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PubMed1985

Properties of succinic semialdehyde dehydrogenase in cultured human lymphoblasts.

A direct assay has been developed for succinic semialdehyde dehydrogenase in sonicates of human lymphocytes and Epstein-Barr Virus transformed cultured lymphoblasts. Enzyme activity was quantified by incubating cell extracts with uniformly labeled [14C]succinic semialdehyde and monitoring the conversion to [14C]succinic acid. Radiolabeled products were separated by liquid partition chromatography on hydrated silicic acid. Kinetic properties and requirements of succinic semialdehyde dehydrogenase in lymphoblast sonicates were investigated in order to determine optimal conditions for the direct assay. Enzyme activity was stimulated by dithiothreitol, ammonium and potassium ions and 0.1% Triton X-100. The concentrations for half maximal activation by ammonium and potassium were 5.2 and 13.7 mM respectively. The mean activity of succinic semialdehyde dehydrogenase in assays in which equimolar NADP+ had been substituted for NAD+ was 19% of the activity of assays which contained NAD+. Substrate Michaelis constants were 21 and 30 microM for NAD+, and 26, 42 and 70 microM for succinic semialdehyde. The enzyme displayed a pH optimum between 8 and 9 and demonstrated a slight temperature activation between 37 degrees and 45 degrees C. A deficiency of succinic semialdehyde dehydrogenase activity was documented in cultured lymphoblasts derived from a patient with gamma-hydroxybutyric aciduria.

Cell-Free System↗
PubMedDate not supplied

[Activation of succinate oxidase in the inner membrane of rat liver mitochondria].

It is shown that the process of activation of succinate oxidase from inner membranes of the rat liver mitochondria by succinate and malonate is specific for the succinate dehydrogenase component of oxidase. These activation constants are comparable with those found by other authors in activation of succinate dehydrogenase and succinate oxidase from oxaloacetate-preincubated submitochondrial fragments of the bull heart. Probably, the 4-fold activation of succinate oxidase from inner membranes of the liver mitochondria reported in this paper depends on separation of endogenous oxaloacetate from the succinate dehydrogenase component of oxidase.

Animals↗
PubMed1996

[Inhibitory effect of vitamin E succinate on the proliferation of cultured bovine choroidal endothelial cells].

We report the effect of vitamin E succinate (VE succinate) on the proliferation of cultured bovine choroidal endothelial cells (BCECs). BCECs were incubated with a medium containing vitamin E (VE) or one of the VE derivatives gamma-tocopherol, VE phosphate, VE succinate, VE nicotinate, VE acetate, or trolox, at a concentration of 10 microM. The proliferation of BCECs was assessed by 3H-thymidine uptake and cell counting. Especially in VE and VE succinate, the proliferation assay was performed on BCECs at two different stages, that is, the proliferating stage and the quiescent stage. The effect of protein kinase C (PKC) stimulator phorbol ester (PMA) on the VE succinate-induced inhibition of BCEC proliferation was also examined. VE succinate was found to significantly inhibit BCEC proliferation at a concentration of 10 microM or greater both by 3H-thymidine uptake assay and by cell counting. This inhibitory effect was not noted in other VE derivatives. The inhibitory effect was the most prominent in the proliferating BCECs and co culture of PMA. VE succinate inhibits the proliferation of cultured BCECs and PKC is involved in this action at least in part.

Animals↗
PubMed1995

Metabolism of succinic acid methyl esters in neural cells.

The metabolism and metabolic effects of succinic acid methyl esters were examined in both NG108-15 mouse neuroblastoma x rat glioma hybrid cells and normal rat brain cells. The conversion of the dimethyl ester of 14C-labeled succinic acid (10 mM) to 14CO2 only represented 5% or less of that found at an equimolar concentration of D-[U- 14C]glucose. Neither the monomethyl nor the dimethyl ester of succinic acid exerted any significant effect upon the metabolism of D-glucose. Likewise, D-glucose (10 mM) failed to significantly affect the oxidation of the dimethyl ester of either [1,4- 14C]succinic acid or [2,3- 14C]succinic acid. It is concluded that, at variance with the situation recently documented in rat pancreatic islets and hepatocytes, the methyl esters of succinic acid are poorly metabolized in neural cells.

Animals↗
PubMed1978

Stimulation of growth and glucose catabolite enzymes by succinate in some thermophilic fungi.

Thermophilic Humicola lanuginosa, Penicillium duponti, Sporotrichum thermophile and Mucor pusillus required succinate in addition to glucose for optimal growth. The requirement for succinate was concentration-dependent and the concentration needed for one half of the maximal growth was 6.14mM. In the presence of succinate, glucose utilization from the medium was markedly increased and this was associated with increased levels of the enzymes of the glycolytic and Krebs cycle pathways. Addition of succinate to cultures growing in glucose at any stage of growth stimulated the growth with the resulting rate of growth remaining high if the addition was made within 3 days of inoculation. Cycloheximide (71.4 micrometer) prevented the succinate-mediated derepression of the enzymes suggesting that succinate may remove the catabolite repression in the presence of glucose.

Cycloheximide↗
PubMed1997

Mucosal blood flow and generation of superoxide in rat experimental colitis induced by succinic acid.

As we consider succinic acid to be an exacerbating factor in ulcerative colitis, we investigated its influence on rat colonic mucosa in terms of mucosal blood flow and superoxide generation. We measured mucosal blood flow by the hydrogen gas clearance method and superoxide generation by the chemiluminescence method, and observed histopathological findings to determine the effects of succinic acid. After the instillation of succinic acid of any concentration tested to the colon, mucosal blood flow decreased. Histopathologically, the higher the concentration of succinic acid, the greater was the erosion formation in the colonic mucosa, while significant polymorpho-nuclear cell infiltration superoxide generation from colon tissue were observed with 0.01% succinic acid compared with higher or lower concentrations. Succinic acid, at fecal concentrations found in active stage ulcerative colitis, appears to be implicated in mucosal injury, mediated by a decrease in colonic mucosal blood flow and infiltration of superoxide-generating polymorpho-nuclear cells into the mucosa.

Animals↗
PubMed1989

Succinate-dependent energy generation in Ascaris suum mitochondria.

Phosphorylation in isolated Ascaris suum mitochondria was much greater in the presence of malate than succinate, but, in the absence of added adenine nucleotides, incubations in succinate resulted in substantial elevations in intramitochondrial ATP levels. Succinate-dependent phosphorylation was stimulated aerobically and this stimulation was due almost entirely to a site I, rotenone-sensitive, phosphorylation. Increased substrate level phosphorylation, coupled to propionate formation, or additional sites of electron-transport associated ATP synthesis were not significant. Under aerobic conditions, 14CO2 evolution from 1,4-[14C]succinate was stimulated and NADH/NAD+ ratios were elevated, but the formation of [14C]propionate was unchanged. It appears that succinate was metabolized to pyruvate and acetate, and NADH, generated from the decarboxylations of malate and pyruvate, was the primary source of reducing power fueling electron-transport. The terminal oxidase and final electron-acceptor are still not clearly defined. However, ferricyanide, H2O2, and 100% oxygen all stimulated succinate-dependent phosphorylation. A possible role for cytochrome c peroxidase in A. suum mitochondrial metabolism is discussed.

Adenine Nucleotides↗
PubMed1992

Succinate-dependent metabolism in Trypanosoma cruzi epimastigotes.

Trypanosoma cruzi epimastigotes permeabilized with digitonin (65 micrograms (mg protein)-1) to measure mitochondrial respiration were exposed to different substrates. Although none of the NADH-dependent substrates stimulated respiration, succinate supported not only oxygen consumption but also oxidative phosphorylation (respiratory control ratio of 1.9 +/- 0.3) indicating that the mitochondria were coupled. The rate of NADH-dependent oxygen consumption by membrane fractions (9.4 +/- 0.7 nmol min-1 (mg protein)-1) was reduced by 50% upon addition of catalase indicating that the electrons from NADH oxidation reduced oxygen to H2O2. NADH-dependent H2O2 production (16 +/- 1 nmol min-1 (mg protein)-1) was confirmed using cytochrome c peroxidase. This activity was inhibited by fumarate by 70%, suggesting a competition between fumarate and oxygen for the electrons from NADH, probably at the fumarate reductase level. The respiratory chain inhibitor antimycin blocked both respiration by intact cells and succinate-dependent cytochrome c by isolated membranes. No inhibition by antimycin was observed when NADH replaced succinate as an electron donor, indicating that the electrons from NADH oxidation reduced cytochrome c through a different route. Malonate blocked not only succinate-cytochrome c reductase and fumarate reductase, but also intact cell motility. These results suggest that succinate has a central role in the intermediate metabolism of i. cruzi, as it may be used for respiration or excreted to the extracellular space under anaerobic conditions. In addition, 2 potential sources of H2O2 were tentatively identified as: (a) the enzyme fumarate reductase; and (b) a succinate-dependent site, which may be the semiquinone form of Coenzyme Q9, as in mammalian mitochondria.

Animals↗
PubMed1997

Schistosoma mansoni sporocysts contain rhodoquinone and produce succinate by fumarate reduction.

Although schistosomes were thought to be one of the few parasitic helminths that do not produce succinate via fumarate reduction, it was recently demonstrated that sporocysts of Schistosoma mansoni produce, under certain conditions, succinate in addition to lactate. This succinate production was only observed when the respiratory chain activity of the sporocysts was inhibited, which suggested that succinate is produced by fumarate reduction. In this report the presence of essential components for fumarate reduction was investigated in various stages of S. mansoni and it was shown that, in contrast to adults, sporocysts contained a substantial amount of rhodoquinone which is essential for efficient fumarate reduction in eukaryotes. This rhodoquinone was not made by modification of ubiquinone obtained from the host, but was synthesized de novo. Furthermore, it was shown that complex II of the electron-transport chain in schistosomes has the kinetic properties of a dedicated fumarate reductase instead of those of a succinate dehydrogenase. The presence of such an enzyme, together with the substantial amounts of rhodoquinone, shows that in S. mansoni sporocysts succinate is produced via fumarate reduction. Therefore, the energy metabolism of schistosomes does not differ in principle from most other parasitic helminths, which are known to rely heavily on fumarate reduction.

Animals↗
PubMed1971

Changes in the liver mitochondrial oxidation of succinate during cold-exposure.

1. Exposure of rats to low environmental temperature resulted in increased activities of several hepatic oxidative-enzyme systems. 2. Simultaneous with increase in liver ubiquinone in cold-exposed rats, the ubiquinone-dependent succinate-neotetrazolium chloride reductase activity also increased. Such an increase could also be obtained by enriching liver with ubiquinone by feeding with an exogenous source. 3. Succinate-neotetrazolium chloride reductase activity could be increased by preincubation of mitochondria with succinate and the mechanism of this activation appears to be different from that obtained on addition of ubiquinone. 4. Succinate-neotetrazolium chloride reductase activity was found to be more labile than succinate dehydrogenase on freezing and thawing and storage, and the presence of succinate gave protection against this loss in hepatic mitochondria obtained from both normal and cold-exposed animals.

Animals↗
PubMed1988

Sodium-gradient-driven, high-affinity, uphill transport of succinate in human placental brush-border membrane vesicles.

Brush-border membrane vesicles isolated from normal human term placentas were shown to accumulate succinate transiently against a concentration gradient, when an inward-directed Na+ gradient was imposed across the membrane. This uptake was almost totally due to transport into intravesicular space, non-specific binding to the membranes being negligible. The dependence of the initial uptake rate of succinate on Na+ concentration exhibited sigmoidal kinetics, indicating interaction of more than one Na+ ion with the carrier system. The Hill coefficient for this ion was calculated to be 2.7. The Na+-dependent uptake of succinate was electrogenic, resulting in the transfer of positive charge across the membrane. Kinetic analysis showed that succinate uptake in these vesicles occurred via a single transport system, with an apparent affinity constant of 4.8 +/- 0.2 microM and a maximal velocity of 274 +/- 4 pmol/20 s per mg of protein. Uptake of succinate was strongly inhibited by various C4 or C5 dicarboxylic acids, whereas monocarboxylic acids, amino acids and glucose showed little or no effect. Li+ and K+ could not substitute for Na+ in the uptake process. Instead, Li+ was found to have a significant inhibitory effect on the Na+-dependent uptake of succinate.

Biological Transport, Active↗
PubMed1991

Rumen succinate production may ameliorate the effects of cobalt-vitamin B-12 deficiency on methylmalonyl CoA mutase in sheep.

When lambs were fed a cobalt-deficient whole barley diet there was a rapid and massive increase in rumen succinate concentrations. Within 2 d of feeding the Co-deficient diet, the rumen succinate concentrations rose 200-fold and peaked at a level 1000-fold higher than that in Co-sufficient controls. Rumen propionate concentrations decreased, suggesting that an alteration in the balance between succinate- and propionate-producing microorganisms had occurred. The rumen succinate can be absorbed and thus may lead to elevated plasma succinate concentrations in Co-deficient animals, whether fed barley or grass. Thus, the absorbed succinate can at least partially overcome the effect on gluconeogenesis of a decreased activity of methylmalonyl CoA mutase induced by Co-deficiency. These findings suggest that impaired propionate metabolism may not be the primary metabolic defect in ovine Co-deficiency.

Absorption↗
PubMed1979

Selection of succinic dehydrogenase mutants of Neurospora crassa.

A method is described which permits the selection of mutants of Neurospora crassa that are deficient in succinic dehydrogenase activity. The method relies on the observation that succinic dehydrogenase-deficient strains fail to reduce the dye nitrotetrazolium blue when overlaid with the dye in the presence of succinate and phenazine methosulfate. Wild-type colonies reduced the dye and turned blue, whereas mutant colonies remained colorless. In this communication we present studies of a mutant, SDH-1, isolated by this method. The mutant had 18% of the succinic dehydrogenase activity of the parent strain used in the mutation experiments as determined from the ratio of Vmax activities obtained from Lineweaver-Burk plots. The SDH-1 mutant segregated in a Mendelian manner when back-crossed to its parent strain. Succinate oxidase activity in SDH-1 was low and was markedly inhibited by adenosine 5'-diphosphate. The succinate oxidase activity of the parent strain was high and was not affected by the presence of adenosine 5'-diphosphate.

Mutation↗
PubMed1992

Diauxic growth of Agrobacterium tumefaciens 15955 on succinate and mannopine.

Diauxic growth was observed upon incubation of Agrobacterium tumefaciens 15955 on a mixture of succinate and mannopine as the carbon source. Diauxic growth was also observed when either fumarate or L-malate was mixed with mannopine. No diauxie was detectable when A. tumefaciens 15955 was grown on a mixture of mannopine and glucose, fructose, sucrose, or L-arabinose. Preferential utilization of succinate was observed in the initial growth phase of diauxie, whereas the final growth phase occurred at the expense of mannopine. Cells harvested during the initial growth phase exhibited a capacity for uptake of [14C]succinate but not of [14C] mannopine. A capacity for [14C]mannopine uptake was expressed during the final growth phase. Extracts from cells grown on a mixture of succinate and mannopine exhibited a low level of mannopine cyclase activity in the initial phase of diauxie. This activity increased substantially in the final phase of growth. Added succinate had no effect on the rate of [14C]mannopine uptake or mannopine cyclase activities of cells previously grown on mannopine. Diauxie was also observed during growth of strain 15955 on a mixture of succinate and octopine.

Agrobacterium tumefaciens↗
PubMed2006

Genetic characterization of a single bifunctional enzyme for fumarate reduction and succinate oxidation in Geobacter sulfurreducens and engineering of fumarate reduction in Geobacter metallireducens.

The mechanism of fumarate reduction in Geobacter sulfurreducens was investigated. The genome contained genes encoding a heterotrimeric fumarate reductase, FrdCAB, with homology to the fumarate reductase of Wolinella succinogenes and the succinate dehydrogenase of Bacillus subtilis. Mutation of the putative catalytic subunit of the enzyme resulted in a strain that lacked fumarate reductase activity and was unable to grow with fumarate as the terminal electron acceptor. The mutant strain also lacked succinate dehydrogenase activity and did not grow with acetate as the electron donor and Fe(III) as the electron acceptor. The mutant strain could grow with acetate as the electron donor and Fe(III) as the electron acceptor if fumarate was provided to alleviate the need for succinate dehydrogenase activity in the tricarboxylic acid cycle. The growth rate of the mutant strain under these conditions was faster and the cell yields were higher than for wild type grown under conditions requiring succinate dehydrogenase activity, suggesting that the succinate dehydrogenase reaction consumes energy. An orthologous frdCAB operon was present in Geobacter metallireducens, which cannot grow with fumarate as the terminal electron acceptor. When a putative dicarboxylic acid transporter from G. sulfurreducens was expressed in G. metallireducens, growth with fumarate as the sole electron acceptor was possible. These results demonstrate that, unlike previously described organisms, G. sulfurreducens and possibly G. metallireducens use the same enzyme for both fumarate reduction and succinate oxidation in vivo.

Culture Media↗
PubMed1976

The accumulation of succinate by the yeast Brettanomyces bruxellensis.

The metabolism of Brettanomyces bruxellensis was investigated to determine the metabolic block responsible for the accumulation of acetate seen in cultures of this yeast. In glucose-grown cultures the major non-volatile intracellular organic acide was succinic acid. These cultures also had low levels of succinic dehydrogenase (succinate dehydrogenase, EC 1.3.99.1) and did not produce CO2 from the carbons of ethanol. It was concluded that a block in the oxidation of ethanol occurred at the level of succinic dehydrogenase. If glucose-grown cultures were transferred to ethanol medium, the block in the metabolism of ethanol was partially overcome; the level of succinic dehydrogenase increased, the concentration of the intracellular succinate decreased, and CO2 could be produced from C-1 of ethanol.

Acetates↗
PubMed1983

Sodium-dependent succinate transport in renal outer cortical brush border membrane vesicles.

The transport of succinate into outer cortical brush border membrane vesicles (early proximal tubule) was studied. Succinate is taken up into an osmotically active space and exhibits the same distribution volume and the same degree of nonspecific binding and trapping as D-glucose. Succinate uptake is markedly enhanced by sodium and slightly enhanced by lithium but shows no stimulation by other monovalent cations tested. Kinetic analysis of the sodium-dependent component of succinate flux indicates a single transport site obeying Michaelis-Menten kinetics (Km = 1 mM and Vmax = 50 nmol X min -1 X mg protein -1 as measured under zero trans conditions at 100 mM NaCl and 28 degrees C with delta psi = 0). Direct evidence is given that succinate transport is coupled to sodium and is rheogenic, involving the net transfer of positive charge. The sodium:succinate coupling stoichiometry is found to be 2:1 by two independent methods.

Animals↗
PubMedDate not supplied

[Correction by succinic acid of behavioral and physiological parameters of neurosis-like condition in white rats].

The neurosis-like state of white rats is accompanied by development of cerebral hypoxia. Negative symptoms of the neurosis-like state (behavioral, anatomic and energy) were decreased by per os administration of succinate (30 mg/kg) during the second half of the neurotization process. Succinate provided chiefly the delayed action on the system arterial tension, on the succinate dehydrogenase and NADH dehydrogenase activity. The effects depended on the propensity of a rat to the catatonic "freezing". The "freezing" was detected by a specific breathing pattern: a short inhale and a long pause. In "freezing" rats succinate corrected the system tension to a greater extent, while in "non-freezing" animals it corrected to a greater extent the succinate and NADH dehydrogenase activities. The positive effect of succinate administration is probably associated with its antihypoxic properties.

Animals↗