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PubMed1996

Succinate:quinone oxidoreductase (complex II) containing a single heme b in facultative alkaliphilic Bacillus sp. strain YN-2000.

Succinate:quinone oxidoreductase (EC 1.3.5.1) was first purified from the facultative alkaliphilic Bacillus sp. strain YN-2000 in the presence of Triton X-100. The isolated enzyme showed high succinate-ubiquinone oxidoreductase activity at pH 8.5. The Km for ubiquinone 1 and the Vmax of the enzyme were determined to be about 5 microM and 48 micromol of ubiquinone 1 per min per mg, respectively. The catalytic activity of the enzyme was 50% inhibited by 9 microM 2-thenoyltrifluoroacetone or 0.8 microM 2-n-heptyl-4-hydroxyquinoline- N-oxide. The enzyme consisted of three kinds of subunits with molecular masses of 66, 26, and 15 kDa, respectively, and contained 1.28 mol of covalently bound flavin adenine dinucleotide, 0.9 mol of heme b, 1.35 mol of menaquinone, 8.3 mol of nonheme iron, and 7.5 mol of inorganic sulfide per mol of enzyme. The enzyme showed symmetrical alpha absorption peaks at 556.5 and 554 nm in the reduced state at room temperature and 77 K, respectively. The potentiometric analysis of the enzyme yielded an Em,7 of heme b of about -64 mV (n = 1). Furthermore, the content of the enzyme was increased up to fivefold when the bacterium was grown at pH 10 compared with pH 7. These results indicate that the succinate:quinone oxidoreductase with a single heme b is involved in the respiratory chain of the alkaliphile at a very alkaline pH.

Bacillus↗
PubMed1997

A succinate dehydrogenase with novel structure and properties from the hyperthermophilic archaeon Sulfolobus acidocaldarius: genetic and biophysical characterization.

The sdh operon of Sulfolobus acidocaldarius DSM 639 is composed of four genes coding for the 63.1-kDa flavoprotein (SdhA), the 36.5-kDa iron-sulfur protein (SdhB), and the 32.1-kDa SdhC and 14.1-kDa SdhD subunits. The four structural genes of the sdhABCD operon are transcribed into one polycistronic mRNA of 4.2 kb, and the transcription start was determined by the primer extension method to correspond with the first base of the ATG start codon of the sdhA gene. The S. acidocaldarius SdhA and SdhB subunits show characteristic sequence similarities to the succinate dehydrogenases and fumarate reductases of other organisms, while the SdhC and SdhD subunits, thought to form the membrane-anchoring domain, lack typical transmembrane alpha-helical regions present in all other succinate:quinone reductases (SQRs) and quinol:ifumarate reductases (QFRs) so far examined. Moreover, the SdhC subunit reveals remarkable 30% sequence similarity to the heterodisulfide reductase B subunit of Methanobacterium thermoautotrophicum and Methanococcus jannaschii, containing all 10 conserved cysteine residues. Electron paramagnetic resonance (EPR) spectroscopic studies of the purified enzyme as well as of membranes revealed the presence of typical S1 [2Fe2S] and S2 [4Fe4S] clusters, congruent with the deduced amino acid sequences. In contrast, EPR signals for a typical S3 [3Fe4S] cluster were not detected. However, EPR data together with sequence information implicate the existence of a second [4Fe4S] cluster in S. acidocaldarius rather than a typical [3Fe4S] cluster. These results and the fact that the S. acidocaldarius succinate dehydrogenase complex reveals only poor activity with caldariella quinone clearly suggest a unique structure for the SQR of S. acidocaldarius, possibly involving an electron transport pathway from the enzyme complex into the respiratory chain different from those for known SQRs and QFRs.

Amino Acid Sequence↗
PubMed1998

atp Mutants of Escherichia coli fail to grow on succinate due to a transport deficiency.

Escherichia coli atp mutants, which lack a functional H+-ATPase complex, are capable of growth on glucose but not on succinate or other C4-dicarboxylates (Suc- phenotype). Suc+ revertants of an atp deletion strain were isolated which were capable of growth on succinate even though they lack the entire H+-ATPase complex. Complementation in trans with the yhiF gene suppressed the growth of the Suc+ mutants on succinate, which implicates the yhiF gene product in the regulation of C4-dicarboxylate metabolism. Indeed, when the E. coli C4-dicarboxylate transporter (encoded by the dctA gene) was expressed in trans, the Suc- phenotype of the atp deletion strain reverted to Suc+, which shows that the reason why the E. coli atp mutant is unable to grow aerobically on C4-dicarboxylates is insufficient transport capacity for these substrates.

Bacterial Proteins↗
PubMed1998

Anaerobic expression of Escherichia coli succinate dehydrogenase: functional replacement of fumarate reductase in the respiratory chain during anaerobic growth.

Succinate-ubiquinone oxidoreductase (SQR) from Escherichia coli is expressed maximally during aerobic growth, when it catalyzes the oxidation of succinate to fumarate in the tricarboxylic acid cycle and reduces ubiquinone in the membrane. The enzyme is similar in structure and function to fumarate reductase (menaquinol-fumarate oxidoreductase [QFR]), which participates in anaerobic respiration by E. coli. Fumarate reductase, which is proficient in succinate oxidation, is able to functionally replace SQR in aerobic respiration when conditions are used to allow the expression of the frdABCD operon aerobically. SQR has not previously been shown to be capable of supporting anaerobic growth of E. coli because expression of the enzyme complex is largely repressed by anaerobic conditions. In order to obtain expression of SQR anaerobically, plasmids which utilize the PFRD promoter of the frdABCD operon fused to the sdhCDAB genes to drive expression were constructed. It was found that, under anaerobic growth conditions where fumarate is utilized as the terminal electron acceptor, SQR would function to support anaerobic growth of E. coli. The levels of amplification of SQR and QFR were similar under anaerobic growth conditions. The catalytic properties of SQR isolated from anaerobically grown cells were measured and found to be identical to those of enzyme produced aerobically. The anaerobic expression of SQR gave a greater yield of enzyme complex than was found in the membrane from aerobically grown cells under the conditions tested. In addition, it was found that anaerobic expression of SQR could saturate the capacity of the membrane for incorporation of enzyme complex. As has been seen with the amplified QFR complex, E. coli accommodates the excess SQR produced by increasing the amount of membrane. The excess membrane was found in tubular structures that could be seen in thin-section electron micrographs.

Anaerobiosis↗
PubMed1989

Chemotaxis inhibition by Gardnerella vaginalis and succinate producing vaginal anaerobes: composition of vaginal discharge associated with G vaginalis.

The influence of six succinate producing vaginal anaerobes and Gardnerella vaginalis on the chemotactic activity of granulocytes was studied by the under agarose method. G vaginalis, Mobiluncus species, and three Gram negative anaerobes elicited hardly any response, but Peptostreptococcus productus showed clear positive chemotaxis, as did the Escherichia coli strain used as a control. Inhibition of the chemotactic response of white blood cells was found with all strains, but the high succinate producers from the genus Bacteroides showed the most pronounced effect. The inhibition of chemotaxis by succinate producing anaerobes in the pathogenesis of non-specific vaginitis (NSV) is postulated, and B ureolyticus or Mobiluncus spp, rather than G vaginalis, are suggested as possible causes of NSV.

Bacteria, Anaerobic↗
PubMed1976

Further studies on aspartate transcarbamoylase: molecular weight of the c3r6 complex and analysis of succinate inhibition in the native enzyme.

The complex which is formed when excess regulatory subunits (r2) of aspartate transcarbamoylase (EC2.1.3.2) are added to a dilute solution of the catalytic subunit (c3) has been studied by gel-filtration on Sephadex G-200. The elution volume indicates a Stokes' radius of between 5.42 and 5.92 nm, depending on the method of calculation. Using the sedimentation coefficient of 7.7S previously determined, the molecular weight is estimated to be close to 200 000, in support of the c3r6 structure proposed earlier for the complex. The calculated frictional coefficient indicates abnormal hydrodynamic properties which are probably due to unusual structure characteristics. The pattern of succinate inhibition of native aspartate transcarbamoylase has also been analyzed. At low concentrations, succinate activates the enzyme, presumably by converting it from the taut state to the relaxed (r) state. Further increase in the succinate concentration leads to competitive inhibition of the R state. Using a novel procedure for analysis of the data, the Michaelis constant for aspartate of the R state has been estimated to be about 7mM. This value is close to the Km of c3r6 for aspartate, measured under identical conditions. The result therefore provides further evidence suggesting that the c3r6 complex resembles the R state of the native enzyme.

Aspartate Carbamoyltransferase↗
PubMed2001

Identification of a system that allows a Rhizobium tropici dctA mutant to grow on succinate, but not on other C4-dicarboxylates.

A defined insertion mutant of a gene encoding a homolog of the rhizobial C4-dicarboxylate permease (dctA) was constructed in Rhizobium tropici strain CIAT899. This mutant (GA1) was unable to grow on fumarate or malate; however, in contrast with other rhizobial dctA mutants, it retained a limited ability to grow on succinate with ammonia as a nitrogen source. Our results suggest the presence of a novel succinate-specific transport system in R. tropici. Biochemical characterization indicated that this alternative transport system in GAI is active and dependent on an energized membrane. It was also induced by succinate and aspartate, and was repressed by glucose and glycerol. Bean plants inoculated with GA1 showed a reduced nitrogen-fixing ability, achieving only 29% of the acetylene reduction activity determined in CIAT899 strain nodules, 33 days after inoculation. Also, bean plants inoculated with GA1 had reduced shoot dry weight compared with plants inoculated with the wild-type strain.

Amino Acid Sequence↗
PubMed1992

Intrafibre distribution of succinate dehydrogenase in cat tibialis anterior motor units.

Using isolated ventral root filament stimulation and glycogen depletion techniques, 14 motor units from the cat tibialis anterior were studied. Based on their mechanical properties, the units were classified as either slow-fatigue resistant, fast-fatigue resistant, fast-fatigue intermediate, or fast-fatigable. Quantitative histochemical and computer assisted image analysis techniques were used to determine the activity of succinate dehydrogenase in a population of fibres in each unit. In addition, the intrafibre distribution of succinate dehydrogenase activity was measured in those same fibres by calculating the enzymatic activity of circumferential layers every 0.5 microns starting from the fibre edge to its centre. It was established that enzymatic activity and radial distance were linearly related in the fibres. A range in succinate dehydrogenase activity (mean coefficient of variation, 29%) was observed among the fibres of a unit. In contrast, the intrafibre distribution of that activity was rather consistent (mean variation, 4%) across the fibres of a unit. Further, the intrafibre distribution was similar among the fibres of units classified as the same type. However, the intrafibre distribution was disparate among the different unit types. These data suggest that the intrafibre distribution of mitochondrial enzymes may contribute to the mechanical properties of a motor unit. In this regard, a hypothesis is proposed that describes how the absolute activity of a mitochondrial enzyme, and the intrafibre distribution of that activity, may interactively contribute to the fatigue resistance of a unit.

Animals↗
PubMed1993

Respiratory, ionic, and functional effects of succinate esters in pancreatic islets.

The methyl esters of succinic acid were introduced a few years ago as new potent insulin secretagogues. In the present study, they were found to increase O2 uptake by rat islets incubated in the absence or presence of D-glucose; to decrease 86Rb outflow from prelabeled islets; to stimulate biosynthetic activity in the islets, with a preferential effect on the synthesis of proinsulin; to inhibit 45Ca efflux from prelabeled islets perifused in the absence of extracellular Ca2+ but to augment 45Ca net uptake and to cause a biphasic stimulation of 45Ca outflow in islets incubated or perifused in the presence of extracellular Ca2+; and to evoke a biphasic stimulation of insulin release. The insulinotropic action of these methyl esters coincided with a shift to the left of the sigmoidal relationship between insulin output and D-glucose concentration, was concentration related in the 2-10 mM range, failed to be duplicated by succinic acid, displayed both Ca2+ dependency and resistance to a lowering of extracellular pH, and was operative in the absence of D-glucose whether or not the islets were stimulated by non-nutrient secretagogues. It is concluded that the respiratory, cationic, biosynthetic, and secretory responses of the islets to succinate methyl esters display the characteristic features usually encountered in the process of nutrient-stimulated insulin release.

Animals↗
PubMed2004

Metabolic analysis of Corynebacterium glutamicum during lactate and succinate productions under oxygen deprivation conditions.

Lactate and succinate were produced from glucose by Corynebacterium glutamicum under oxygen deprivation conditions without growth. Addition of bicarbonate to the reaction mixture led not only to a 3.6-fold increase in succinate production rate, but also to a 2.3- and 2.5-fold increase, respectively, of the rates of lactate production and glucose consumption, compared to the control. Furthermore, when small amounts of pyruvate were added to the reaction mixture, acid production rates and the glucose consumption rate were multiplied by a factor ranging from 2 to 3. These phenomena were paralleled by an increase in the NAD(+)/NADH ratio, thus corroborating the view that the efficient regeneration of NAD(+) could be triggered by the addition of either bicarbonate or pyruvate. To investigate the global metabolism of corynebacteria under oxygen deprivation conditions, we engineered several strains where the genes coding for key metabolic enzymes had been inactivated by gene disruption and replacement. A lactate dehydrogenase (LDH)-deficient mutant was not able to produce lactate, suggesting this enzyme has no other isozyme. Although a pyruvate carboxylase (pyc) mutant exhibited similar behavior to that of the wild type, phosphoenolpyruvate carboxylase (ppc) mutants were characterized by a dramatic decrease in succinate production, which was concomitant to decreased lactate production and glucose consumption rates. This set of observations corroborates the view that in coryneform bacteria under oxygen deprivation conditions the major anaplerotic reaction is driven by the ppc gene product rather than by the pyc gene product. Moreover, intracellular NADH concentrations in C. glutamicum were observed to correlate to oxygen-deprived metabolic flows.

Acids↗
PubMed2005

Hereditary paraganglioma/pheochromocytoma and inherited succinate dehydrogenase deficiency.

Mitochondrial complex II, or succinate dehydrogenase, is a key enzymatic complex involved in both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation as part of the mitochondrial respiratory chain. Germline succinate dehydrogenase subunit A (SDHA) mutations have been reported in a few patients with a classical mitochondrial neurodegenerative disease. Mutations in the genes encoding the three other succinate dehydrogenase subunits (SDHB, SDHC and SDHD) have been identified in patients affected by familial or 'apparently sporadic' paraganglioma and/or pheochromocytoma, an autosomal inherited cancer-susceptibility syndrome. These discoveries have dramatically changed the work-up and genetic counseling of patients and families with paragangliomas and/or pheochromocytomas. The subsequent identification of germline mutations in the gene encoding fumarase--another TCA cycle enzyme--in a new hereditary form of susceptibility to renal, uterine and cutaneous tumors has highlighted the potential role of the TCA cycle and, more generally, of the mitochondria in cancer.

Animals↗
PubMed1980

Assignment of a gene for succinate dehydrogenase to human chromosome 1 by somatic cell hybridization.

A Chinese hamster cell mutant has been described with little or no activity of succinate dehydrogenase (SODERBERG et al., 1977). We described here the selection and characterization of human-hamster hybrids obtained from the fusion of these mutant cells and human lymphoblasts or HT1080 fibrosarcoma cells. The presence of human chromosome 1, identified by cytogenetic techniques and isozyme analysis, is correlated with the restoration of succinate dehydrogenase activity in the hybrids, and segregants are described in which the loss of all or part of human chromosome 1 has also led to a loss of this activity. We present in one of the two structural genes for the 70,000 and 30,000 dalton peptides, respectively, which constitute succinate dehydrogenase. One of these two genes is therefore mapped on human chromosome 1.

Animals↗
PubMed1997

Nutritional value of succinic acid monoethyl ester in starvation.

Rats were fasted for 48 h, but infused with either NaCl or the sodium salt of monoethyl succinic acid (EMS), both delivered at a rate of 80 mumol/g body weight per day. The infusion of EMS, as compared to NaCl, failed to affect paraovarian adipose tissue or liver weight, liver or muscle glycogen, and insulinemia. It accentuated the starvation-induced fall in body weight, and decreased both liver and muscle protein content. Nevertheless, the succinate ester increased plasma D-glucose concentration, delayed the rise in ketonemia, maintained a higher glucokinase/hexokinase activity ratio in liver and pancreatic islets, and allowed for a more efficient stimulation of insulin release by D-glucose or 2-ketoisocaproate in isolated pancreatic islets. These findings indicate that monoethyl succinate displays a significant nutritional value when infused in starved rats.

3-Hydroxybutyric Acid↗
PubMed1991

Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.

We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations with superimposed episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia. Cycle exercise testing revealed low maximal oxygen uptake (12 ml/min per kg; healthy sedentary men = 39 +/- 5) with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise. The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v O2 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7 +/- 2.1) despite normal oxygen carrying capacity and Hgb-O2 P50. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Qmax, patient = 303 ml/min per kg, normal men 238 +/- 36) and the slope of increase in Q relative to VO2 (i.e., delta Q/delta VO2) from rest to exercise was exaggerated (delta Q/delta VO2, patient = 29, normal men = 4.7 +/- 0.6) indicating uncoupling of the normal approximately 1:1 relationship between oxygen delivery and utilization in dynamic exercise. Studies of isolated skeletal muscle mitochondria in our patient revealed markedly impaired succinate oxidation with normal glutamate oxidation implying a metabolic defect at the level of complex II of the mitochondrial respiratory chain. A defect in Complex II in skeletal muscle was confirmed by the finding of deficiency of succinate dehydrogenase as determined histochemically and biochemically. Immunoblot analysis showed low amounts of the 30-kD (iron-sulfur) and 13.5-kD proteins with near normal levels of the 70-kD protein of complex II. Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase assessed enzymatically and immunologically whereas activities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consistent with the hypothesis that this defect impairs muscle oxidative metabolism by limiting the rate of NADH production by the tricarboxylic acid cycle.

Aconitate Hydratase↗
PubMed1980

Assay of succinate dehydrogenase activity by the tetrazolium method: evaluation of an improved technique in skeletal muscle fractions.

An improved spectrophotometric method for measuring succinate dehydrogenase (EC 1.3.99.1) activity with the use of 2-(p-iodophenyl)-3-(p-nitrophenyl)-5-phenyltetrazolium chloride (INT) is described. The procedure has been evaluated in mitochondrial fractions and homogenates of frog skeletal muscle. For mitochondrial suspensions, extraction of formazan with alcohol was found to be superior to extraction with ethyl acetate. For homogenates, complete extraction of formazan required sequential treatment with alcohol and ethyl acetate; the generally employed procedure of extracting once with ethyl acetate alone led to serious underestimation of the amount of formazan in the tissue. Observations of mitochondrial suspension incubated with various concentrations of INT led to the selection of 0.8 mM INT for optimal results. Higher concentrations, although commonly used, can exert undesirable inhibitory effects on succinate dehydrogenase activity, especially at low concentrations of mitochondria and after longer periods of incubation. The problem of instability of succinate dehydrogenase was solved by the addition of buffer at pH 7.5.

Animals↗
PubMed1992

Biochemical mechanisms involved in monomethyl succinate-induced insulin secretion.

Esters of succinic acid stimulate insulin secretion from pancreatic beta-cells. Using collagenase-isolated rat islets, the transduction mechanisms involved were investigated. In freshly isolated perifused islets, monomethyl succinate (MMSucc), in the presence of basal (2.75 mM) glucose, stimulated insulin release in a biphasic pattern. This secretory response was dependent on extracellular calcium movement into the beta-cell, since the calcium channel blocker nitrendipine (5 microM) abolished it. The glucokinase inhibitor mannoheptulose (20 mM) had no effect on its secretory action, while the protein kinase-C inhibitor staurosporine (20 nM) reduced secretion to MMSucc. In addition, while ineffective alone, the diacylglycerol kinase inhibitor monooleoylglycerol (25 microM) potentiated MMSucc-induced insulin release. A similarly amplified response occurred in the presence of forskolin (0.25 microM), a compound that elevates islet cAMP levels. The sodium salt of succinic acid (20 mM) had no effect on insulin release in the presence or absence of forskolin. Prior treatment with MMSucc in the presence of 2.75 mM glucose sensitized islets to the usually weak insulin secretory effect of 7.5 mM glucose. Other groups of islets were incubated for 2 h with myo-[2-3H]inositol to label their phosphoinositide pools. These islets were subsequently stimulated, and the kinetics of [3H]inositol efflux and insulin secretion were measured. MMSucc induced a rapid and sustained dose-dependent increase in [3H]inositol efflux rates. In batch-incubated islets, MMSucc increased inositol phosphate levels. Finally, MMSucc (20 mM), in the presence of 8 mM glucose, did not influence the detritiation of [5-3H]glucose, but reduced the oxidation of [U-14C] glucose. These results support the following conclusions. First, MMSucc is a potent activator of islet phosphoinositide hydrolysis. Second, the activation of protein kinase-C appears to contribute to the acute insulin secretory effect of MMSucc. Third, MMSucc-induced increases in phosphoinositide hydrolysis contribute at least in part to its ability to acutely stimulate insulin release and prime the beta-cell to subsequent stimulation. Finally, mitochondrial events associated with the oxidative metabolism of MMSucc may underlie its insulinotropic action.

Alkaloids↗
PubMed2004

Production of fumaric acid using rice bran and subsequent conversion to succinic acid through a two-step process.

The fungal production of fumaric acid using rice bran and subsequent bacterial conversion of succinic acid using fungal culture broth were investigated. Since the rice bran contains abundant proteins, amino acids, vitamins, and minerals, it is suitable material that fungi use as a nitrogen source. The effective concentration of rice bran to produce fumaric acid was 5 g/L. A large amount of rice bran caused excessive fungal growth rather than enhance fumaric acid production. In addition, we could produce fumaric acid without the addition of zinc and iron. Fungal culture broth containing approx 25 g/L of fumaric acid was directly employed for succinic acid conversion. The amount of glycerol and yeast extract required for succinic acid conversion was reduced to 70 and 30%, respectively, compared with the amounts cited in previous studies.

Biochemistry↗
PubMedDate not supplied

Inhibition of succinic dehydrogenase and F0F1-ATP synthase by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS).

This study shows that incubation of rat liver mitochondria in the presence of the thiol/ amino reagent 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) is followed by inhibition of both succinate supported respiration and oxidative phosphorylation. Half-maximal inhibition of succinic dehydrogenase activity and succinate oxidation by mitochondria was attained at 55.3 and 60.8 microM DIDS, respectively. DIDS did inhibit the net ATP synthesis and ATP<=>[32P]Pi exchange reaction catalyzed by submitochondrial particles in a dose-dependent manner (Ki = 31.7 microM and Ki = 32.7 microM), respectively. The hydrolytic activities of uncoupled heart submitochondrial particles and purified F1-ATPase were also inhibited 50% by 31.9 and 20.9 microM DIDS, respectively.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗