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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↗

PubMed1979

Anaerobic growth of Escherichia coli K12 with fumarate as terminal electron acceptor. Genetic studies with menaquinone and fluoroacetate-resistant mutants.

Fifteen independent menaquinone biosynthesis mutants (men) of Escherichia coli K12, selected for their inability to use fumarate as terminal electron acceptor, were investigated. Two nutritionally distinct groups were detected. The major group (13 mutants) responded to 1,4-dihydroxy-2-naphthoate (DHN), 2-succinylbenzoate (SB) and its dilactone, whereas the minor group (2 mutants) only responded to DHN. DHN was at least five times more effective than SB but it inhibited growth at concentrations greater than 10 microM. For anaerobic growth on glucose minimal medium the auxotrophs responded to much lower concentrations of DHN and SB and these intermediates could be replaced by uracil. Anaerobic growth tests showed that glycerol, formate and H2 are good substrates for E. coli when fumarate is the ultimate electron acceptor but growth with lactate or with fumarate alone is poor. All 15 men mutations were located between glpT and purF at approximately 49 min in the E. coli linkage map. Cotransduction frequencies with relevant markers were: nalA (21%), glpT (35%) and purF (15%). The presence of at least three genetically distinct classes (menC and menD, SB-requirers; menB, DHN-requirers) was indicated using abortive transduction as a complementation test and three-factor genetic analysis. The relative orientation nalA...menC-(D,B)...purF was indicated. Fluoroacetate-resistant mutants were isolated and four different classes were identified: ack, lacking acetate kinase; pta, lacking phosphotransacetylase; facA, lacking both of these activities; and facB, which retained both of these enzyme activities. Some of the pta mutants and all of the facA mutants failed to grow on media containing fumarate as terminal electron acceptor or anaerobically on glucose minimal medium. All four types had genetic lesions clustered between the men and purF sites. Average cotransduction frequencies with relevant markers were: nalA (4%), men (27 to 35%) and purF (71 to 80%).

Anaerobiosis↗

PubMed1989

Influence of increased aspartate availability on lysine formation by a recombinant strain of Corynebacterium glutamicum and utilization of fumarate.

Aspartate availability was increased in Corynebacterium glutamicum strains to assess its influence on lysine production. Upon addition of fumarate to a strain with a feedback-resistant aspartate kinase, the lysine yield increased from 20 to 30 mM. This increase was accompanied by the excretion of malate and succinate. In this strain, fumaric acid was converted to aspartate by fumarate hydratase, malate dehydrogenase, and aspartate amino transferase activity. To achieve the direct conversion of fumarate to aspartate, shuttle vectors containing the aspA+ (aspartase) gene of Escherichia coli were constructed. These constructions were introduced into C. glutamicum, which was originally devoid of the enzyme aspartase. This resulted in an aspartase activity of 0.3 U/mg (70% of the aspartase activity in E. coli) with plasmid pZ1-9 and an activity of up to 1.05 U/mg with plasmid pCE1 delta. In aspA+-expressing strains, lysine excretion was further increased by 20%. Additionally, in strains harboring pCE1 delta, up to 27 mM aspartate was excreted. This indicates that undetermined limitations in the sequence of reactions from aspartate to lysine exist in C. glutamicum.

Aspartate Ammonia-Lyase↗

PubMed1975

Anaerobic energy-yielding reaction associated with transhydrogenation from glycerol 3-phosphate to fumarate by an Escherichia coli system.

A particulate subcellular fraction from Escherichia coli K-12 induced in anaerobic sn-glycerol 3-phosphate (G3P) dehydrogenase and fumarate reductase can catalyze under anaerobic conditions the transfer of hydrogens from G3P to fumarate, with attendant generation of high-energy phosphate. The phsophorylation process is more sensitive than the transhydrogenation process to inhibition by the detergent Triton X-100. The same is true with respect to sensitivity to sodium azide, carbonyl cyanide m-chlorophenylhydrazone and N,N'-dicyclohexylcarbodiimide. Such a preparation derived from cells with beta-galactoside permease can accumulate thiomethyl beta-D-galactoside anaerobically, and the accumulation can be stimulated twofold by adding G3P and fumarate. Mutants lacking the membrane-associated Mg2+-dependent adenosine triphosphatase cannot grow anaerobically on glycerol with fumarate as the hydrogen acceptor, although they can grow aerobically on glycerol alone.

Adenosine Triphosphatases↗

PubMed1979

Purification and characterization of membrane-bound fumarate reductase from anaerobically grown Escherichia coli.

Fumarate reductase has been purified 100-fold to 95% homogeneity from the cytoplasmic membrane of Escherichia coli, grown anaerobically on a defined medium containing glycerol plus fumarate. Optimal solubilization of total membrane protein and fumarate reductase activity occurred with nonionic detergents having a hydrophobic-lipophilic balance (HLB) number near 13 and we routinely solubilized the enzyme with Triton X-100 (HLB number = 13.5). Membrane enzyme extracts were fractionated by hydrophobic-exchange chromatography on phenyl Sepharose CL-4B to yield purified enzyme. The enzyme whether membrane bound, in Triton extracts, or purified, had an apparent Km near 0.42 mM. Two peptides with molecular weights of 70 000 and 24 000, predent in 1:1 molar ratios, were identified by sodium dodecyl sulfate polyacrylamide slab-gel electrophoresis to coincide with enzyme activity. A minimal native molecular weight of 100 000 was calculated for fumarate reductase by Stephacryl S-200 gel filtration in the presence of sodium cholate. This would indicate that the enzyme is a dimer. The purified enzyme has low, but measurable, succinate dehydrogenase activity.

Anaerobiosis↗

PubMed1990

[Fumaric acid therapy in psoriasis; a double-blind, placebo-controlled study].

Thirty-nine patients with psoriasis (12 females, 27 males) entered a randomised, double-blind, placebo-controlled study on the efficacy of fumaric acid therapy in an outpatient setting. During 16 weeks the patients were treated with tablets containing a combination of dimethylfumarate and different salts of monoethylfumarate, with octylhydrogen fumarate or with placebo tablets. All patients were treated with identical indifferent topical therapy and followed an elimination diet (avoidance of spices, wine and nuts). Thirty-four patients completed the study. Five patients dropped out because of side effects or aggravation of the skin lesions. The patients treated with the combination of monoethyl- and dimethylfumarate showed a significantly better therapeutic response compared with those who were treated with placebo or octylhydrogen fumarate. Side effects of the fumarate containing tablets were flushing, diarrhoea, a reversible elevation of transaminases, lymphocytopenia and eosinophilia. One patient developed a disturbance of the kidney function which normalised after discontinuation of the therapy.

Adult↗

PubMed1985

A sodium-stimulated membrane-bound fumarate reductase system in Bacteroides amylophilus.

Membrane vesicles derived from whole cells of the strictly anaerobic rumen bacterium Bacteroides amylophilus exhibited fumarate reductase activity with NADH, FADH2, FMNH2, or reduced viologens as electron donors. The fumarate reductase system is most likely localized on the cytoplasmic side of the plasma membrane. Cytochromes and menaquinone were not detectable. The NADH-dependent activity was inactivated by oxygen, an endogenous protease, and by irradiation at 254 nm. The electron transport inhibitor HpHOQnO and Zn2+ were identified as strong inhibitors of the fumarate reductase reaction. Two types of functional SH-groups might be operative in this system as probed by ClHgSO3H. The oxidation of NADH by fumarate was stimulated by low concentrations of Na+. Concentrations of Na+ in the range of 4 to 30 mM had a pronounced influence on growth rate and cell yield of B. amylophilus. In the presence of 1 mM NaCl growth was observed only after a lag-period of 15 h.

Bacteroides↗

PubMed1989

Interactions of oxaloacetate with Escherichia coli fumarate reductase.

Fumarate reductase of Escherichia coli is converted to a deactivated state when tightly bound by oxaloacetate (OAA). Incubation of the inhibited enzyme with anions or reduction of the enzyme by substrate restores both the activity of the enzyme and its sensitivity to thiol reagents. In these respects the enzyme behaves like cardiac succinate dehydrogenase. Close to an order of magnitude difference was found to exist between the affinities of OAA for the oxidized (KD approximately 0.12 microM) and reduced (KD approximately 0.9 microM) forms of fumarate reductase. Redox titrations of deactivated fumarate reductase preparations have confirmed that reductive activation, as in cardiac succinate dehydrogenase (B. A. C. Ackrell, E. B. Kearney, and D. Edmondson (1975) J. Biol. Chem. 250, 7114-7119), is the result of reduction of the covalently bound FAD moiety and not the non-heme iron clusters of the enzyme. However, the processes differed for the two enzymes; activation of fumarate reductase involved 2e- and 1H+, consistent with reduction of the flavin to the anionic hydroquinone form, whereas the process requires 2e- and 2H+ in cardiac succinate dehydrogenase. The reason for the difference is not known. The redox potential of the FAD/FADH2 couple in FRD (Em approximately -55 mV) was also slightly more positive than that in cardiac succinate dehydrogenase (-90 mV).

Escherichia coli↗

PubMed1985

In vivo detection of a three iron cluster in fumarate reductase from Escherichia coli.

Escherichia coli with plasmid amplified expression of fumarate reductase was grown anaerobically on a medium containing fumarate and glycerol and investigated by electron paramagnetic resonance spectroscopy. Anaerobically harvested cells exhibit an EPR signal characteristic of a reduced [2Fe-2S] cluster. Anaerobic addition of fumarate results in diminution of the reduced [2Fe-2S] signal and the appearance of the EPR signal associated with the oxidized 3Fe cluster. The results provide the first evidence for a trinuclear iron-sulfur cluster that exists in vivo, and suggest that the 3Fe cluster in purified fumarate reductase samples is not an artifact of the isolation procedure. The significance of this observation is discussed in relation to the physiological relevance of trinuclear iron-sulfur clusters.

Circular Dichroism↗

PubMed1986

Isolation of fumarate reductase from Desulfovibrio multispirans, a sulfate reducing bacterium.

Fumarate reductase was isolated and purified 100-fold to homogeneity from Desulfovibrio multispirans, a new species of sulfate-reducing bacteria. The enzyme contained 1 mol of non-covalently bound FAD and four subunits with Mr 45,000, 32,000, 30,000 and 27,000. EPR spectroscopy showed the existence of two iron-sulfur clusters. The absorption spectrum showed a broad region of high absorbance from 450 nm to 300 nm with a protein peak at 278 nm. The ratio of A278:A400 was 2.60. The specific activity was 110 mumoles H2/mg of protein. The Km for fumarate was 2.5 mM. The activation energy was 8.7 kcal/mol. Electron transport from H2 to fumarate in intact cells was inhibited by 2-heptyl-4-hydroxy-quinoline-N-oxide, a quinone inhibitor, indicating the participation of quinone (probably menaquinone) in fumarate reduction.

Desulfovibrio↗

PubMed1986

Fumarate reductase and other mitochondrial activities in Trypanosoma cruzi.

Subcellular fractions obtained from Trypanosoma cruzi epimastigotes broken by freezing and thawing were assayed for fumarate reductase activity with reduced methyl viologen as electron donor and fumarate as electron acceptor under anaerobic conditions. Two distinct activities were detected: one in the mitochondrial membranes, 115 mU(mg protein)-1, accounting for 96% of the total and the other in the cytosol, 3 mU(mg protein)-1, accounting for 3% of the total. The activity of membrane-bound fumarate reductase correlated statistically with either the activity or the amount of mitochondrial markers such as succinate and NADH dehydrogenases, cytochromes b + c558, cytochrome a611 and 5,7-diene sterols in the obtained subcellular fractions (580 X g, 12 000 X g, and 105 000 X g sediments and supernatant). Mitochondrial fumarate reductase was inhibited by succinate, malonate, cyanide, and 2-thenoyltrifluoroacetone (TTFA); whereas the soluble enzyme was inhibited by succinate and not by TTFA. The 12 000 X g sediment (mitochondrial membranes) showed after dithionite addition, absorption maxima at 611, 560 and 530 nm accounting for the presence of cytochrome b560, c558 and a611. A CO-binding cytochrome o was also detected. A scheme of the T. cruzi mitochondrial respiratory chain is presented.

Animals↗

PubMed1987

The narL gene product activates the nitrate reductase operon and represses the fumarate reductase and trimethylamine N-oxide reductase operons in Escherichia coli.

Escherichia coli, which can utilize O2, nitrate, fumarate, or trimethylamine N-oxide (Me3NO) as terminal electron acceptor, preferentially utilizes the one with the highest redox potential. Thus O2 prevents induction of nitrate, fumarate, and Me3NO reductases, and nitrate curtails the induction of fumarate and Me3NO reductases. Under anaerobic conditions the narL gene product, in the presence of nitrate, is known to activate transcription of the narC operon, which encodes nitrate reductase. This study shows that the same product plays a role in the repression by nitrate of the operons (frd and tor) that encode fumarate and Me3NO reductases. In contrast, the anaerobic repression of ethanol dehydrogenase by nitrate does not require the narL product. Expression of narL does not require the fnr gene product, a pleiotropic activator that is required for full expression of narC, frd, and tor.

Bacterial Proteins↗

PubMed1987

Nucleotide sequence and comparative analysis of the frd operon encoding the fumarate reductase of Proteus vulgaris. Extensive sequence divergence of the membrane anchors and absence of an frd-linked ampC cephalosporinase gene.

The fumarate reductase of Escherichia coli is a bioenergetically important membrane-bound flavoenzyme consisting of four subunits. A and B comprise a membrane-extrinsic catalytic domain whereas C and D are hydrophobic polypeptides which link the catalytic centres to the electron-transport chain. The nucleotide sequence of the frd operon encoding the fumarate reductase of the distantly related bacterium, Proteus vulgaris has been determined and used to predict the primary structures of the respective subunits. Extensive amino acid sequence identity (greater than 80%) was found between the fumarate reductase A and B subunits of P. vulgaris and E. coli. In contrast, the primary structures of the P. vulgaris and E. coli C and D proteins are much less closely related (about 60% homology) although the overall hydrophobicity of their three membrane-spanning segments has been conserved. In most enteric bacteria, the frd operon is followed by genes, ampR and/or ampC, required for the genetic regulation and biosynthesis of a cephalosporinase. The corresponding region of the P. vulgaris genome is occupied by an operon (orf A'BCD) containing at least four genes which are clearly unrelated to the ampC system. Intriguingly the primary structures of the OrfA and OrfD proteins suggest that, like fumarate reductase, they may be components of a membrane-bound enzyme complex involved in energy metabolism.

Amino Acid Sequence↗

PubMed1987

Cloning and expression of the genes of two fumarate reductase subunits from Wolinella succinogenes.

The fumarate reductase complex of the anaerobic bacterium Wolinella succinogenes catalyzes the electron transfer from menaquinol to fumarate. Two structural genes coding for subunits of the enzyme have been cloned in Escherichia coli. The genes were isolated from a lambda EMBL3 phage gene bank by immunological screening and subcloned in an expression vector. The genes frdA and frdB, which encode the FAD protein (Frd A, Mr 79,000) and the iron-sulfur protein (Frd B, Mr 31,000) of the fumarate reductase complex, were cloned together with a W. succinogenes promoter. The gene order was promoter-frdA-frdB. The FAD protein and the iron-sulfur protein were expressed in the correct molar mass in E. coli from the clones. The identity of the frdA gene and the suggested polarity were confirmed by comparing the amino-terminal sequence of the Frd A protein with that predicted from the 5'-terminal nucleotide sequence of frdA. The frdA and frdB genes are present only once in the genome. A region downstream of frdB, possibly a gene encoding cytochrome b of the fumarate reductase complex, hybridizes with a second site in the genome.

Amino Acid Sequence↗

PubMed1989

Purification and characterization of an anabolic fumarate reductase from Methanobacterium thermoautotrophicum.

An oxygen-sensitive fumarate reductase has been purified from the cytosol fraction of the cells of the archaebacterium Methanobacterium thermoautotrophicum. A major portion of the purification was performed inside an anaerobic chamber, employing reducing agents to maintain low redox potentials. The apparent molecular weight of the native enzyme is 78,000. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated a minimal subunit molecular weight of about 20,000. Iodoacetamide (1 mM) and copper chloride (5 mM) caused significant loss in the enzyme activity. The optimum temperature for the enzymatic activity was 75 degrees C. The pH optimum was found to be 7.0. The fumarate reductase had an apparent Km of 0.20 mM for fumarate. Purified enzyme was colorless; spectroscopic studies indicated the absence of flavins as a cofactor. The spectral data, however, suggested the presence of an unknown cofactor tightly bound to the enzyme. Fumarate reductase is involved in the anabolic rather than the catabolic metabolism of M. thermoautotrophicum.

Anaerobiosis↗

PubMed1977

Double-blind, controlled study of clemastine fumarate, chlorpheniramine and placebo in the symptomatic treatment of seasonal allergic rhinitis in desensitized and nondesensitized patients.

In double-blind trials clemastine fumarate 2.68 mg. chlorpheniramine 4 mg and placebo were randomly assigned to two groups of patients with seasonal allergic rhinitis. Thirty-nine desensitized patients were given one of the three test drugs in a parallel design; 67 nondesensitized patients each received two of the three drugs in a crossover design. Assessment of drug activity in each study was by whole body plethysmography and intranasal color photography as well as by subjective methods. Objective measurements showed clemastine fumarate was significantly superior to placebo and often better than chlorpheniramine in decreasing true nasal resistance and relieving nasal congestion. High placebo responses characterized the subjective evaluations, although the active drugs were clearly better. Responses varied somewhat between desensitized and nondesensitized patients. The number of reports of sedative effect, high in all groups, seemed to be more closely related to these antihistamine conditioned patients than to activity of the drugs themselves, based on previous reports of low sedation with clemastine fumarate. The techniques described proved very useful in distinguishing relative activity of antihistamines. Clemastine fumarate, the new antihistamine studied, appears to offer certain advantages over the older drug, chlorpheniramine.

Airway Resistance↗

PubMed1987

Malic enzyme, malate dehydrogenase, fumarate reductase and succinate dehydrogenase in the larvae of Taenia crassiceps (Zeder, 1800).

Malate dehydrogenase, malic enzyme, succinate dehydrogenase, and fumarate reductase activities have been studied in the cytoplasm and mitochondria of Taenia crassiceps larvae. The results show that these larvae contain enzymes for anaerobic acquisition of energy with terminal fumarate reductase, but some facts, as the high ratio of succinate dehydrogenase activity to fumarate reductase activity and the low proportion of fumarate reductase in the whole NADH oxidase activity in mitochondria, suggest that aerobic processes are also involved in the energy acquisition in this parasite.

Aerobiosis↗

PubMed1990

Signal transduction in Halobacterium depends on fumarate.

The isolation of a straight-swimming mutant of Halobacterium halobium is reported which has a defect in switching the rotational sense of its flagellar motor. Cells of this mutant strain could be complemented with an extract from wild-type cells by mild sonication and resealing of the cells in fresh medium. The switch factor responsible for restoration of wild-type behaviour was isolated from membrane vesicle preparations. Its chemical nature is proposed to be that of fumarate on the basis of chemical, chromatographic and mass spectrometric analysis. Since the switch factor (fumarate) was released from a membrane-bound state by heat and was accumulated into mutant cells that lack this compound, it is proposed that a membrane-bound protein exists which specifically binds the switch factor. Both the switch factor and fumarate cause stimulus-induced responses in cells at the level of one or few molecules.

Cell Movement↗