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PubMed2000

Transport of C(4)-dicarboxylates in Wolinella succinogenes.

C(4)-dicarboxylate transport is a prerequisite for anaerobic respiration with fumarate in Wolinella succinogenes, since the substrate site of fumarate reductase is oriented towards the cytoplasmic side of the membrane. W. succinogenes was found to transport C(4)-dicarboxylates (fumarate, succinate, malate, and aspartate) across the cytoplasmic membrane by antiport and uniport mechanisms. The electrogenic uniport resulted in dicarboxylate accumulation driven by anaerobic respiration. The molar ratio of internal to external dicarboxylate concentration was up to 10(3). The dicarboxylate antiport was either electrogenic or electroneutral. The electroneutral antiport required the presence of internal Na(+), whereas the electrogenic antiport also operated in the absence of Na(+). In the absence of Na(+), no electrochemical proton potential (delta p) was measured across the membrane of cells catalyzing fumarate respiration. This suggests that the proton potential generated by fumarate respiration is dissipated by the concomitant electrogenic dicarboxylate antiport. Three gene loci (dcuA, dcuB, and dctPQM) encoding putative C(4)-dicarboxylate transporters were identified on the genome of W. succinogenes. The predicted gene products of dcuA and dcuB are similar to the Dcu transporters that are involved in the fumarate respiration of Escherichia coli with external C(4)-dicarboxylates. The genes dctP, -Q, and -M probably encode a binding-protein-dependent secondary uptake transporter for dicarboxylates. A mutant (DcuA(-) DcuB(-)) of W. succinogenes lacking the intact dcuA and dcuB genes grew by nitrate respiration with succinate as the carbon source but did not grow by fumarate respiration with fumarate, malate, or aspartate as substrates. The DcuA(-), DcuB(-), and DctQM(-) mutants grew by fumarate respiration as well as by nitrate respiration with succinate as the carbon source. Cells of the DcuA(-) DcuB(-) mutant performed fumarate respiration without generating a proton potential even in the presence of Na(+). This explains why the DcuA(-) DcuB(-) mutant does not grow by fumarate respiration. Growth by fumarate respiration appears to depend on the function of the Na(+)-dependent, electroneutral dicarboxylate antiport which is catalyzed exclusively by the Dcu transporters. Dicarboxylate transport via the electrogenic uniport is probably catalyzed by the DctPQM transporter and by a fourth, unknown transporter that may also operate as an electrogenic antiporter.

Anaerobiosis↗
PubMed1998

The electron transport chain in anaerobically functioning eukaryotes.

Many lower eukaryotes can survive anaerobic conditions via a fermentation pathway that involves the use of the reduction of endogenously produced fumarate as electron sink. This fumarate reduction is linked to electron transport in an especially adapted, anaerobically functioning electron-transport chain. An aerobic energy metabolism with Krebs cycle activity is accompanied by electron transfer from succinate to ubiquinone via complex II of the respiratory chain. On the other hand, in an anaerobic metabolism, where fumarate functions as terminal electron acceptor, electrons are transferred from rhodoquinone to fumarate, which is the reversed direction. Ubiquinone cannot replace rhodoquinone in the process of fumarate reduction in vivo, as ubiquinone can only accept electrons from complex II and cannot donate them to fumarate. Rhodoquinone, with its lower redox potential than ubiquinone, is capable of donating electrons to fumarate. Eukaryotic fumarate reductases were shown to interact with rhodoquinone (a benzoquinone), whereas most prokaryotic fumarate reductases interact with the naphtoquinones menaquinone and demethylmenaquinone. Fumarate reductase, the enzyme essential for the anaerobic functioning of many eukaryotes, is structurally very similar to succinate dehydrogenase, the Krebs cycle enzyme catalysing the reverse reaction. In prokaryotes these enzymes are differentially expressed depending on the external conditions. Evidence is now emerging that also in eukaryotes two different enzymes exist for succinate oxidation and fumarate reduction that are differentially expressed.

Anaerobiosis↗
PubMed1995

Rhodoquinone and complex II of the electron transport chain in anaerobically functioning eukaryotes.

Many anaerobically functioning eukaryotes have an anaerobic energy metabolism in which fumarate is reduced to succinate. This reduction of fumarate is the opposite reaction to succinate oxidation catalyzed by succinate-ubiquinone oxidoreductase, complex II of the aerobic respiratory chain. Prokaryotes are known to contain two distinct enzyme complexes and distinct quinones, menaquinone and ubiquinone (Q), for the reduction of fumarate and the oxidation of succinate, respectively. Parasitic helminths are also known to contain two different quinones, Q and rhodoquinone (RQ). This report demonstrates that RQ was present in all examined eukaryotes that reduce fumarate during anoxia, not only in parasitic helminths, but also in freshwater snails, mussels, lugworms, and oysters. It was shown that the measured RQ/Q ratio correlated with the importance of fumarate reduction in vivo. This is the first demonstration of the role of RQ in eukaryotes, other than parasitic helminths. Furthermore, throughout the development of the liver fluke Fasciola hepatica, a strong correlation was found between the quinone composition and the type of metabolism: the amount of Q was correlated with the use of the aerobic respiratory chain, and the amount of RQ with the use of fumarate reduction. It can be concluded that RQ is an essential component for fumarate reduction in eukaryotes, in contrast to prokaryotes, which use menaquinone in this process. Analyses of enzyme kinetics, as well as the known differences in primary structures of prokaryotic and eukaryotic complexes that reduce fumarate, support the idea that fumarate-reducing eukaryotes possess an enzyme complex for the reduction of fumarate, structurally related to the succinate dehydrogenase-type complex II, but with the functional characteristics of the prokaryotic fumarate reductases.

Animals↗
PubMed1981

Influence of Nutritional Conditions on Production of l-Glutamine by Flavobacterium rigense.

The nutritional conditions for the production of l-glutamine by Flavobacterium rigense strain 703 were investigated. The optimum concentration of ammonia for achieving the highest yield of l-glutamine (25 mg/ml of broth) was relatively broad, from 0.9 to 1.6%, whereas fumaric acid had a narrow optimum range, near 5.5%. High concentration of inorganic ions such as chloride or sulfate ion clearly inhibited cell growth. Therefore, ammonium salts other than (NH(4))(2)-fumarate were unsuitable for the highest production. The optimum concentration of (NH(4))(2)-fumarate was 7%. To reduce the concentration of fumaric acid in the medium, many substances were evaluated as substitutes. The fumaric acid concentration required for highest l-glutamine yield could not be replaced by any one of the compounds tested. However, part of fumaric acid could be replaced with succinic acid and cupric ion; 4% (NH(4))(2)-fumarate plus 2.5% succinic acid or 5% (NH(4))(2)-fumarate plus 1 mM cupric ion produced results similar to 7% (NH(4))(2)-fumarate in the fermentation medium.

Journal Article↗
PubMed2006

Crystallographic studies of the binding of ligands to the dicarboxylate site of Complex II, and the identity of the ligand in the "oxaloacetate-inhibited" state.

Mitochondrial Complex II (succinate:ubiquinone oxidoreductase) is purified in a partially inactivated state, which can be activated by removal of tightly bound oxaloacetate (E.B. Kearney, et al., Biochem. Biophys. Res. Commun. 49 1115-1121). We crystallized Complex II in the presence of oxaloacetate or with the endogenous inhibitor bound. The structure showed a ligand essentially identical to the "malate-like intermediate" found in Shewanella Flavocytochrome c crystallized with fumarate (P. Taylor, et al., Nat. Struct. Biol. 6 1108-1112) Crystallization of Complex II in the presence of excess fumarate also gave the malate-like intermediate or a mixture of that and fumarate at the active site. In order to more conveniently monitor the occupation state of the dicarboxylate site, we are developing a library of UV/Vis spectral effects induced by binding different ligands to the site. Treatment with fumarate results in rapid development of the fumarate difference spectrum and then a very slow conversion into a species spectrally similar to the OAA-liganded complex. Complex II is known to be capable of oxidizing malate to the enol form of oxaloacetate (Y.O. Belikova, et al., Biochim. Biophys. Acta 936 1-9). The observations above suggest it may also be capable of interconverting fumarate and malate. It may be useful for understanding the mechanism and regulation of the enzyme to identify the malate-like intermediate and its pathway of formation from oxaloacetate or fumarate.

Animals↗
PubMed2002

Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas.

Germline mutations in the fumarate hydratase gene at 1q43 predispose to dominantly inherited skin and uterine leiomyomata and leiomyosarcomas. The enzyme, which is a component of the tricarboxylic acid cycle, acts as a tumour suppressor. To evaluate fumarate hydratase in respective sporadic tumours, we analysed a series of 26 leiomyosarcomas and 129 uterine leiomyomas (from 21 patients) for somatic mutations in fumarate hydratase and allelic imbalance around 1q43. None of the 26 leiomyosarcomas harboured somatic mutations in fumarate hydratase. Fifty per cent of leiomysarcomas tested showed evidence of allelic imbalance at 1q, but this was not confined to the vicinity of fumarate hydratase. Only 5% (seven out of 129) of the leiomyomas showed allele imbalance at 1q42-q43 and no somatic mutations in fumarate hydratase were observed. Our findings indicate that mutations in fumarate hydratase do not play a major role in the development of sporadic leiomyosarcomas or uterine leiomyomas

Adult↗
PubMed1978

Energy supply for active transport in anaerobically grown Escherichia coli.

Escherichia coli K-12, grown under anaerobic conditions with glucose as the sole source of carbon and energy without any terminal electron acceptor added, contains a fumarate reductase system in which electrons are transferred from formate or reduced nicotinamide adenine dinucleotide via menaquinone and cytochromes to fumarate reductase. This fumarate reductase system plays an important role in the metabolic energy supply of E. coli, grown under so-called "glycolytic conditions," as is indicated by the growth yields and maximal growth rates of mutants impaired in electron transfer or adenosine triphosphatase (uncB). In mutants deficient in menaquinone, cytochromes, or fumarate reductase, these values are considerably lower than in mutants deficient in ubiquinone or a functional adenosine triphosphatase. Electron transfer in this fumarate reductase system leads to the generation of a membrane potential, as is indicated by the uptake of the lipophilic cation triphenylmethylphosphonium by membrane vesicles prepared from cytochrome-sufficient and uncB cells. The generation of a proton-motive force by the fumarate reductase system was also demonstrated by the uptake of amino acids under anaerobic conditions in membrane vesicles of cytochrome containing and uncB cells grown under glycolytic conditions. Membrane vesicles of cytochrome-deficient cells failed to accumulate triphenyl-methylphosphonium and amino acids under these conditions, indicating that cytochromes are essential for the generation of a proton-motive force. Using glutamine uptake as an indication of the generation of ATP and proline uptake as an indication of the generation of a proton-motive force, it was demonstrated in whole cells that the proton-motive force is formed by ATP hydrolysis in cytochrome-deficient cells and by electron transfer in the uncB cells. In cytochrome-containing cells it was not possible to distinguish between these two possibilities, but the growth parameters suggest that, under glycolytic conditions, the proton-motive force is generated via electron transfer in the fumarate reductase system rather than via ATP hydrolysis.

Adenosine Triphosphate↗
PubMed1999

Functioning of DcuC as the C4-dicarboxylate carrier during glucose fermentation by Escherichia coli.

The dcuC gene of Escherichia coli encodes an alternative C4-dicarboxylate carrier (DcuC) with low transport activity. The expression of dcuC was investigated. dcuC was expressed only under anaerobic conditions; nitrate and fumarate caused slight repression and stimulation of expression, respectively. Anaerobic induction depended mainly on the transcriptional regulator FNR. Fumarate stimulation was independent of the fumarate response regulator DcuR. The expression of dcuC was not significantly inhibited by glucose, assigning a role to DcuC during glucose fermentation. The inactivation of dcuC increased fumarate-succinate exchange and fumarate uptake by DcuA and DcuB, suggesting a preferential function of DcuC in succinate efflux during glucose fermentation. Upon overexpression in a dcuC promoter mutant (dcuC*), DcuC was able to compensate for DcuA and DcuB in fumarate-succinate exchange and fumarate uptake.

Anaerobiosis↗
PubMed2000

Succinate: quinone oxidoreductases: new insights from X-ray crystal structures.

Membrane-bound succinate dehydrogenases (succinate:quinone reductases, SQR) and fumarate reductases (quinol:fumarate reductases, QFR) couple the oxidation of succinate to fumarate to the reduction of quinone to quinol and also catalyse the reverse reaction. SQR (respiratory complex II) is involved in aerobic metabolism as part of the citric acid cycle and of the aerobic respiratory chain. QFR is involved in anaerobic respiration with fumarate as the terminal electron acceptor, and is part of an electron transport chain catalysing the oxidation of various donor substrates by fumarate. QFR and SQR complexes are collectively referred to as succinate:quinone oxidoreductases (EC 1.3.5.1), have very similar compositions and are predicted to share similar structures. The complexes consist of two hydrophilic and one or two hydrophobic, membrane-integrated subunits. The larger hydrophilic subunit A carries covalently bound flavin adenine dinucleotide and subunit B contains three iron-sulphur centres. QFR of Wolinella succinogenes and SQR of Bacillus subtilis contain only one hydrophobic subunit (C) with two haem b groups. In contrast, SQR and QFR of Escherichia coli contain two hydrophobic subunits (C and D) which bind either one (SQR) or no haem b group (QFR). The structure of W. succinogenes QFR has been determined at 2.2 A resolution by X-ray crystallography (C.R.D. Lancaster, A. Kröger, M. Auer, H. Michel, Nature 402 (1999) 377-385). Based on this structure of the three protein subunits and the arrangement of the six prosthetic groups, a pathway of electron transfer from the quinol-oxidising dihaem cytochrome b to the site of fumarate reduction and a mechanism of fumarate reduction was proposed. The W. succinogenes QFR structure is different from that of the haem-less QFR of E. coli, described at 3.3 A resolution (T.M. Iverson, C. Luna-Chavez, G. Cecchini, D.C. Rees, Science 284 (1999) 1961-1966), mainly with respect to the structure of the membrane-embedded subunits and the relative orientations of soluble and membrane-embedded subunits. Also, similarities and differences between QFR transmembrane helix IV and transmembrane helix F of bacteriorhodopsin and their implications are discussed.

Animals↗
PubMed1994

Purification and properties of a novel cytochrome: flavocytochrome c from Shewanella putrefaciens.

The major soluble cytochrome isolated from microaerobically grown cells of Shewanella putrefaciens has been shown to be a novel type of flavocytochrome with fumarate reductase activity. This flavocytochrome, located in the periplasmic fraction of cell extracts, has been purified to homogeneity and shown to contain 4 mol of haem c and 1 mol of non-covalently bound FAD per mol of protein. An M(r) value of 63,800 is estimated from sequence analysis assuming 4 mol of haem/mol of protein. In the presence of the artificial electron donor, reduced methyl viologen, the flavocytochrome catalysed the reduction of fumarate but not that of nitrite, dimethylsulphoxide, trimethylamine-N-oxide or sulphite. The pH optimum was 7.4 with calculated pKa values of 6.8 and 8.0 for contributing catalytic groups. The Km and kcat. values for fumarate reduction were 21 microM and 250 s-1 respectively, whereas the corresponding values for succinate oxidation with 2,6-dichlorophenol-indophenol as electron carriers were 200 microM and 0.07 s-1 respectively. Mesaconic acid was a competitive inhibitor of fumarate reduction with a Ki of 2 microM. Zymogram staining of polyacrylamide gels with purified protein showed a band of fumarate reductase activity. Polyclonal antibodies, raised to the purified flavocytochrome, were shown to titrate out fumarate reductase activity. We conclude that the physiological role of this enzyme is as a fumarate reductase. Optical absorption spectra of the flavocytochrome indicated that all the haems were of the c-type and gave alpha, beta and gamma peaks at 552.3, 523 and 418 nm in the reduced spectrum with epsilon values of 30.2, 15.9 and 188.2 mM-1.cm-1 respectively. Oxidized spectra showed no 695 nm band that would be indicative of His-Met coordination. Two redox potentials were resolved at -220 mV and -320 mV. The cytochrome was reduced by formate in the presence of particulate cell fractions. The relationship of this cytochrome to other low-potential flavocytochromes c is discussed.

Amino Acids↗
PubMed2005

Comparative assessment of the bioavailability, efficacy and safety of a modified-release (MR) carbonyl iron tablet and oral conventional iron preparation in adult Indian patients with nutritional iron deficiency anaemia.

The objective of the study is to evaluate the bioavailability, efficacy and safety of a new modified-release (MR) formulation of carbonyl iron (45 mg) relative to a commercially available conventional formulation of ferrous fumarate (300 mg) in adult Indian patients with clinical and laboratory diagnosis of nutritional iron deficiency anaemia. This prospective, comparative, randomised, double-blind study was carried out among 60 patients received a single daily dose of either MR carbonyl iron or ferrous fumarate for 12 weeks. The effect of therapy on haematological parameters and iron status and estimation of bioavailability were the main efficacy outcomes. There was a significant (p<0.05) increase in mean haemoglobin levels, reticulocyte counts, haematocrit and mean corpuscular volume in MR carbonyl iron group compared to ferrous fumarate group. There was also an increase in mean serum iron and ferritin levels and a corresponding decrease in total iron binding capacity in MR carbonyl iron group compared to ferrous fumarate group at the end of 12 weeks therapy. The estimated overall bioavailability of MR carbonyl iron was about 147% that of ferrous fumarate. Both the formulations were equally well-tolerated and adverse events were mainly gastrointestinal in nature. The prevalence of adverse events was slightly more in the ferrous fumarate group. It can be concluded that the MR formulation of carbonyl iron was more efficacious than ferrous fumarate in correcting haematologic abnormalities and improving iron status in patients with nutritional iron deficiency anaemia. In conditions where efficacy is an important consideration, the higher bioavailability of MR carbonyl iron may make it the treatment of choice for nutritional iron deficiency anaemia.

Administration, Oral↗
PubMed1996

The cytosolic pathway of L-malic acid synthesis in Saccharomyces cerevisiae: the role of fumarase.

Saccharomyces cerevisiae accumulates L-malic acid but not only minute amounts of fumaric acid. A 13C-nuclear magnetic resonance study following the label from glucose to L-malic acid indicates that the L-malic acid is synthesized from pyruvic acid via oxaloacetic acid. From this, and from previously published studies, we conclude that a cytosolic reductive pathway leading from pyruvic acid via oxaloacetic acid to L-malic acid is responsible for the L-malic acid production in yeast. The non-production of fumaric acid can be explained by the conclusion that, in the cell, cytosolic fumarase catalyzes the conversion of fumaric acid to L-malic but not the reverse. This conclusion is based on the following findings. (a) The cytosolic enzyme exhibits a 17-fold higher affinity towards fumaric acid than towards L-malic acid; the Km for L-malic acid is very high indicating that L-malic acid is not an in vivo substrate of the enzyme. (b) Overexpression of cytosolic fumarase does not cause accumulation of fumaric acid (but rather more L-malic acid). (c) According to 13C NMR studies there is no interconversion of cytosolic L-malic and fumaric acids.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗
PubMed2004

Phenyl methyl ethers: novel electron donors for respiratory growth of Desulfitobacterium hafniense and Desulfitobacterium sp. strain PCE-S.

Desulfitobacterium hafniense and Desulfitobacterium sp. strain PCE-S grew under anoxic conditions with a variety of phenyl methyl ethers as electron donors in combination with fumarate as electron acceptor. The phenyl methyl ethers were O-demethylated to the corresponding phenol compounds. O-demethylation was strictly dependent on the presence of fumarate; no O-demethylation occurred with CO2 as electron acceptor. One mol phenyl methyl ether R-O-CH3 was O-demethylated to R-OH per 3 mol fumarate reduced to succinate. The growth yields with vanillate or syringate plus fumarate were approximately 15 g cells (dry weight) per mol methyl moiety converted. D. hafniense utilized vanillate or syringate as an electron donor for reductive dehalogenation of 3-Cl-4-hydroxyphenylacetate, whereas strain PCE-S was not able to dechlorinate tetrachloroethene with phenyl methyl ethers. Crude extracts of both organisms showed O-demethylase activity in the O-demethylase assay with vanillate or syringate as substrates when the organism was grown on syringate plus fumarate. Besides the homoacetogenic bacteria, only growing cells of Desulfitobacterium frappieri PCP-1 have thus far been reported to be capable of phenyl methyl ether O-demethylation. This present study is the first report of Desulfitobacteria utilizing phenyl methyl ethers as electron donors for fumarate reduction and for growth.

Anisoles↗
PubMed2000

Oxidation of acetate through reactions of the citric acid cycle by Geobacter sulfurreducens in pure culture and in syntrophic coculture.

Geobacter sulfurreducens strain PCA oxidized acetate to CO2 via citric acid cycle reactions during growth with acetate plus fumarate in pure culture, and with acetate plus nitrate in coculture with Wolinella succinogenes. Acetate was activated by succinyl-CoA:acetate CoA-transferase and also via acetate kinase plus phosphotransacetylase. Citrate was formed by citrate synthase. Soluble isocitrate and malate dehydrogenases NADP+ and NAD+, respectively. Oxidation of 2-oxoglutarate was measured as benzyl viologen reduction and strictly CoA-dependent; a low activity was also observed with NADP+. Succinate dehydrogenase and fumarate ductase both were membrane-bound. Succinate oxidation was coupled to NADP+ reduction whereas fumarate reduction was coupled to NADPH and NADH Coupling of succinate oxidation to NADP+ or cytochrome(s) reduction required an ATP-dependent reversed electron transport. Net ATP synthesis proceeded exclusively through electron transport phosphorylation. During fumarate reduction, both NADPH and NADH delivered reducing equivalents into the electron transport chain, which contained a menaquinone. Overall, acetate oxidation with fumarate proceeded through an open loop of citric acid cycle reactions, excluding succinate dehydrogenase, with fumarate reductase as the key reaction for electron delivery, whereas acetate oxidation in the syntrophic coculture required the complete citric acid cycle.

Acetates↗
PubMed1984

Kinetic mechanism and location of rate-determining steps for aspartase from Hafnia alvei.

Coupled spectrophotometric assays that monitor the formation of fumarate and ammonia in the direction of aspartate deamination and aspartate in the direction of fumarate amination were used to collect initial velocity data for the aspartase reaction. Data are consistent with rapid equilibrium ordered addition of Mg2+ prior to aspartate but completely random release of Mg2+, NH4+, or fumarate. In addition to Mg2+, Mn2+ can also be used as a divalent metal with Vmax 80% and a Kaspartate 3.5-fold lower than when Mg2+ is used. Monovalent cations such as Li+, K+, Cs+, and Rb+ are competitive vs. either aspartate or NH4+ but noncompetitive vs. fumarate. A primary deuterium isotope effect of about 1 on both V and V/Kaspartate is obtained with (3R)-L-aspartate-3-d, while a primary 15N isotope effect on V/Kaspartate of 1.0239 +/- 0.0014 is obtained in the direction of aspartate deamination. A secondary isotope effect on V of 1.13 +/- 0.04 is obtained with L-aspartate-2-d. In addition, a secondary isotope effect of 0.81 +/- 0.05 on V is obtained with fumarate-d2, while a value of 1.18 +/- 0.05 on V is obtained by using (2S,3S)-L-aspartate-2,3-d2. These data are interpreted in terms of a two-step mechanism with an intermediate carbanion in which C-N bond cleavage limits the overall rate and the rate-limiting transition state is intermediate between the carbanion and fumarate.

Ammonia↗
PubMed2006

Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF.

The stability and transcriptional activity of the hypoxia-inducible factors (HIFs) are regulated by two oxygen-dependent events that are catalyzed by three HIF prolyl 4-hydroxylases (HIF-P4Hs) and one HIF asparaginyl hydroxylase (FIH). We have studied possible links between metabolic pathways and HIF hydroxylases by analyzing the abilities of citric acid cycle intermediates to inhibit purified human HIF-P4Hs and FIH. Fumarate and succinate were identified as in vitro inhibitors of all three HIF-P4Hs, fumarate having K(i) values of 50-80 microM and succinate 350-460 microM, whereas neither inhibited FIH. Oxaloacetate was an additional inhibitor of all three HIF-P4Hs with K(i) values of 400-1000 microM and citrate of HIF-P4H-3, citrate being the most effective inhibitor of FIH with a K(i) of 110 microM. Culturing of cells with fumarate diethyl or dimethyl ester, or a high concentration of monoethyl ester, stabilized HIF-1alpha and increased production of vascular endothelial growth factor and erythropoietin. Similar, although much smaller, changes were found in cultured fibroblasts from a patient with fumarate hydratase (FH) deficiency and upon silencing FH using small interfering RNA. No such effects were seen upon culturing of cells with succinate diethyl or dimethyl ester. As FIH was not inhibited by fumarate, our data indicate that the transcriptional activity of HIF is quite high even when binding of the coactivator p300 is prevented. Our data also support recent suggestions that the increased fumarate and succinate levels present in the FH and succinate dehydrogenase-deficient tumors, respectively, can inhibit the HIF-P4Hs with consequent stabilization of HIF-alphas and effects on tumor pathology.

Cell Line↗
PubMed2006

Determination of electron donors by comparing reaction rates for in situ bioremediation of nitrate-contaminated groundwater.

Groundwater contaminated by nitrates occurs frequently. In this research, fumarate, acetate, formate, lactate, propionate, ethanol, and methane were evaluated as a potential electron donor and carbon source by comparing the denitrification rate for the in situ bioremediation of nitrate contaminated groundwater. The denitrification rate for each substance was the quickest in the order of: fumarate > hydrogen > formate/Lactate > ethanol > propionate > methanol > acetate. Microcosm studies were performed with fumarates and acetates. When fumarates were used as a substrate, nitrates were removed completely at a rate of 0.66 mmol/day, while the conversion rate from nitrate to nitrogen gas and other by-products was 87%. For the microcosm test, 42 mg of fumarates were needed to remove 30 mg of NO(3)--N/L. When using acetate as a sole carbon source, 31% of nitrates were removed during the initial adjustment period. Among the removed fractions, however, 83% of the nitrates were removed by the cell growth. Overall, the nitrate removal rate was 0.37 mmol/day when acetate was used as a sole carbon source. The acetate showed longer lag time before denitrification occurred, which implied that fumarate would have been a better carbon source compared to acetate as more amounts were utilized for nitrate removal than cell growth.

Acetates↗
PubMed1985

Response of starter pigs to supplementation of corn-soybean meal diets with organic acids.

Four growth experiments were conducted to assess the effects of organic acid supplementation on performance of starter and finisher pigs. Three 4-wk starter experiments utilized 392 pigs fed simple corn-soybean meal diets. A fourth experiment employed 135 finisher pigs in a 6-wk study. Each of the starter experiments was initiated immediately after weaning; piglets were 30 +/- 3 d of age. In Exp. 1, weanling pigs fed a 19% crude protein, simple corn-soybean meal diet were compared with pigs fed similar diets supplemented with 2% propionic, fumaric, or citric acid. Addition of each acid improved (P less than .07) efficiency of gain, while propionate depressed (P less than .05) feed intake. Additions of 1, 2, 3 or 4% fumarate were made in Exp. 2, resulting in linear daily gain and feed efficiency improvements (P less than .05). In Exp. 3, a possible protein-sparing effect of fumaric acid was investigated. Increasing protein levels from 16 to 20% improved daily gain (P less than .01) and feed efficiency (P less than .0001); fumarate supplementation (2%) increased (P less than .01) gain:feed. However, there was no protein X fumaric acid interaction. In Exp. 4, no treatment effects were noted with performance of finisher pigs fed a 14% crude protein, corn-soybean meal diet was compared with that of pigs fed similar diets supplemented with 1.5 or 3% fumaric acid.

Animals↗