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PubMed1975

The role of protein and lipids in stabilizing the activity of bovine heart succinate dehydrogenase.

When incubated in an air atmosphere, solubilized succinate dehydrogenase (succinate:(acceptor) oxidoreductase, EC 1.3.99.1) quickly loses the capability to recombine with membrane components to catalyze mitochondrial related electron transport activities. At 0 degrees the loss in reconstitution capability is a first-order process; the half-life of the enzyme is 1.6 hr at this temperature. The enzyme is stabilized by recombining it with submitochondrial particles or with a cytochrome b preparation-phospholipid mixture. The presence of the cytochrome b preparation in the succinate dehydrogenase-cytochrome b-phospholipid complex is obligatory, indicating that protein-protein interactions between succinate dehydrogenase and other membrane components are important in stabilizing the capability of the flavoprotein to transfer electrons to other respiratory components. Treatment of this complex with phospholipase C results in loss of most of the succinate-dichlorophenolindophenol reductase activity and almost complete hydrolysis of phospholipid. Succinate dehydrogenase maintains its capability to participate in mitochondrial electron transport for several hours if the phospholipase treated complex is reconstituted with lysolecithin at the time of assay. Phospholipids are therefore not required for the stabilization process, but rather for formation of an active reductase complex. A lipophilic environment, if required for stabilization, can be provided by diglycerides. Diglycerides also can provide an environment conducive to electron transfer from succinate to ubiquinone but do so less efficiently than intact phospholipids.

Animals↗

PubMed1977

3-Nitropropionate, the toxic substance of Indigofera, is a suicide inactivator of succinate dehydrogenase.

We have shown that 3-nitropropionate, an isoelectronic analogue of succinate, is a suicide inactivator of succinate dehydrogenase [succinate:(acceptor) oxidoreductase, EC 1.3.99.1] as follows. (i) When rat liver mitochondria oxidize succinate in the presence of 3-nitropropionate carbanion, the rate of O(2) consumption decreases exponentially to a zero value. This pattern is duplicated by subsequent additions of mitochondria. The dependence of the apparent first-order rate constant for enzyme inhibition, as well as the number of enzyme turnovers completed before inhibition, on the concentrations of 3-nitropropionate carbanion and succinate are those expected for an active site-directed and irreversible inhibitor. (ii) The inactivated enzyme is not resuscitated by centrifugation and washing of the mitochondria, in contrast to malonate-treated enzyme, and malonate protects against irreversible, inhibition. (iii) The inhibitor species is 3-nitropropionate carbanion and no external nucleophile is required for inhibition. (iv) The respiratory rates, respiratory control ratios, and ADP/O ratios obtained with NAD-linked substrates are unaffected by 3-nitropropionate carbanion. These results show that 3-nitropropionate carbanion is a highly specific, time-dependent, and irreversible inhibitor of succinate dehydrogenase. By analogy with the reaction of nitroethane with D-amino acid oxidase, the data are consistent with the hypothesis that the carbanionic inhibitor forms a covalent N-5 adduct with the active site flavin. However, the precise mechanism of inactivation, as well as mechanistic extrapolations to the oxidation of succinate, must await the elucidation of the structure of the modified enzyme. We can now explain the toxicity of plants such as Indigofera endecaphylla for mammals and fowl as being due to the irreversible blockage of the Krebs cycle by 3-nitropropionate carbanion.

Animals↗

PubMed1977

Rhodanese-Mediated sulfur transfer to succinate dehydrogenase.

The interaction of the sulfurtransferase rhodanese (EC 2.8.1.1) with succinate dehydrogenase (EC 1.3.99.1), yeast alcohol dehydrogenase (EC 1.1.1.1) and bovine serum albumin was studied. Succinate dehydrogenase incorporates the sulfane sulfur of [35S]rhodanese and, in the presence of unlabelled rhodanese, also incorporates that of [35S]thiosulfate. Rhodanese releases most of its transferable sulfur and is re-loaded in the presence of thiosulfate. Rhodanese undergoes similar modifications with yeast alcohol dehydrogenase but this latter does not bind 35S in amounts comparable to those incorporated in succinate dehydrogenase: nearly all the 35S released by [35S]rhodanese is with low-molecular-weight compounds. Bovine serum albumin also binds very little sulfur and [35S]rhodanese present in the reaction mixture does not discharge its radioactive sulfur nor does it take up sulfur from thiosulfate. Sulfur release from rhodanese appears to depend on the presence of - SH groups in the acceptor protein. Sulfur incorporated into succinate dehydrogenase was analytically determined as sulfide. A comparison of the optical spectra of succinate dehydrogenase preparations incubated with or without rhodanese indicates that there is an effect of the sulfurtransferase on the iron-sulfur absorption of the flavorprotein. The interaction of rhodanese with succinate dehydrogenase greatly decreases the catalytic activity of rhodanese with respect to thiocyanate formation. This is attributed to modifications in rhodanese associated with the reduction of sulfane sulfur to sulfide. Thiosulfate in part protects from this deactivation. The reconstitutive capacity of succinate dehydrogenase increased in parallel with sulfur incorporated in that enzyme following its interaction with rhodanese.

Alcohol Oxidoreductases↗

PubMed1976

Thermodynamic and EPR characteristics of two ferredoxin-type iron-sulfur centers in the succinate-ubiquinone reductase segment of the respiratory chain.

Two distinct ferredosin-type iron-sulfur centers (designated as Centers S-1 and S-2) are present in the soulble succinate dehydrogenase in approximately equivalent concentrations to that of bound flavin. Both Centers S-1 and S-2 exhibit electron paramagnetic resonance absorbance in the reduced state at the same magnetic field (gz = 2.03, gy = 1.93, and gx = 1.91) with similar line shape. Center S-2 is reducible only chemically with dithionite and remains oxidized under physiological conditions. Thus, its functional role is unknown; however, thermodynamic and EPR characterization of this iron-sulfur center has revealed important molecular events related to this dehydrogenase. The midpoint potentials of Centers S-1 and S-2 determined in the soluble succinate dehydrogenase preparations are -5 +/- 15 mV and -400 +/- 15 mV, respectively, while corresponding midpoint potentials determined in particulate preparations, such as succinate-cytochrome c reductase or succinate-ubiquinone reductase, are 0 +/- 15 mV and -260 +/- 15 mV. Reconstitution of soluble succinate dehydrogenase with the cytochrome b-c1 complex is accompanied by a reversion of the Center S-I midpoint from -400 +/- 15 mV to -250 +/- 15 mV with a concomitant restoration of antimycin A-sensitive succinate-cytochrome c reductase activity. There observations indicate that, during the reconstitution process, Center S-I is restored to its original molecular environment. In the reconstitutively active succinate dehydrogenase, the relaxation time of Center S-2 is much shorter than that of S-1, thus Center S-2 spectra are well discernible only below 20 K (at 1 milliwatt of power), while the resonance absorbance of Center S-1 is detectable at higher temperatures and readily saturates below 15 K. Over a wide temperature range the power saturation of Center S-1 resonance absorbance is relieved by Center S-2 in the paramagnetic state, and the Center S-2 central resonance absorbance is broadened by Center S-1 spins, due to a spin-spin interaction between these centers. These observations indicate an adjacent location of these centers in the enzyme molecule. In reconstitutively inactive enzymes, subtle modification of the enzyme structure appears to shift the temperature dependence of Center S-2 relaxation to the higher temperature. Thus the EPR signals of Center S-2 are also detectable at higher temperature. In this system a splitting of the central peak of the Center S-2 spectrum due to spin-spin interaction was observed at extremely low temperatures, while this was not observed in reconstitutively active enzymes or in paritculate preparations. This spin-spin interaction phenomena of inactive enzymes disappeared upon chemical reactivation with concomitant appearance of the reconstitutive activity. These observations provide a close correlation between the molecular integrity of the enzyme and its physiological function.

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↗

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↗

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↗

PubMed1976

Succinate accumulation in man during exercise.

It has been demonstrated in several diving vertebrates that succinate, a component of the Krebs cycle, accumulates in blood during breath-hold dives. The production of succinate is thought to result from amino acid catabolism. Our purpose was to determine whether succinate accumulation occurs in man during muscular activity requiring anaerobic energy contribution. Experiments using an endurance athlete included apneic work on an underwater ergometer and treadmill running to exhaustion. During 1 min breath-hold "dives" in cold water while exercising at a work rate equivalent to 62% of VO2max, venous succinate increased from 42 mumoles/l (M X 10(-6)) at rest to 125 M X 10(-6). The treadmill run elicited VO2max and increased succinate from a similar resting value to 93 M X 10(-6). Increases in alanine, lactate, and pyruvate were observed for both types of exercise. The findings confirm that succinate accumulation also occurs in man. It was suggested that amino acid catabolism may provide a source of anaerobic energy production in addition to glycolysis. However, the importance of the proposed energy pathway remains to be quantified.

Adult↗

PubMed1979

Characterization of a succinate dehydrogenase complex solubilized from the cytoplasmic membrane of Bacillus subtilis with the nonionic detergent Triton X-100.

A succinic dehydrogenase (SDH) complex has been purified from Triton X-100-solubilized membranes from Bacillus subtilis by precipitation with specific antibody. Radioactively labeled precipitated complex was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography of the gels. The complex contained equimolar amounts of three polypeptides with approximate molecular weights of 65,000, 28,000, and 19,000. Five succinic dehydrogenase-negative mutants, belonging to the citF group, contained the 65,000-dalton polypeptide in a soluble form in the cytoplasm. Each 65,000-dalton polypeptide had about one molecule of flavin bound. Another citF mutant, citF11, which lacks the 65,000-dalton polypeptide, contained a membrane-bound 28,000-dalton polypeptide. The wild-type succinic dehydrogenase complex contained cytochrome, probably a cytochrome b. The 19,000-dalton polypeptide is suggested to represent the apoprotein of this cytochrome. The 65,000-dalton and the 28,000-dalton polypeptides are thought to constitute succinic dehydrogenase and to correspond to the flavoprotein and the ironprotein, respectively, as described for succinic dehydrogenase isolated from beef heart mitochondria or Rhodospirillum rubrum chromatophores. The results presented suggest that in B. subtilis succinic dehydrogenase is attached to a cytochrome b in the membrane via the 28,000-dalton (ironprotein) polypeptide.

Bacillus subtilis↗

PubMed1976

Acetate kinase from Veillonella alcalescens. Regulation of enzyme activity by succinate and substrates.

Acetate kinase of Veillonella alcalescens has been shown to be highly regulated enzyme exhibiting two levels of control: the requirement for succinate as a heterotropic allosteric effector, and cooperative binding at the substrate level. Succinate addition was necessary for enzymatic activity in both the direction of acyl phosphate synthesis and that of ATP synthesis. Control at the substrate level was apparent in the cooperative binding (Hill coefficients of 2) of acetyl phosphate, ATP, and ADP. Typical Michaelis kinetic data were observed for succinate (Ka = 20 mM for acetyl phosphate synthesis, 0.4 mM for ATP synthesis), acetate, and propionate. The primary effect of succinate was to increase the apparent Vmax of the enzymatic reaction for the variable substrates, ATP, ADP, and acetyl phosphate. The results are interpreted as evidence that, as a heterotropic effector of the acetate kinase reaction, succinate may regulate levels of propionyl-CoA (produced from propionyl phosphate by action of phosphotransacetylase), a compound required for the conversion of succinate to propionate. Acetase kinase has been shown to be a probable dimeric protein composed of two subunits of molecular weight 44,000 each.

Acetates↗

PubMed1978

The indispensability of phospholipid and ubiquinone in mitochondrial electron transfer from succinate to cytochrome c.

The indispensability of phospholipid and ubiquinone (Q) in mitochondrial electron transfer was studied by depleting phospholipid and Q in succinate-cytochrome c reductase and then replenishing the depleted enzyme. More than 90% of phospholipid and Q was removed by repeated ammonium sulfate-cholate fractionation. The depleted succinate-cytochrome c reductase showed no enzymatic activity for succinate leads to c or QH2 leads to c and yet retained most of the succinate leads to Q activity. All enzymatic activity was restored upon the addition of Q and phospholipid. Restoration required the addition of Q prior to the addition of phospholipid. Reversing the addition sequence or addition of a mixture of phospholipid and Q resulted only in a small restoration of activities. The conditions for restoration are given in detail. Removal of phospholipid from succinate-cytochrome c reductase resulted in reduction of cytochrome c1 in the absence of exogenous electron donor. Replenishing the preparation with phospholipid brought about the reoxidation of cytochrome c1 in the absence of electron acceptor or oxygen.

Animals↗

PubMedDate not supplied

[Reaction ability and alkylation kinetics of sulfhydride groups of soluble succinate dehydrogenase].

Inhibition kinetics of succinate--an acceptor of oxidoreductase activity of soluble succinate dehydrogenase by N-ethylmaleimide is studied. The alkylation reaction is described by the kinetic equation of the first order, its stechiometric coefficient being 1. The binding of enzyme sulphhydride groups by p-chloromercuriumbenzoate blocks the enzyme alkylation and its inhibition by oxaloacetate. Succinate protects succinate dehydrogenase from the inhibitory effect of N-ethylmaleimide. The reaction of the enzyme with an alkylating agent in the presence of different substrate concentrations corresponds kinetically to the model, according to which a sulphhydride group acts in the active site of the enzyme. pKa of this group is 7.0 at 20degreesC. The dependency of the maximal substrate oxidation reaction rate and that of the enzyme alkylation rate on pH coinside at the pH range 5.8--7.8. The presence of anions in the alkylation medium decreases the reaction ability of the active site with respect to N-ethylmaleimide. A mechanism of the initial stage of succinate oxidation with the cooperation of the sulphhydride group of the enzyme active site is postulated.

Binding Sites↗

PubMed1975

Mechanism of the protective effect of succinic semialdehyde and its derivatives in hypoxia.

Preliminary injection of succinic semialdehyde into animals in experiments with hypoxia led to a lower concentration of free ammonia in their brain tissues than in control experiments in which the compound was not given. The enzyme system of the liver tissue catalyzes the oxidation of NAD-H-2 by succinic semialdeyde and its dervitives with a free adelhyde group.The conversion of succinic semialdeyde and its derivatives in the liver tissue leading to the formation of the oxidized form of NAD,which is deficient in hypoxia, and the prevention of accumulation of free ammonia in the brain tissue by preliminary administration of succinic semialdehyde are the possible mechanisms of the antihypoxic properties of succinic semialdehyde and its derivatives.

Aldehydes↗

PubMed1979

Purification of a reconstitutively active iron-sulfur protein (oxidation factor) from succinate . cytochrome c reductase complex of bovine heart mitochondria.

Oxidation factor, a protein required for electron transfer from succinate to cytochrome c in the mitochondrial respiratory chain, has been purified from isolated succinate . cytochrome c reductase complex. Purification of the protein has been followed by a reconstitution assay in which restoration of ubiquinol . cytochrome c reductase activity is proportional to the amount of oxidation factor added back to depleted reductase complex. The purified protein is a homogeneous polypeptide on acrylamide gel electrophoresis in sodium dodecyl sulfate and migrates with an apparent Mr = 24,500. Purified oxidation factor restores succinate . cytochrome c reductase and ubiquinol . cytochrome c reductase activities to depleted reductase complex. It is not required for succinate dehydrogenase nor for succinate . ubiquinone reductase activities of the reconstituted reductase complex. Oxidation factor co-electrophoreses with the iron-sulfur protein polypeptide of ubiquinol . cytochrome c reductase complex. The purified protein contains 56 nmol of nonheme iron and 36 nmol of acid-labile sulfide/mg of protein and possesses an EPR spectrum with the characteristic "g = 1.90" signal identical to that of the iron-sulfur protein of the cytochrome b . c1 complex. In addition, the optimal conditions for extraction of oxidation factor, including reduction with hydrosulfite and treatment of the b . c1 complex with antimycin, are identical to those which facilitate extraction of the iron-sulfur protein from the b . c1 complex. These results indicate that oxidation factor is a reconstitutively active form of the iron-sulfur protein of the cytochrome b . c1 complex first discovered by Rieske and co-workers (Rieske, J.S., Maclennan, D.H., and Coleman, R. (1964) Biochem. Biophys. Res. Commun. 15, 338-344) and thus demonstrate that this iron-sulfur protein is required for electron transfer from ubiquinol to cytochrome c in the mitochondrial respiratory chain.

Animals↗

PubMedDate not supplied

[Effect of benemycin and sodium succinate on metabolism of protons in mitochondria of guinea pig lung and liver tissues].

The data of studies on proton metabolism in mitochondria of the guinea pig lungs and liver with application of benemycin and sodium succinate show that benemycin does not affect the metabolism of protons in the lungs and liver mitochondria. Sodium succinate activates the release of protons from the lungs and liver mitochondria in state 4 according to Chance. When using sodium succinate for reducing the effect of benemycin on theorganism it is found that sodium succinate inhibits the utilization of protons of the lungs and liver mitochondria in state 3 according to Chance and activates this release in state 4, thus favouring an increase in their concentration in the extra-mitochondrial space. Sodium succinate increases survival rate of animals which were administered benemycin to.

Animals↗

PubMed1979

[Inhibition of succinate and NADH oxidases of submitochondrial particles by iron chelators and sulfhydryl reagents].

The inhibition of succinate- and NADH-oxidase activities of submitochondrial particles by 4,7-diphenyl-1,10-phenantroline was studied. The inhibition was shown to increase when the particles were pretreated with SH-reagents. The treatment of submitochondrial particles with ethanol in the presence of 1,10-phenantroline resulted in a complete inactivation of succinate oxidase and succinate: tetramethyl-n-phenyldiamine reductase; the succinate PMS reductase activity was only partially inhibited after such treatment. It is concluded that tetramethyl-n-phenyldiamine and phenazine metasulfate react with different sites of the succinate dehydrogenase complex. The changes in the properties of submitochondrial particles after ethanol--phenantroline treatment are apparently due to the effect of non-polar solvent rather than to the extraction of non-haem iron.

Animals↗

PubMed1976

Protection by GABA and succinic semialdehyde of seed germination and some enzymatic activities against high concentration of hydroxylamine.

Hydroxylamine was found to stimulate germination of Lupinus albus at concentrations inferior to 10 mM and to inhibit it greatly at 20 mM concentration. This inhibition was partially restored by GABA or succinic semialdehyde. Hydroxylamine, at high concentrations, behaved as inhibitor in vivo on GABA 2-oxyglutarate amino-transferase and succinic semialdehyde dehydrogenase NAD-dependent, whereas it behaved as activator on succinic semialdehyde dehydrogenase NADP-dependent. No effects were observed on the enzymatic activities and the inhibited germination was partially restored, after GABA and succinic semialdehyde had been added to a growth medium with a 20 mM hydroxylamine concentration. A possible protection mechanism of GABA and succinic semialdehyde against hydroxylamine action is discussed.

Aminobutyrates↗

PubMed1977

Inability of methylprednisolone sodium succinate to decrease infarct size or preserve enzyme activity measured 24 hours after coronary occlusion in the dog.

Methylprednisolone sodium succinate (50 mg/kg) was given 30 minutes before or after the start of a 90 minute occlusion of the left circumflex coronary artery (LCX) in one group of dogs. In a second group, methylprednisolone sodium succinate was given 15 minutes after permanent occlusion of the left anterior descending artery (LAD). Infarct size was determined by dehydrogenase staining after 24 or 96 hours. Heart slices were incubated with nitro-blue tetrazolium and nonstaining infarcted tissue was dissected and weighed. Myocardial depletion of creatine phosphokinase activity (CPK) and lactate dehydrogenase activity (LDH) were determined 24 hours after temporary LCX occlusion. When measured after 24 hours, methylprednisolone sodium succinate treatment did not reduce infarct size or decrease enzyme loss. After temporary LCX occlusion infarct size was 30.4 +/- 3.6% of left ventricular weight in control dogs and 30.0 +/- 2.3% in treated dogs. No significant difference in infarct size was observed in hearts examined 24 or 96 hours after myocardial infarction. After permanent LAD occlusion, infarct size in control dogs was 39.2 +/- 1.6% of left ventricular weight and 33.7 +/- 3.5% in treated dogs. CPK activity in the LCX area decreased by 26.5 +/- 7% in controls and by 28.1% +/- 7% in treated dogs. Treated dogs sustained a significantly greater fall in arterial blood pressure after LCX occlusion than did controls. During LCX occlusion and upon reperfusion, methylprednisolone sodium succinate treated dogs exhibited a significantly greater number of premature ventricular beats. Since infarct size and enzyme depletion were not reduced when measured after 24 hours, methylprednisolone sodium succinate treatment does not appear to have enhanced myocardial cell viability.

Animals↗