebo. Adverse events (flush, gastrointestinal disturbances) were initially relatively frequent, but decreased thereafter. CONCLUSION: Fumaric acid derivatives were found to be effective and safe in the treatment of psoriasis.

Abdominal Pain↗
PubMed2003

Validation of a RP-HPLC method for the assay of formoterol and its related substances in formoterol fumarate dihydrate drug substance.

A stability-indicating reversed-phase high performance liquid chromatographic (HPLC) method has been developed and validated for the assay of formoterol fumarate and the related substances, namely, formoterol fumarate desformyl and formoterol fumarate acetamide analogs, in the active pharmaceutical ingredient. The separation was achieved by isocratic elution using an Alltech Alltima C18 (150 x 4.6 mm) column, a mobile phase consisting of ammonium acetate (50 mM; pH 5.0)-ethanol (65:35, v/v), a flow rate of 1.0 ml/min and UV detection at 242 nm. The detection and quantitation limits were 0.03 and 08 microg/ml, respectively, while the linear range of detection was between 0.03 and 255 microg/ml. Comparative determinations of formoterol fumarate in three lots of bulk drugs using the proposed HPLC method and the standard potentiometric titration method of pharmacopoeia show that both methods are equivalent for pure drug substance assay. However, the HPLC method allowed the separation and quantitation of the impurities not achievable with the official methods in the bulk drugs. This study shows that the proposed method is accurate, linear, and sensitive as stability indicating assay method for formoterol fumarate in the bulk drug.

Chromatography, High Pressure Liquid↗
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↗
PubMed1998

Bioconversion of fumaric acid to succinic acid by recombinant E. coli.

Succinic acid was produced efficiently from fumaric acid by a recombinant E. coli strain DH5 alpha/pGC1002 containing multicopy fumarate reductase genes. The effects of initial fumaric acid and glucose concentration on the production of succinic acid were investigated. Succinic acid reached 41 to over 60 g/L in 48.5 h starting with 50 to 64 g/L fumaric acid. Significant substrate inhibition was observed at initial fumaric acid concentration of 90 g/L. L-Malic acid became the major fermentation product under these conditions. Provision of glucose (5-30 g/L) to the fermentation medium stimulated the initial succinic acid production rate over two folds.

Acetic Acid↗
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↗
PubMed1993

Classification of fumarate reductases and succinate dehydrogenases based upon their contrasting behaviour in the reduced benzylviologen/fumarate assay.

Reduction of fumarate by soluble beef heart succinate dehydrogenase has been shown previously by voltammetry to become increasingly retarded as the potential is lowered below a threshold potential of -80 mV at pH 7.5. The behaviour resembles that of a tunnel diode, an electronic device exhibiting the property of negative resistance. The enzyme thus acts to oppose fumarate reduction under conditions of high thermodynamic driving force. We now provide independent evidence for this phenomenon from spectrophotometric kinetic assays. With reduced benzylviologen as electron donor, we have studied the reduction of fumarate catalysed by various enzymes classified either as succinate dehydrogenases or fumarate reductases. For succinate dehydrogenases, the rate increases as the concentration of reduced dye (driving force) decreases during the reaction. In contrast, authentic fumarate reductases of anaerobic cells (and 'succinate dehydrogenase' from Bacillus subtilis) neither exhibit the electrochemical effect nor deviate from simple kinetic behaviour in the cuvette assay. The 'tunnel-diode' effect may thus represent an evolutionary adaptation to aerobic 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↗
PubMed2002

Molecular mechanism for the regulation of human mitochondrial NAD(P)+-dependent malic enzyme by ATP and fumarate.

The regulation of human mitochondrial NAD(P)+-dependent malic enzyme (m-NAD-ME) by ATP and fumarate may be crucial for the metabolism of glutamine for energy production in rapidly proliferating tissues and tumors. Here we report the crystal structure at 2.2 A resolution of m-NAD-ME in complex with ATP, Mn2+, tartronate, and fumarate. Our structural, kinetic, and mutagenesis studies reveal unexpectedly that ATP is an active-site inhibitor of the enzyme, despite the presence of an exo binding site. The structure also reveals the allosteric binding site for fumarate in the dimer interface. Mutations in this binding site abolished the activating effects of fumarate. Comparison to the structure in the absence of fumarate indicates a possible molecular mechanism for the allosteric function of this compound.

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↗
PubMed2002

Absorption of calcium fumarate salts is equivalent to other calcium salts when measured in the rat model.

Calcium absorption from fumarate salts (calcium fumarate and calcium malate fumarate), which have recently been considered for use as sources for food and beverage enrichment, was compared to that from calcium citrate malate, calcium citrate, and calcium carbonate. Salts were instrinsically labeled with 45Ca and orally administered to Sprague-Dawley rats. Fractional absorption of calcium from each salt was determined using the femur uptake model. Fractional absorption from the five salts (0.30-0.27) was not significantly different (p > 0.05). Thus, when measured in the rat model, calcium from calcium fumarate and calcium malate fumarate is absorbed equally well as compared to other salts, which are common calcium sources in many foods, beverages, and supplements.

Absorption↗
PubMed2003

Beneficial effects of fumarate therapy in psoriasis vulgaris patients coincide with downregulation of type 1 cytokines.

BACKGROUND: Fumarates have been shown to be effective in psoriasis vulgaris. OBJECTIVES: To find out whether successful therapy is associated with modulation of cytokines. METHODS: We determined interferon (IFN)-gamma, interleukin (IL)-4 and IL-10 secretion capacities of peripheral blood mononuclear cells (PBMC) after phytohaemagglutinin stimulation, and IL-12p70 and IL-10 secretion capacities of PBMC after endotoxin stimulation in psoriasis vulgaris patients during treatment with fumarates. In a cohort study, 12 patients (five men, median age 50 years; seven women, median age 46 years) with psoriasis vulgaris were followed during 24 months of fumarate treatment. In addition, we followed 14 healthy controls (six men, median age 31 years; eight women, median age 29 years) without skin diseases during 12 months to investigate possible changes in the cytokine secretion capacity of PBMC as a result of seasonal changes. Disease activity in patients was determined by Psoriasis Area and Severity Index (PASI) score. Blood was collected for measurement by enzyme-linked immunosorbent assay of cytokine levels after stimulation of PBMC. RESULTS: Within 6 months of fumarate treatment, the mean +/- SD PASI score had decreased to 22 +/- 9% of its initial value. These beneficial effects coincided with lymphocytopenia and a significant (P < 0.05) downregulation of IFN-gamma expression by circulating blood cells, followed by a significant downregulation of IL-4 expression. Notably, production of the cytokine synthesis inhibitor IL-10 by PBMC was unchanged. CONCLUSIONS: The beneficial effects of fumarates may be attributed to their downregulatory action on type 1 cytokines.

Cohort Studies↗
PubMed1997

Isolation and characterization of a transposon mutant of Shewanella putrefaciens MR-1 deficient in fumarate reductase.

A transposon mutant, designated CMTn-3, of Shewanella putrefaciens MR-1 that was deficient in fumarate reduction was isolated and characterized. In contrast to the wild-type, CMTn-3 could not grow anaerobically with fumarate as the electron acceptor, and it lacked benzyl viologen-linked fumarate reductase activity. Consistent with this, CMTn-3 lacked a 65 kDa c-type cytochrome, which is the same size as the fumarate reductase enzyme. CMTn-3 retained the wild-type ability to use nitrate, iron(III), manganese(IV) and trimethylamine N-oxide (TMAO) as terminal electron acceptors. The results indicate that the loss of the fumarate reductase enzyme does not affect other anaerobic electron transport systems in this bacterium.

Base Sequence↗
PubMed2001

Inhibition of dendritic cell differentiation by fumaric acid esters.

Fumaric acid esters have proved to be effective for the systemic treatment of severe psoriasis vulgaris. These compounds have been shown to induce a Th2-like cytokine secretion pattern in T cells and to reduce keratinocyte proliferation in vitro. Dendritic cells seem to be of major importance as regulatory cells driving the psoriatic tissue reaction. Monocytes or CD34-positive myeloid progenitor cells are precursors of dendritic cells that can be generated in vitro by culture with granulocyte-macrophage colony-stimulating factor and interleukin-4. Using this model the effect of fumaric acid esters on granulocyte-macrophage colony-stimulating factor/interleukin-4-induced differentiation of monocyte-derived dendritic cells was investigated. The results of this study show that dimethylfumarate as well as methylhydrogenfumarate-calcium-salt (0.01-100 microg per ml) concentration-dependently inhibit monocyte-derived dendritic cell differentiation. This was reflected by an inhibition of CD1a, CD40, CD80, CD86, and HLA-DR expression as well as by a reduced capacity of dimethylfumarate-treated monocyte-derived dendritic cells to stimulate lymphocytes in the allogeneic mixed lymphocyte reaction. Other fumaric acid esters showed no effect on monocyte-derived dendritic cell-differentiation. At higher concentrations (30-100 microg per ml) dimethylfumarate, but not methylhydrogenfumarate calcium-salt induced apoptosis in monocyte-derived dendritic cells as measured by expression of Apo 2.7 and DNA fragmentation (TUNEL assay). These data point to a high susceptibility of the monocyte/dendritic cell system to dimethylfumarate and its main metabolite methylhydrogenfumarate. Other fumaric acid esters investigated were without effect. As the effects of fumarates on monocyte-derived dendritic cells observed occur at concentrations 20-fold lower compared with lymphocytes, our data seem to be of relevance in explaining the possible mode of action of these compounds in psoriasis.

Adjuvants, Immunologic↗
PubMed2006

Succinate dehydrogenase functioning by a reverse redox loop mechanism and fumarate reductase in sulphate-reducing bacteria.

Sulphate- or sulphur-reducing bacteria with known or draft genome sequences (Desulfovibrio vulgaris, Desulfovibrio desulfuricans G20, Desulfobacterium autotrophicum [draft], Desulfotalea psychrophila and Geobacter sulfurreducens) all contain sdhCAB or frdCAB gene clusters encoding succinate : quinone oxidoreductases. frdD or sdhD genes are missing. The presence and function of succinate dehydrogenase versus fumarate reductase was studied. Desulfovibrio desulfuricans (strain Essex 6) grew by fumarate respiration or by fumarate disproportionation, and contained fumarate reductase activity. Desulfovibrio vulgaris lacked fumarate respiration and contained succinate dehydrogenase activity. Succinate oxidation by the menaquinone analogue 2,3-dimethyl-1,4-naphthoquinone depended on a proton potential, and the activity was lost after degradation of the proton potential. The membrane anchor SdhC contains four conserved His residues which are known as the ligands for two haem B residues. The properties are very similar to succinate dehydrogenase of the Gram-positive (menaquinone-containing) Bacillus subtilis, which uses a reverse redox loop mechanism in succinate : menaquinone reduction. It is concluded that succinate dehydrogenases from menaquinone-containing bacteria generally require a proton potential to drive the endergonic succinate oxidation. Sequence comparison shows that the SdhC subunit of this type lacks a Glu residue in transmembrane helix IV, which is part of the uncoupling E-pathway in most non-electrogenic FrdABC enzymes.

Amino Acid Sequence↗
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↗