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PubMed2002

Chromate/nitrite interactions in Shewanella oneidensis MR-1: evidence for multiple hexavalent chromium [Cr(VI)] reduction mechanisms dependent on physiological growth conditions.

Inhibition of hexavalent chromium [Cr(VI)] reduction due to nitrate and nitrite was observed during tests with Shewanella oneidensis MR-1 (previously named Shewanella putrefaciens MR-1 and henceforth referred to as MR-1). Initial Cr(VI) reduction rates were measured at various nitrite concentrations, and a mixed inhibition kinetic model was used to determine the kinetic parameters-maximum Cr(VI) reduction rate and inhibition constant [V(max,Cr(VI)) and K(i,Cr(VI))]. Values of V(max,Cr(VI)) and K(i,Cr(VI)) obtained with MR-1 cultures grown under denitrifying conditions were observed to be significantly different from the values obtained when the cultures were grown with fumarate as the terminal electron acceptor. It was also observed that a single V(max,Cr(VI)) and K(i,Cr(VI)) did not adequately describe the inhibition kinetics of either nitrate-grown or fumarate-grown cultures. The inhibition patterns indicate that Cr(VI) reduction in MR-1 is likely not limited to a single pathway, but occurs via different mechanisms some of which are dependent on growth conditions. Inhibition of nitrite reduction due to the presence of Cr(VI) was also studied, and the kinetic parameters V(max,NO2) and K(i,NO2) were determined. It was observed that these coefficients also differed significantly between MR-1 grown under denitrifying conditions and fumarate reducing conditions. The inhibition studies suggest the involvement of nitrite reductase in Cr(VI) reduction. Because nitrite reduction is part of the anaerobic respiration process, inhibition due to Cr(VI) might be a result of interaction with the components of the anaerobic respiration pathway such as nitrite reductase. Also, differences in the degree of inhibition of nitrite reduction activity by chromate at different growth conditions suggest that the toxicity mechanism of Cr(VI) might also be dependent on the conditions of growth. Cr(VI) reduction has been shown to occur via different pathways, but to our knowledge, multiple pathways within a single organism leading to Cr(VI) reduction has not been reported previously.

Chromium↗
PubMed1994

Initial kinetic and mechanistic characterization of Escherichia coli fumarase A.

The protein encoded by the fumA gene in Escherichia coli is shown herein to be a highly efficient and specific catalyst of the fumarase reaction. In an investigation of 21 substrate analogs, this protein only had substantial activity as a hydro-lyase on fumarate, malate, acetylene dicarboxylate, fluorofumarate, and 2(S),3(S)-tartrate. The kcat and kcat/Km for the hydration of fumarate by this protein are 3100 s-1 and 5 x 10(6) mol-1 s-1, respectively. It is likely that one physiological role of this protein is a catalyst of the fumarase reaction; therefore, it is appropriate to name it fumarase A. Fumarase A specifically removes the 3-pro-R in the dehydration of (2S)-malate. The product of the action of fumarase A on acetylene dicarboxylate, fluorofumarate and 2(S),3(S)-tartrate is oxalacetate. The nitronate form of 2-hydroxy-3-nitro-propionate is a potent inhibitor of fumarase A, implying that the enzyme forms an intermediate with an anion at C-3. No kinetic isotope effect was found with (2S,3R)-3-[2H]malate. The effects of pH on the kcat and kcat/Km for fumarate as a substrate show that the pKas of the groups involved in catalysis differ markedly from porcine fumarase. The possible roles of the proteins encoded by the three fumarase genes in E. coli are briefly discussed.

Animals↗
PubMed1978

The pathway of formation of acetate and succinate from pyruvate by Bacteroides succinogenes.

Bacteroides succinogenes produces acetate and succinate as major products of carbohydrate fermentation. An investigation of the enzymes involved indicated that pyruvate is oxidized by a flavin-dependent pyruvate cleavage enzyme to acetyl-CoA and CO2. Active CO2 exchange is associated with the pyruvate oxidation system. Reduction of flavin nucleotides is CoASH-dependent and does not require ferredoxin. Acetyl-CoA is further metabolized via acetyl phosphate to acetate and ATP. Reduced flavin nucleotide is used to reduce fumarate to succinate by a particulate flavin-specific fumarate reductase reaction which may involve cytochrome b. Phosphoenolpyruvate (PEP) is carboxylated to oxalacetate by a GDP- specific PEP carboxykinase. Oxalacetate, in turn, is converted to malate by a pyridine nucleotide-dependent malate dehydrogenase. The organism has a NAD-dependent glyceraldehyde-3-phosphate dehydrogenase. The data suggest that reduced pyridine nucleotides generated during glycolysis are oxidized in malate formation and that the electrons generated during pyruvate oxidation are used to reduce fumarate to succinate.

Acetates↗
PubMed1986

Phorphorylative electron transport chains lacking a cytochrome bc1 complex.

Electron transport-coupled phosphorylation with fumarate as terminal acceptor in Wolinella succinogenes yields less than 1 ATP/2 electrons. The delta mu H generated by the electron transport is 0.18 V and the H+/electron ratio is 1. The electron transport chain is made up of two dehydrogenases (hydrogenase and formate dehydrogenase) that catalyze the reduction of menaquinone, and fumarate reductase which catalyzes the oxidation of menaquinol. C-type cytochromes are not involved. The phosphorylative electron transport with sulfur as terminal acceptor in W. succinogenes or Desulfuromonas acetoxidans does not involve known quinones. The ATP yields should be even smaller than those with fumarate. Succinate oxidation by sulfur, which is a catabolic reaction in D. acetoxidans, is accomplished by reversed electron transport.

Electron Transport↗
PubMed1999

[Immunomodulating therapy of psoriasis vulgaris].

BACKGROUND: Newest studies have shown that psoriasis is not primarily a skin disorder but an immunological disturbance under the skin. The skin manifestations are a result of overstimulation of superficial skin cells (Langerhans cells) due to increased production of interleukin 2, 6 and 8 as well as transforming growth-factor-alpha. Interleucin-10 production is diminished. In a recent study (11 German University Skin Clinics) fumaric acid was shown to improve the skin leasons in 80% of treated patients. OWN EXPERIENCES: Our own studies on 54 patients which where treated in addition with intravenous thymus extract (Thymoject) and selenium (Selenase) showed a faster healing rate with fumaric acid alone. From these results one can postulate that the above treatments (fumaric acid, thymus and selenium) have a synergystic effect. CONCLUSIONS: Internal immunmodulating treatments should therefore have preference over external symptomatic treatments like UV-light, ointments, salt water bath, etc.

Administration, Oral↗
PubMed2001

Periplasmic methacrylate reductase activity in Wolinella succinogenes.

The cell homogenate and the soluble cell fraction of Wolinella succinogenes grown with formate and fumarate catalyzed the oxidation of benzyl viologen radical by methacrylate [apparent Km=0.23 mM, Vmax=1.0 U (mg cell protein) -1] or acrylate [apparent Km=0.50 mM, Vmax=0.77 U (mg cell protein) -1]. Crotonate did not serve as an oxidant. A mutant of W. succinogenes lacking the fccABC operon was unable to catalyze methacrylate or acrylate reduction. In contrast, the inactivation of fccC alone had no effect on these activities. Methacrylate reduction by benzyl viologen radical was not catalyzed by fumarate reductase isolated from the membrane of W. succinogenes. Cells grown with formate and fumarate did not catalyze methacrylate reduction by formate, and W. succinogenes did not grow with formate and methacrylate as catabolic substrates. The results suggest that the reduction of methacrylate or acrylate by benzyl viologen radical is most likely catalyzed either by the periplasmic flavoprotein FccA or by a complex consisting of FccA and the predicted c-type cytochrome FccB. The metabolic function of the fccABC operon remains unknown.

Cell Membrane↗
PubMed1999

Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder inhalation via Aerolizer.

OBJECTIVE: The pharmacokinetics of the long-acting beta2-agonist formoterol fumarate, which is a racemate of the (S,S)- and (R,R)-enantiomers were evaluated in 12 healthy (eight male, four female) volunteers after a single inhaled high dose of 120 microg of formoterol fumarate. The tolerability and safety were also assessed. METHODS: Each volunteer inhaled the single 120-microg dose through the Aerolizer device within 2-5 min, using ten 12-microg dry powder capsules for inhalation. Formoterol, i.e., the sum of both enantiomers, was determined in plasma over 24 h, whereas the separate enantiomers were determined in urine over 48 h. Incidence, seriousness and severity of adverse experiences, electrocardiogram (ECG), including the corrected QT interval (QTc) calculation, systolic blood pressure, heart rate, and plasma potassium levels were recorded. RESULTS: In nine of the 12 volunteers, the peak plasma concentration of formoterol was observed already at 5 min after inhalation. The absorption kinetics were complex, as depicted by multiple peaks or shoulders within 0.5-6 h after inhalation. Mean with (SD; n = 12) of maximum concentration (Cmax) and area under the curve (AUC) of formoterol in plasma were 266 (108) pmol x l(-1) and 1330 (398) pmol x l(-1), respectively. The moderate inter-individual variability in systemic exposure of formoterol reflects the homogeneous pharmacokinetics of the drug. A predominant slow elimination of formoterol from plasma with a mean half-life (t1/2) of 10 h was demonstrated. Assuming linear kinetics in plasma suggested by urinary data, the steady-state trough plasma levels of formoterol for a b.i.d. dosing regimen are predicted to amount to 20% of Cmax. In urine, mean with (SD; n = 10) of the amount excreted over 48 h was 3.61 (0.89)% of dose for the pharmacologically active (R,R)-enantiomer and 4.80 (1.33)% of dose for the (S,S)-enantiomer. The terminal half-lives calculated from the excretion rate-time curves, i.e., 13.9 h and 12.3 h for the (R,R)- and (S,S)-enantiomer, respectively, confirm the slow elimination of formoterol from plasma. The dose inhaled was 10 times the most frequently recommended dose (12 microg) and 5 times the highest recommended dose (24 microg). Ten of 12 subjects experienced mild and transient nervousness. Pulse readings demonstrated the maximum mean increase of 25.8 beats x min(-1) at 6 h. The mean maximum QTc increase was 25 msec at 6 h. Pulse and QTc values returned to baseline or close to baseline values at 24 h or before. Potassium levels in plasma decreased in eight out of 12 subjects; the lowest mean value was 3.53 mmol x l(-1) at 2 h post-dose. The lowest individual potassium measurement was 2.95 mmol x l(-1) between 15 min and 6 h. By 8 h post-dose all values had returned to within the normal ranges. CONCLUSIONS: The extremely fast appearance of formoterol in plasma shows the predominance of airways absorption shortly after inhalation. Due to a terminal elimination half-life of about 10 h, sustained systemic concentrations of formoterol are predicted for a twice daily treatment regimen without noteworthy accumulation. The excreted amounts in percent of dose of the enantiomers in urine and the enantiomer ratio are similar to data reported previously after lower doses and suggest linear kinetics for doses between 12 microg and 120 microg of formoterol fumarate. The expected side effects on heart rate, QTc interval, and plasma potassium were small and had no clinical consequences in spite of the very high dose of 120 microg (5 to 10 times the recommended therapeutic dose of Foradil). It should be noted that the impact of high doses may be greater in patients. Nevertheless these findings provide reassurance on the safety margin of formoterol after accidental and intentional overdosing.

Administration, Inhalation↗
PubMed2003

Lactic acid production by Rhizopus oryzae transformants with modified lactate dehydrogenase activity.

Rhizopus oryzae is capable of producing high levels of lactic acid by the fermentation of glucose. Yields typically vary over 60-80%, with the remaining glucose diverted primarily into ethanol fermentation. The goal of this work was to increase lactate dehydrogenase (LDH) activity, so lactic acid fermentation could more effectively compete for available pyruvate. Three different constructs, pLdhA71X, pLdhA48XI, and pLdhA89VII, containing various lengths of the ldhA gene fragment, were transformed into R. oryzae. This fungus rarely integrates DNA used for transformation, but instead relies on extra-chromosomal replication in a high-copy number. Plasmid pLdhA48XI was linearized prior to transformation in order to facilitate integration into the pyrG gene used for selection. Isolates transformed with ldhA containing plasmid were compared with both the wild-type parent strain and the auxotrophic recipient strain containing vector only. All isolates transformed with pLdhA71X or pLdhA48XI had multiple copies of the ldhA gene that resulted in ldhA transcript accumulation, LDH specific activity, and lactic acid production higher than the controls. Integration of plasmid pLdhA48XI increased the stability of the strain, but did not seem to offer any benefit for increasing lactic acid production. Since lactic acid fermentation competes with ethanol and fumaric acid production, it was not unexpected that increased lactic acid production was always concomitant with decreased ethanol and fumaric acid. Plasmid pLdhA71X, containing a large ldhA fragment (6.1 kb), routinely yielded higher levels of lactic acid than the smaller region (3.3 kb) used to construct plasmid pLdhA48XI. The greatest levels of ldhA transcript and enzyme production occurred with isolates transformed with plasmid pLdhA89VII. However, these transformants always produced less lactic acid and higher amounts of ethanol, fumaric, and glycerol compared with the control.

Cloning, Molecular↗
PubMed1997

Influence of monomethylfumarate on monocytic cytokine formation--explanation for adverse and therapeutic effects in psoriasis?

Although the effectiveness of systemic antipsoriatic treatment with fumaric acid esters has been proven, their mode of action is still not understood. Recent results indicate their potency in inducing cytokine production in stimulated T cells. Since monocytes and their cytokines are also considered to be of pathogenic importance in psoriasis, we investigated the effect of monomethylfumarate (MMF) on proinflammatory (TNF-alpha, IL-12) and antiinflammatory (IL-10, IL-1RA) cytokine production by peripheral blood mononuclear cells (PBMC) and separated monocytes. In 24-h PBMC cultures from both psoriatic patients (n = 6-13) and healthy volunteers (n = 7-9), MMF at 100 microM induced secretion of TNF-alpha, IL-10, and IL-1RA. Kinetics of IL-10 protein and mRNA expression indicated de novo production. Moreover, MMF significantly augmented endotoxin-induced synthesis of TNF-alpha, IL-10 and IL-1RA. In contrast, no influence on IL-12 secretion was found. Similar effects of MMF in purified monocytes indicated these cells to be responsible for aberrant cytokine formation. Furthermore, enhanced expression of costimulatory molecules after MMF stimulation confirmed monocyte activation. Multiple restimulation with fumaric acid esters in vitro, however, and immunomonitoring in a patient during Fumaderm initial therapy suggested that initial monocyte activation is followed by subsequent deactivation associated with an antiinflammatory response. Our results may explain the well-known effects of therapy with fumaric acid esters. Thus, initial treatment is often accompanied by adverse effects which may be caused by MMF-induced TNF-alpha formation. The change in the IL-10/IL-12 balance as a result of elective induction of IL-10, however, may have antipsoriatic activity by diminishing type-1/proinflammatory cytokine over-expression and the antigen-presenting capacity of monocytes/macrophages, and by upregulation of IL-1RA.

Cells, Cultured↗
PubMed1992

Purification, characterization and preliminary X-ray study of fumarase from Saccharomyces cerevisiae.

Fumarase (fumarate hydratase, EC 4.2.1.2) from Saccharomyces cerevisiae has been purified to homogeneity by a method including acetone fractionation, DEAE ion-exchange and dye-sorbent affinity chromatography. The suggested method allows fumarase purification with a yield higher than 60% and may be used to obtain large enzyme quantities. The native protein consists of four subunits with a approximately 50 kDa molecular mass each and has an isoelectric point at pH 6.5 +/- 0.3. The equilibrium constant for fumarate hydration is about 4.3 (25 degrees C, pH 7.5), the Michaelis constants for fumarate and 1-malate are approximately 30 microM and approximately 250 microM, respectively. The enzyme is activated by substrates and multivalent anions, the activation seems to be of a non-competitive type. The fumarase complex with meso-tartaric acid has been crystallized by the vapor diffusion method. The unit cell parameters are a = 93.30, b = 94.05 and c = 106.07 A, space group P2(1)2(1)2(1). The unit cell contains 2 protein molecules. The crystals diffract to at least 2.6 A resolution and are suitable for X-ray structure analysis.

Chemical Fractionation↗
PubMed1984

Succinate dehydrogenase in various tissues of Anodonta couperiana, Elliptio buckleyi and Mercenaria campechiensis (Mollusca: Bivalvia).

The specific activities, kinetic constants and pH optima for succinate dehydrogenase were determined in mantle, gill and adductor muscle from three bivalves (Anodonta couperiana, Elliptio buckleyi and Mercenaria campechiensis). In general the Km values for succinate and Ki values for fumarate differed in all bivalve tissues whereas the Ki for malonate was consistently low. The ratio of Ki (fumarate) to Km (succinate) was less than one for all tissues studied. This is similar to many facultative anaerobes with fumarate reductase activity.

Animals↗
PubMed2005

Influence of micro-environmental pH on the gel layer behavior and release of a basic drug from various hydrophilic matrices.

The purpose of this investigation is to understand the influence of gastrointestinal (GI) pH on the gel layer formation and its dynamics for various hydrophilic/swellable matrices, in the process of developing a pH-independent controlled release system for a basic drug, oxybutynin hydrochloride (OXB). Cylindrical matrices (8-mm diameter) without and with fumaric acid, were readily prepared by direct compression. Formulations were evaluated for in vitro drug release, and gel layer dynamics was studied by viscosity measurements and texture profiling analysis. In the in vitro drug release study, OXB, which shows pH-dependent solubility, showed faster release from all the matrices in pH 1.2 medium. Release rates enhanced to a lesser extent with change of medium from pH 6.8 to pH 1.2, for HPMC polymer matrices. Anionic polymer matrices showed drastic differences in the release rates when medium was changed from pH 6.8 to pH 1.2. Addition of fumaric acid to matrices demonstrated pH-independent drug release, which was attributed to the micro-environmental pH manipulation within the hydrated gel layer. Viscosity and texture profiling studies revealed that saturation solubility of drug at swelling front play a major role in the pH-dependent drug release from HPMC matrices, while both saturation solubility and the altered gel consistency as a function of pH are involved with anionic polymer matrices. Presence of fumaric acid in HPMC matrices showed efficient retardation and pH-independent drug release. In conclusion, understanding the influence of GI physiological pH on the gel layer dynamics and manipulating the micro-environmental pH provides efficient and predictable in vivo performance from these swellable cylindrical matrices.

Drug Carriers↗
PubMed2006

Microenvironmental pH and microviscosity inside pH-controlled matrix tablets: an EPR imaging study.

Incorporation of pH modifiers is a commonly used strategy to enhance the dissolution rate of weakly basic drugs from sustained release solid dosage forms. Electron paramagnetic resonance imaging (EPRI) was applied to spatially monitor pH(M) and the rotational correlation time (tau(R)), a parameter which is closely related to the surrounding microviscosity inside HPMC (hydroxypropylmethylcellulose) matrix tablets. Fumaric, citric, and succinic acid were employed as pH modifiers. 4-(methylamino)-2-ethyl-5,5-dimethyl-4-pyridine-2-yl-2,5-dihydro-1H-imidazole-1-oxyl (MEP) was used as spin label. Fumaric and citric acid reduced the pH(M) to equal extents in the initial phase. With the progress of hydration, the more soluble citric acid diffused out from the tablet resulting in an increase in pH(M), originating at the outer layers. In contrast, fumaric acid maintained a constantly reduced pH(M) inside the entire tablet. Due to its lower acidic strength, succinic acid did not reduce the pH(M) as effectively as the other pH modifiers used. The more water-soluble acids stimulated the water penetration into the matrix system, thereby rapidly decreasing tau(R). Once the matrix tablets were hydrated, the included pH modifiers influenced tau(R) insignificantly. EPRI, a novel approach for monitoring pH(M) and tau(R) non-invasively and spatially resolved, was used successfully for the optimization of an pH-controlled formulation.

Chemistry, Pharmaceutical↗
PubMed2002

Succinate:quinone oxidoreductases from epsilon-proteobacteria.

The epsilon-proteobacteria form a subdivision of the Proteobacteria including the genera Wolinella, Campylobacter, Helicobacter, Sulfurospirillum, Arcobacter and Dehalospirillum. The majority of these bacteria are oxidase-positive microaerophiles indicating an electron transport chain with molecular oxygen as terminal electron acceptor. However, numerous members of the epsilon-proteobacteria also grow in the absence of oxygen. The common presence of menaquinone and fumarate reduction activity suggests anaerobic fumarate respiration which was demonstrated for the rumen bacterium Wolinella succinogenes as well as for Sulfurospirillum deleyianum, Campylobacter fetus, Campylobacter rectus and Dehalospirillum multivorans. To date, complete genome sequences of Helicobacter pylori and Campylobacter jejuni are available. These bacteria and W. succinogenes contain the genes frdC, A and B encoding highly similar heterotrimeric enzyme complexes belonging to the family of succinate:quinone oxidoreductases. The crystal structure of the W. succinogenes quinol:fumarate reductase complex (FrdCAB) was solved recently, thus providing a model of succinate:quinone oxidoreductases from epsilon-proteobacteria. Succinate:quinone oxidoreductases are being discussed as possible therapeutic targets in the treatment of several pathogenic epsilon-proteobacteria.

Citric Acid Cycle↗
PubMed2002

Rotenone-insensitive NADH dehydrogenase is a potential source of superoxide in procyclic Trypanosoma brucei mitochondria.

The rotenone-insensitive NADH dehydrogenase isolated from mitochondria of the procyclic form of Trypanosoma brucei has the ability to produce superoxide anions (Biochemistry 41 (2002) 3065). Superoxide production by the purified enzyme was 60% inhibited by diphenyl iodonium (DPI), stimulated significantly by ubiquinone analogues, and unaffected by metal ions. Production of reactive oxygen species (ROS) in intact cells was not affected by addition of rotenone with proline and malate as substrates; however, addition of rotenone inhibited 41% ROS production with succinate as substrate. These results suggest that complex I is not involved in production of ROS and that succinate-linked reversed electron transport occurs in trypanosome mitochondria. Superoxide formation in mitochondria with NADH as substrate was stimulated by antimycin A but was unaffected by myxothiazol plus stigmatellin, indicating that bc(1) complex is not a source of superoxide. DPI and fumarate inhibited by 68 and 36%, respectively, the rate of superoxide production with NADH as substrate. Addition of both fumarate and DPI blocked 70% superoxide production in mitochondria, a total inhibition similar to that observed with DPI addition alone. These results suggest that the rotenone-insensitive NADH dehydrogenase in addition to NADH fumarate reductase is a potential source of superoxide production in procyclic trypanosome mitochondria.

Animals↗
PubMedDate not supplied

Chromate reduction in Shewanella oneidensis MR-1 is an inducible process associated with anaerobic growth.

Cr(VI) reduction was observed during tests with Shewanella oneidensis MR-1 (previously named S. putrefaciens MR-1) while being grown with nitrate or fumarate as electron acceptor and lactate as electron donor. From the onset of anoxic growth on fumarate, we measured a gradual and progressive increase in the specific Cr(VI) reduction rate with incubation time until a maximum was reached at late exponential/early stationary phase. Under denitrifying conditions, the specific Cr(VI) reduction rate was inhibited by nitrite, which is produced during nitrate reduction. However, once nitrite was consumed, the specific reduction rate increased until a maximum was reached, again during the late exponential/early stationary phase. Thus, under both fumarate- and nitrate-reducing conditions, an increase in the specific Cr(VI) reduction rate was observed as the microorganisms transition from oxic to anoxic growth conditions, presumably as a result of induction of enzyme systems capable of reducing Cr(VI). Although Cr(VI) reduction has been studied in MR-1 and in other facultative bacteria under both oxic and anoxic conditions, a transition in specific reduction rates based on physiological conditions during growth is a novel finding. Such physiological responses provide information required for optimizing the operation of in situ systems for remediating groundwater contaminated with heavy metals and radionuclides, especially those that are characterized by temporal variations in oxygen content. Moreover, such information may point the way to a better understanding of the cellular processes used by soil bacteria to accomplish Cr(VI) reduction.

Anaerobiosis↗
PubMed2002

Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.

Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43 (refs 4-6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor.

Alleles↗
PubMed1969

Regulation of gluconeogenesis and lipogenesis. The regulation of mitochondrial pyruvate metabolism in guinea-pig liver synthesizing precursors for gluconeogenesis.

1. The carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase in guinea-pig liver mitochondria was determined by measuring the amount of (14)C from H(14)CO(3) (-) fixed into organic acids in the presence of pyruvate, ATP, Mg(2+) and P(i). The main products of pyruvate carboxylation were malate, fumarate and citrate. Pyruvate utilization, metabolite formation and incorporation of (14)C from H(14)CO(3) (-) into these metabolites in the presence and the absence of ATP were examined. The synthesis of phosphoenolpyruvate from pyruvate and bicarbonate is minimal during continued oxidation of pyruvate. Larger amounts of phosphoenolpyruvate are formed from alpha-oxoglutarate than from pyruvate. Addition of glutamate, alpha-oxoglutarate or fumarate did not appreciably increase formation of phosphoenolpyruvate when pyruvate was used as substrate. With alpha-oxoglutarate as substrate addition of fumarate resulted in increased formation of phosphoenolpyruvate, whereas addition of succinate inhibited phosphoenolpyruvate formation. In the presence of added oxaloacetate guinea-pig liver mitochondria synthesized phosphoenolpyruvate in amount sufficiently high to play an appreciable role in gluconeogenesis. 2. Addition of fatty acids of increasing carbon chain length caused a strong inhibition of pyruvate oxidation and phosphoenolpyruvate formation, and greatly promoted carbon dioxide fixation and malate, citrate and acetoacetate accumulation. The incorporation of (14)C from H(14)CO(3) (-), [1-(14)C]pyruvate and [2-(14)C]pyruvate into organic acids formed was examined. 3. It is concluded that guinea-pig liver pyruvate carboxylase contributes significantly to gluconeogenesis and that fatty acids and metabolites play an important role in its regulation.

Adenosine Triphosphate↗