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PubMed1997

Identification of the yeast ACR1 gene product as a succinate-fumarate transporter essential for growth on ethanol or acetate.

The protein encoded by the ACR1 gene in Saccharomyces cerevisiae belongs to a family of 35 related membrane proteins that are encoded in the fungal genome. Some of them are known to transport various substrates and products across the inner membranes of mitochondria, but the functions of 28 members of the family are unknown. The yeast ACR1 gene was introduced into Escherichia coli on an expression plasmid. The protein was over-produced as inclusion bodies, which were purified and solubilised in the presence of sarkosyl. The solubilised protein was reconstituted into liposomes and shown to transport fumarate and succinate. Its physiological role in S. cerevisiae is probably to transport cytoplasmic succinate, derived from isocitrate by the action of isocitrate lyase in the cytosol, into the mitochondrial matrix in exchange for fumarate. This exchange activity and the subsequent conversion of fumarate to oxaloacetate in the cytosol would be essential for the growth of S. cerevisiae on ethanol or acetate as the sole carbon source.

Acetates↗

PubMed1989

Systemic therapy with fumaric acid derivates: new possibilities in the treatment of psoriasis.

For the past two decades fumaric acid (FA) therapy has become an increasingly popular treatment in Western Europe for psoriasis. FA therapy originally was developed by Schweckendiek and subsequently standardized by Schäfer. Schäfer's fumaric acid compound therapy (FACT) consists of the oral intake of dimethylfumaric acid ester (DMFAE) and several salts of monoethylfumaric acid ester (MEFAE) in combination with topical fumaric acid therapy (1% to 3% MEFAE in an ointment or FA in bathing oils) and a diet. Schäfer claimed excellent results in a large number of patients. Preliminary studies by German dermatologists, however, revealed contradictory therapeutic results and serious side effects, and FA treatment was soon abandoned by dermatologists. To assess the value of FA therapy we conducted an open pilot study of 36 patients in which FACT therapy appeared to be rather effective. Thereafter, several controlled studies with MEFAE sodium in two different dosages versus placebo, and DMFAE versus placebo, were done. The results indicated that MEFAE sodium in dosages up to 240 mg daily was ineffective, whereas daily dosages of 720 mg resulted in a significant decrease in scaling and itching but did not affect extension of the eruption. DMFAE, 240 mg daily, produced a significant amelioration and prevented extension. Side effects of FA treatment were nausea, diarrhea, general malaise, and severe stomachache. Mild disturbances of liver and kidney function during treatment were observed with the 720 mg dosage of MEFAE and with the 240 mg dosage of DMFAE. Moreover, a relative lymphopenia with a selective decrease of suppressor T lymphocytes occurred in about 50% of the patients treated with DMFAE.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed2001

Modification of oligo(poly(ethylene glycol) fumarate) macromer with a GRGD peptide for the preparation of functionalized polymer networks.

A novel macromer, oligo(poly(ethylene glycol) fumarate) (OPF), was synthesized by the reaction between poly(ethylene glycol) (PEG) of molecular weight 1000 (PEG 1.0K) and fumaryl chloride. The oligo(PEG fumarate) (OPF 1.0K) was modified with a peptide known to modulate cellular functions, Gly-Arg-Gly-Asp (GRGD), after being activated with 4-nitrophenyl chloroformate (NPC). The determined yield of the GRGD modification in 0.1 M sodium bicarbonate buffer of pH 8.3 was 83% as determined by NMR measurements. The OPF 1.0K and the OPF 1.0K modified with GRGD were cross-linked with an unsaturated biodegradable polyester, poly(propylene fumarate) (PPF), by photopolymerization. The cross-linked PPF was characterized by Fourier transform infrared (FT-IR) spectroscopy and contact angle measurements. The equilibrium contact angle of water on the cross-linked PPF surface decreased with the incorporation of OPF 1.0K and the OPF 1.0K modified with GRGD. The results suggest that the OPF macromer can be used for the preparation of functionalized networks incorporating cell adhesion specific sequences.

Biopolymers↗

PubMedDate not supplied

Photoinitiated cross-linking of the biodegradable polyester poly(propylene fumarate). Part I. Determination of network structure.

In this work, we investigated the mechanism involved in the photoinitiated cross-linking of the polyester poly(propylene fumarate) (PPF) using the initiator bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO). It was hypothesized that BAPO has the ability to cross-link PPF into solid polymer networks, without the use of a cross-linking monomer, because two pairs of radicals, both involving a fast adding phosphinoyl radical, were formed upon UV irradiation of BAPO. Spectroscopic investigation first confirmed the addition of BAPO derived radicals to the PPF olefin. Investigations of fumarate conversion and bulk network properties were then undertaken, using the BAPO initiator and a monoacylphosphine oxide (MAPO) initiator which contains a single photolabile bond. Results show that a single BAPO phosphinoyl radical was primarily responsible for the formation of a highly cross-linked PPF network and the additional radical pair which may be formed does not dramatically alter fumarate conversion or bulk network properties. From these results, the network structure of BAPO initiated, photo-cross-linked PPF may be deduced. Finally, this study demonstrates a method for inferring cross-linked network structures by contrasting properties of bulk materials formed from similar cross-linking initiators.

Biocompatible Materials↗

PubMed1999

Open conformation of a flavocytochrome c3 fumarate reductase.

Fumarate reductases and succinate dehydrogenases play central roles in the metabolism of eukaryotic and prokaryotic cells. A recent medium resolution structure of the Escherichia coli fumarate reductase (Frd) has revealed the overall organization of the membrane-bound complex. Here we present the first high resolution X-ray crystal structure of a water-soluble bacterial fumarate reductase in an open conformation. This structure reveals a mobile domain that modulates substrate access to the active site and provides new insights into the mechanism of this widespread and important family of FAD-containing respiratory proteins.

Amino Acid Sequence↗

PubMed1999

Structural and mechanistic mapping of a unique fumarate reductase.

The 1.8 A resolution crystal structure of the tetraheme flavocytochrome c3, Fcc3, provides the first mechanistic insight into respiratory fumarate reductases or succinate dehydrogenases. The multi-redox center, three-domain protein shows a 40 A long 'molecular wire' allowing rapid conduction of electrons through a new type of cytochrome domain onto the active site flavin, driving the reduction of fumarate to succinate. In this structure a malate-like molecule is trapped in the enzyme active site. The interactions between this molecule and the enzyme suggest a clear mechanism for fumarate reduction in which the substrate is polarized and twisted, facilitating hydride transfer from the reduced flavin and subsequent proton transfer. The enzyme active site in the oxidized form is completely buried at the interface between the flavin-binding and the clamp domains. Movement of the cytochrome and clamp domains is postulated to allow release of the product.

Amino Acid Sequence↗

PubMed2006

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer.

The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.

Fumarate Hydratase↗

PubMed1976

Effects of dicyclohexylcarbodi-imide on proton translocation coupled to fumarate reduction in anaerobically grown cells of Escherichia coli K-12.

The addition of dicyclohexylcarbodi-imide to anaerobic cells of Escherichia coli K12 decreases both the observed extent of proton translocation coupled to fumarate reduction by endogenous substrates and the t 1/2 of proton re-entry after such translocation, but does not affect fumarate uptake. Dicyclohexylcarbodi-imide also inhibits fumarate reductase activity in cell extracts.

Anaerobiosis↗

PubMed1977

Proton translocation coupled to electron flow from endogenous substrates to fumarate in anaerobically grown Escherichia coli K12.

Observed leads to H+/2e- values for proton translocation during the reduction of fumarate by endogenous substrates in anaerobic cells of Escherichia coli K12 varied with fumarate concentration. This variation was probably due mainly to incomplete fumarate utilization. Under optimum conditions a minimum value for leads to H+/2e- of 1.04+/-0.20 was obtained.

Anaerobiosis↗

PubMed1979

Properties and function of fumarate reductase (NADH) in Streptococcus lactis.

The fumarate reductase (NADH) present in cell-free extracts of S. lactis C10 was purified approximately 100-fed by chromatography on DEAE-cellulose in the presence of the non-ionic detergent Teric X-10, and some of the properties of this partially purified enzyme were characterized. Fumarate was able to act as a terminal electron acceptor and decreased the amount of lactate formed and oxygen used during the metabolism of pyruvate by resting cells of S. lactis. Anaerobic growth of S. lactis on glycerol was not observed and fumarate reduction was not coupled with glycerol-3-phosphate oxidation.

Anaerobiosis↗

PubMed1996

Molecular characterization of potato fumarate hydratase and functional expression in Escherichia coli.

The tricarboxylic acid cycle enzyme fumarase (fumarate hydratase; EC 4.2.1.2) catalyzes the reversible hydration of fumarate to L-malate. We report the molecular cloning of a cDNA (StFum-1) that encodes fumarase from potato (Solanum tuberosum L.). RNA blot analysis demonstrated that StFum-1 is most strongly expressed in flowers, immature leaves, and tubers. The deduced protein contains a typical mitochondrial targeting peptide and has a calculated molecular mass of 50.1 kD (processed form). Potato fumarase complemented a fumarase-deficient Escherichia coli mutation for growth on minimal medium that contains acetate or fumarate as the sole carbon source, indicating that functional plant protein was produced in the bacterium. Antiserum raised against the recombinant plant enzyme recognized a 50-kD protein in wild-type but not in StFum-1 antisense plants, indicating specificity of the immunoreaction. A protein of identical size was also detected in isolated potato tuber mitochondria. Although elevated activity of fumarase was previously reported for guard cells (as compared with mesophyll cells), additional screening and genomic hybridization data reported here do not support the hypothesis that a second fumarase gene is expressed in potato guard cells.

Amino Acid Sequence↗

PubMed2002

Fumarate-mediated inhibition of erythrose reductase, a key enzyme for erythritol production by Torula corallina.

Torula corallina, a strain presently being used for the industrial production of erythritol, has the highest erythritol yield ever reported for an erythritol-producing microorganism. The increased production of erythritol by Torula corallina with trace elements such as Cu(2+) has been thoroughly reported, but the mechanism by which Cu(2+) increases the production of erythritol has not been studied. This study demonstrated that supplemental Cu(2+) enhanced the production of erythritol, while it significantly decreased the production of a major by-product that accumulates during erythritol fermentation, which was identified as fumarate by instrumental analyses. Erythrose reductase, a key enzyme that converts erythrose to erythritol in T. corallina, was purified to homogeneity by chromatographic methods, including ion-exchange and affinity chromatography. In vitro, purified erythrose reductase was significantly inhibited noncompetitively by increasing the fumarate concentration. In contrast, the enzyme activity remained almost constant regardless of Cu(2+) concentration. This suggests that supplemental Cu(2+) reduced the production of fumarate, a strong inhibitor of erythrose reductase, which led to less inhibition of erythrose reductase and a high yield of erythritol. This is the first report that suggests catabolite repression by a tricarboxylic acid cycle intermediate in T. corallina.

Aldehyde Reductase↗

PubMed1982

Gas-liquid chromatography technique for detection of hippurate hydrolysis and conversion of fumarate to succinate by microorganisms.

A gas-liquid chromatography technique which allows simultaneous detection of hippuric acid (N-benzoylglycine) hydrolysis and conversion of fumaric acid to succinic acid by microorganisms uses a new medium, hippurate-formate-fumarate broth, and a gas chromatograph equipped with a thermal conductivity detector. This technique gave more reproducible results than other tests used in the study for detecting hippurate hydrolysis and also gave consistent results in detecting succinic acid produced from utilization of fumaric acid.

Bacteria↗

PubMedDate not supplied

Stereochemical considerations on concomitant allergic contact dermatitis to ester of the cis-trans isomeric compounds maleic acid and fumaric acid.

Allergic contact dermatitis from esters of fumaric acid or esters of maleic acid is rare. The case of a chemist with allergic reactions to esters both of fumaric acid and of maleic acid is presented. Extremely high sensitivity of the patient to diethyl fumarate was noted. The formation of identical complete antigens from esters of these two cis-trans isomeric acids may be an explanation of the patient's double allergy. This is discussed from a stereochemical point of view. These stereochemical considerations point to a general mechanism where cis-trans isomeric alpha,beta-unsaturated carbonyl compounds are converted into the same complete antigen.

Administration, Cutaneous↗

PubMed2003

Effect of physiological temperature on the mechanical properties and network structure of biodegradable poly(propylene fumarate)-based networks.

Poly(propylene fumarate) (PPF)-based networks have exhibited increases in mechanical properties during their initial stages of degradation. This study was designed to investigate whether physiological temperatures are the source of this reinforcing behavior by influencing the formation of additional crosslinks within the network. Utilizing a model PPF network formed with the crosslinking agent poly(propylene fumarate)-diacrylate (PPF-DA), cylindrical specimens were stored in an inert environment and conditioned at -20 and 37 degrees C while their mechanical properties and network structure were monitored over a six week period. The PPF/PPF-DA specimens exposed to physiological temperatures showed an increase in compressive modulus from 1674 +/- 88 to 2059 +/- 75 MPa. The double bond conversion improved as well, from 64 +/- 1 to 70 +/- 1%, indicating that crosslinks were being formed in the network. The additional reactivity occurred exclusively with unreacted fumarate bonds. PPF/PPF-DA networks stored at -20 degrees C showed no changes in mechanical properties; however, they increased when subsequently conditioned at 37 degrees C. The results were used to explain that PPF-based networks undergo a biphasic degradation behavior due to the competing hydrolytic degradation and thermal induced crosslinking. In addition, heat treating the networks at higher temperatures can be utilized as a means to further reinforce PPF-based materials.

Biocompatible Materials↗

PubMed1999

Longterm treatment of psoriasis using fumaric acid preparations can be associated with severe proximal tubular damage.

Fumaric acid preparations are used as longterm and effective treatment of psoriasis. Apart from gastrointestinal, dermatological and hematological side-effects, transient renal damage was observed during treatment with fumaric acid. The case of a 38 year old woman who was treated with fumaric acid (420 mg bid) for 5 years before she complained of fatigue and weakness. According to clinical laboratory she had developed severe proximal tubular damage. Hypophosphatemia, glycosuria and proteinuria persisted although medication was stopped immediately.

Adult↗

PubMed1991

Antifungal activity of fumaric acid in mice infected with Candida albicans.

An examination was made on the effect of fumaric acid on an experimental systemic candidiasis. Male ICR mice were innoculated into the tail veins with 10(6) yeast cells of Candida albicans and treated with daily intraperitoneal injections of fumaric acid at the dose of 40 mg/kg/d. The results indicated that the administration of fumaric acid was effective in prolonging the survival of animals after the fungal challenge and prevented one-fifth of the treated animals from dying of candidiasis.

Animals↗

PubMed2006

Methane emissions from beef cattle: effects of fumaric acid, essential oil, and canola oil.

The objective of this study was to identify feed additives that reduce enteric methane emissions from cattle. We measured methane emissions, total tract digestibility (using chromic oxide), and ruminal fermentation (4 h after feeding) in growing beef cattle fed a diet supplemented with various additives. The experiment was designed as a replicated 4 x 4 Latin square with 21-d periods and was conducted using 16 Angus heifers (initial BW of 260 +/- 32 kg). Treatments were: control (no additive), fumaric acid (175 g/d) with sodium bicarbonate (75 g/d), essential oil and spice extract (1 g/d), or canola oil (4.6% of DMI). The basal diet consisted of 75% whole-crop barley silage, 19% steam-rolled barley, and 6% supplement (DM basis). Four large chambers (2 animals fed the same diet per chamber) were equipped to measure methane emissions for 3 d each period. Adding canola oil to the diet decreased (P = 0.009) total daily methane emissions by 32% and tended (P = 0.09) to decrease methane emissions as a percentage of gross energy intake by 21%. However, much of the reduction in methane emissions was due to decreased (P < 0.05) feed intake and lower (P < 0.05) total tract digestibility of DM and fiber. Digestibility of all nutrients was also lowered (P < 0.05) by feeding essential oil, but there were no effects on ruminal fermentation or methane emissions. In contrast, adding fumaric acid to the diet increased total VFA concentration (P = 0.03), increased propionate proportions (P = 0.01), and decreased the acetate:propionate ratio (P = 0.002), but there was no measurable effect on methane emissions. The study demonstrates that canola oil can be used to reduce methane losses from cattle, but animal performance may be compromised due to lower feed intake and decreased fiber digestibility. Essential oils had no effect on methane emissions, whereas fumaric acid caused potentially beneficial changes in ruminal fermentation but no measurable reductions in methane emissions.

Animal Feed↗