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PubMed1988

Oxidation of [U-14C]succinic semialdehyde in cultured human lymphoblasts: measurement of residual succinic semialdehyde dehydrogenase activity in 11 patients with 4-hydroxybutyric aciduria.

The oxidation of [U-14C]succinic semialdehyde to 14CO2 has been investigated in cultured lymphoblasts to develop a whole cell assay for succinic semialdehyde dehydrogenase. We have previously demonstrated deficiency of this enzyme in extracts of white cells derived from 13 patients with 4-hydroxybutyric aciduria. Major goals were the demonstration of greater residual succinic semialdehyde dehydrogenase activity in patient cell lines and the better representation of physiology in vivo. In 18 control lymphoblast lines, the conversion of [U-14C]succinic semialdehyde to 14CO2 was 1579 +/- 310 dpm. The mean value in lymphoblasts derived from 11 patients with deficiency of succinic semialdehyde dehydrogenase was 112 +/- 36 dpm approximating 7% of the mean control value. Analysis of organic acids produced from [U-14C]succinic semialdehyde in control lymphoblasts indicated that 14CO2 emanated from the tricarboxylic acid cycle; the major metabolic products were succinic and lactic acids. In the presence of 5mM malonic and 2-propylpentanoic (valproic) acids, 14CO2 production in a control lymphoblast line was decreased by 68 and 45%, respectively. The whole cell assay is less laborious than our previously described assay employing cell extracts, and the general trend was the demonstration of higher residual levels of activity for lymphoblasts derived from patients.

Aldehyde Oxidoreductases↗
PubMed2006

A factorial study of combination hypertension treatment with metoprolol succinate extended release and felodipine extended release results of the Metoprolol Succinate-Felodipine Antihypertension Combination Trial (M-FACT).

BACKGROUND: Many hypertensive patients require combination therapy to achieve target blood pressure (BP). beta-Blockers and dihydropyridine calcium channel blockers are effective as monotherapy in hypertensive patients and have complementary mechanisms for lowering BP. METHODS: This multicenter, randomized, placebo-controlled, unbalanced factorial study included a 4- to 5-week single-blind placebo, 9-week, double-blind treatment as well as a 2-week double-blind, down-titration period. Patients (N = 1092) were randomized to one of 16 treatment groups: extended-release (ER) metoprolol succinate (25, 100, or 400 mg), ER felodipine (2.5, 10, or 20 mg), ER felodipine/ER metoprolol succinate (2.5/25, 2.5/100, 2.5/400, 10/25, 10/100, 10/400, 20/25, 20/100, or 20/400 mg), or placebo. RESULTS: At baseline, treatment groups were well balanced; mean sitting BP was 152.6/99.9 mm Hg. Monotherapy with ER metoprolol succinate induced dose-related reductions in sitting systolic/diastolic BP (DBP) (mean 8.1/7.7 to 9.7/11.1 mm Hg) as did ER felodipine (mean 7.7/7.7 to 14.0/11.8) and the combinations reflected additive effects (mean 13.8/11.0 to 19.8/15.2). The decline in the placebo group was 2.1/4.0 mm Hg. All combinations were more effective than their components (P < .05 for all but ER metoprolol succinate 25/ER felodipine 20). When compared with the highest doses of the individual agents (ER metoprolol succinate 400 mg; ER felodipine 20 mg), the low-dose combination ER metoprolol succinate 25/ER felodipine 2.5 was approximately as effective (differences in DBP <1 mm Hg). The most common adverse events leading to discontinuation were peripheral edema (4%), headache (2%), and fatigue (1%). Higher rates of peripheral edema and flushing were associated with high-dose ER felodipine, either alone or in combination. CONCLUSIONS: The antihypertensive effects of ER metoprolol succinate and ER felodipine are dose-related, and when given in combination, their BP-lowering effects are additive over a wide dose range. Low-dose combination therapy is comparable in effectiveness to high-dose monotherapy but is better tolerated.

Administration, Oral↗
PubMed1985

Differential labeling of the subunits of respiratory complex III with [3H]succinic anhydride, [14C]succinic anhydride, and p-diazobenzene-[35S]sulfonate.

Exposure of antimycin-treated Complex III (ubiquinol-cytochrome c reductase) purified from bovine heart mitochondria to [3H]succinic anhydride plus [35S]p-diazobenzenesulfonate (DABS) resulted in somewhat uniform relative labeling of the eight measured subunits of the complex by [3H]succinic anhydride. In contrast, relative labeling by [35S]DABS was similar to [3H]succinic anhydride for the subunits of high molecular mass, i.e., core proteins, cytochromes, and the iron-sulfur protein, but greatly reduced for the polypeptides of molecular mass below 15 kDa. With Complex II depleted in the iron-sulfur protein the relative labeling of core protein I by exposure of the complex to [3H]succinic anhydride was significantly enhanced, whereas labeling of the polypeptides represented by SDS-PAGE bands 7 and 8 was significantly inhibited. Dual labeling of the subunits of Complex III by 14C- and 3H-labeled succinic anhydride before and after dissociation of the complex by sodium dodecyl sulfate, respectively, was measured with the complex in its oxidized, reduced, and antimycin-inhibited states. Subunits observed to be most accessible or reactive to succinic anhydride were core protein II, the iron-sulfur protein, and polypeptides of SDS-PAGE bands 7,8, and 9. Two additional polypeptides of molecular masses 23 and 12kDa, not normally resolved by gel-electrophoresis, were detected. Reduction of the complex resulted in a significant change of 14C/3H labeling ratio of core protein only, whereas treatment of the complex with antimycin resulted in decreases in 14C/3H labeling ratios of core proteins I and II, cytochrome c1, and a polypeptide of molecular mass 13kDa identified as an antimycin-binding protein.

Animals↗
PubMed2002

Succinate accumulation in pig large intestine during antibiotic-associated diarrhea and the constitution of succinate-producing flora.

Succinate was the major organic acid detected in the hindgut content of pigs suffering from antibiotic-associated diarrhea. Antibiotic-associated diarrhea was induced by an oral dose of polymyxin B sulfate (3,000,000 units/day) or an intramuscular injection of enrofloxacin (0.6 g enrofloxacin/day). In the large intestine of enrofloxacin-treated pigs, Gram-negative facultative anaerobic rods phylogenetically related to Escherichia coli and Gram-positive facultative anaerobic non-spore-forming rods phylogenetically related to Lactobacilli were isolated as succinate producers. Succinate-producing Lactobacilli were only isolated as the succinate producer in polymyxin B sulfate-treated pigs. In contrast to antibiotic-associated diarrhea pigs, bacteria belonging to Bacteroidaceae, Fusobacteria, and Enterobacteriaceae were detected as succinate producers in a non-treated pig. In antibiotic-associated diarrhea conditions, antibiotic-resistant Enterobacteria, E. coli in particular, and Lactobacilli may contribute to an abnormal succinate accumulation and may affect water absorption in the hindgut that relates to an expression of antibiotic-associated diarrhea.

Animals↗
PubMed1978

Colorimetric determination of succinic acid using yeast succinate dehydrogenase.

An enzymatic method for the rapid determination of succinic acid in biological fluids was developed utilizing yeast mitochondria as a source of succinate dehydrogenase. The yeast enzyme catalyzes a complete stoichiometric reduction of 2- (p-iodophenyl)-3-(p-nitrophenyl)-5-tetrazolium chloride to a red formazan. The formazan is extracted into ethylacetate and its absorbance measured at 490 nm. The method is simple, specific, reproducible, and very sensitive (0.01 to 0.14 mumol). The yeast enzyme can be stored in liquid nitrogen for periods of at least 30 days with no significant change in specific activity. In this respect it is superior to a variety of succinate dehydrogenase preparations from animal tissues. The method was applied to measurement of succinic acid excreted by nonproliferating yeast cells metabolizing glucose. Derepressed yeast cells secreted several-fold as much succinic acid as repressed cells submitted to identical test conditions.

Animals↗
PubMed1983

Modification of the thermodynamic properties of the electron-transferring groups in mitochondrial succinate dehydrogenase upon binding of succinate.

The redox properties of the covalently-bound flavin and of the tetrahedral iron-sulfur center S1 of succinate dehydrogenase were studied as a function of the binding of different ligands to the enzyme. The midpoint potential of both flavin and S1 increases by some 200 mV when protein binds succinate to a site having Kdsucc = 0.8-1.0 mM, thus different from the substrate binding site. Succinate binding increases the potential of the oxidized flavin/semiquinone half-cell more than that of the semiquinone/reduced flavin one: this results in higher semiquinone formation with increasing succinate. Malonate and fumarate appear to mimic, in this regard, the effect of succinate. The increase in midpoint potential of S1 upon binding of dicarboxylic acid is related to an increase in hydrophobicity of the cluster environment. The possible molecular basis for the modulation of the flavin potential is discussed together with the significance of this shift on the catalytic behaviour of the protein.

Binding Sites↗
PubMed1984

[Dissociation constants of succinate dehydrogenase complexes with succinate, fumarate and malonate].

The rates of the oxidized (Eox) and reduced (Ered) (by NAD . H through the ubiquinone pool) succinate dehydrogenase inhibition by N-ethyl-maleimide are equal and obey pseudo-first order kinetics. The protection of the enzyme against irreversible alkylation was used to quantitate the dissociation constants for Eox and Ered complexes with fumarate, succinate and malonate under conditions when no intramolecular redox reactions might occur. the membrane-bound succinate dehydrogenase catalyzes the succinate : phenazine-methosulphate reductase reaction in the presence of thenoyltrifluoroacetone by a Slater-Bonner mechanism. A comparison of the constants measured by the protection with those derived from the steady-state kinetics shows that succinate affinity for Eox is about 10 times higher than that for Ered; the reverse relations were found for fumarate, whereas the affinity for malonate only slightly depends on the redox state of the enzyme. The data obtained suggest that the dicarboxylate binding at the active site induces changes in the enzyme redox potential. The surface charge does not contribute significantly to the energy of the dicarboxylate binding to the active site of the membrane-bound enzyme.

Animals↗
PubMed1975

The steady state activity of succinate dehydrogenase in the presence of opposing effectors.II. Reductive activation of succinate dehydrogenase in presence of oxaloacetate.

The extent of the deactivation of the mitochondrial succinate dehydrogenase by oxaloacetate is a function of the redox state of the enzyme. Oxidized enzyme is deactivated by much lower concentrations of oxaloacetate than those needed to deactivate reduced enzyme. An accurate method for measuring this relationship is the redox titration of the enzymic activity of succinate dehydrogenase, carried out in the presence of oxaloacetate. For each concentration of oxaloacetate a different redox titration curve was reported with the apparent mid-potential decreasing with increasing oxaloacetate. These results are compatible with a model which proposes that both oxidized and reduced enzymes can form the catalytically non-active complex with oxaloacetate, but that the complex formed the the oxidized enzyme is more stable than that formed by the reduced enzyme. When the oxaloacetate concentration is low, reduction of the enzyme will lower the fraction of the succinate dehydrogenase-oxaloacetate complex, a reaction which we observe as reductive activation of the enzyme. If this experiment is repeated in the presence of high concentration of oxaloacetate, no activation of the enzyme takes place, but the low stability of the reduced enzyme oxaloacetate complex is revealed by the rapid exchange of the enzyme-bound oxaloacetate with the free ligand. The rate of this exchange is extremely slow at high positive potential and becomes faster upon lowering of the poise potential. The reductive activation of the succinate dehydrogenase is regarded as a two step reaction. In the first step the reduced non-active complex releases the oxaloacetate and in the second step the active form of the enzyme is evolved. These two steps can be observed experimentally; Reductive activation at a redox potential higher than the mid-potential of the oxaloacetate-malate couple (minus 166 mV) is characterized by Ea = 18 Kca/mole, the final equilibrium level of activation decreases upon lowering of the temperature. Reduction activation of the enzyme at minus 240 mV is a very rapid reaction which goes to completion at all temperatures tested and has an activation energy of 12.5 Kcal/mole. The mechanism of the reductive activation and its possible role in the regulation of succinate dehydrogenase in the mitochondria is discussed.

Enzyme Activation↗
PubMed1987

Growth of Paracoccus denitrificans on [2,3-13C]succinate and [1,4-13C]succinate. I. The flux of carbon in energy metabolism and the operation of the TCA cycle.

The metabolism of Paracoccus denitrificans, grown on either [2,3-13C]succinate or [1,4-13C]succinate, was investigated by using gas chromatography-mass spectrometry. The distribution of label in a group of metabolites closely related to the TCA-cycle intermediates showed that the flux of carbon from succinate in energy metabolism in vivo was via pyruvate (malic enzyme) and acetyl CoA. The labelling pattern of the carboxyl groups showed that one fifth of the succinate pool was formed by the regeneration of succinate via the TCA cycle, and four fifths was supplied externally as substrate from the medium.

Carbon Isotopes↗
PubMed2002

2-Aminopyridinium-succinate-succinic acid (2/1/1).

In the title compound, 2C(5)H(7)N(2)(+).C(4)H(4)O(4)(2-).C(4)H(6)O(4), cyclic eight-membered hydrogen-bonded rings exist involving 2-aminopyridinium and succinate ions. The succinic acid and succinate moieties lie on inversion centres. Succinic acid molecules and succinate ions are linked into zigzag chains by O-H.O hydrogen bonds, with O.O distances of 2.6005 (16) A.

Journal Article↗
PubMed2004

Development of a solid-phase extraction method for simultaneous extraction of adipic acid, succinic acid and 1,4-butanediol formed during hydrolysis of poly(butylene adipate) and poly(butylene succinate).

A solid-phase extraction (SPE) method was developed for the simultaneous extraction of dicarboxylic acids and diols formed during hydrolysis of poly(butylene succinate), PBS, and poly(butylene adipate), PBA. Four commercial non-polar SPE columns, three silica based: C8, C18, C18 (EC), and one resin based: ENV+, were tested for the extraction of succinic acid, adipic acid and 1,4-butanediol, the expected final hydrolysis products of PBS and PBA. ENV+ resin was chosen as a solid-phase, because it displayed the best extraction efficiency for 1,4-butanediol and succinic acid. Linear range for the extracted analytes was 1-500 ng/microl for adipic acid and 2-500 ng/microl for 1,4-butanediol and succinic acid. Detection and quantification limits for the analytes were between 1-2 and 2-7 ng/microl, respectively, and relative standard deviations were between 3 and 7%. Good repeatability and low detection limits made the developed SPE method and subsequent gas chromatography-mass spectrometry (GC-MS) analysis a sensitive tool for identification and quantification of hydrolysis products at early stages of degradation.

Adipates↗
PubMed1988

Growth of Paracoccus denitrificans on [2,3-13C]succinate and [1,4-13C]succinate. III. Biosynthetic pathways.

The biosynthesis in vivo of a number of amino acids, sugars, and purines in Paracoccus denitrificans grown on either [2,3-13C]succinate or [1,4-13C]succinate was investigated by using gas chromatography-mass spectrometry. The distribution of label in the TCA-cycle-related amino acids indicated that carbon intermediates of energy metabolism were utilized as precursors for the biosynthesis of these amino acids in vivo. The biosynthesis of glycine, serine, phenylalanine and glycerol from labelled succinate in vivo were consistent with phosphoenol pyruvate as an intermediate. A mechanism for the formation of C4, C5 and C6 sugars without the use of fructose-1,6-bisphosphate aldolase (which has not been detected in P. denitrificans) is proposed. The 13C-enrichments of ribose in the bacterium indicate that there are at least three routes of ribose biosynthesis operating during growth on labelled succinate. The probability distribution of labelled purine molecules was successfully predicted for adenine, guanine and adenosine, thus confirming their generally accepted route of biosynthesis in vivo.

Amino Acids↗
PubMed1985

[Prognostic value of determining the succinate dehydrogenase activity of lymphocytes and the therapeutic effectiveness of sodium succinate in resuscitation of rats].

In the experiments on male rats recovered after clinical death caused by acute hemorrhage and mechanical asphyxia undulatory changes of lymphocyte succinate dehydrogenase activity were revealed: enzyme inhibition during clinical death, activation in the first minutes of resuscitation with subsequent moderate reduction in activity. Lymphocyte succinate dehydrogenase activity was shown to be a reliable prognostic criterion. Pre-injection of sodium succinate at a dose of 20 mg/kg improved considerably the resuscitation results especially during the first two days of rehabilitation period.

Animals↗
PubMed1999

Comparison of catalytic activity and inhibitors of quinone reactions of succinate dehydrogenase (Succinate-ubiquinone oxidoreductase) and fumarate reductase (Menaquinol-fumarate oxidoreductase) from Escherichia coli.

Escherichia coli succinate-ubiquinone oxidoreductase (SQR) and menaquinol-fumarate reductase (QFR) are excellent model systems to understand the function of eukaryotic Complex II. They have structural and catalytic properties similar to their eukaryotic counterpart. An exception is that potent inhibitors of mammalian Complex II, such as thenoyltrifluoroacetone and carboxanilides, only weakly inhibit their bacterial counterparts. This lack of good inhibitors of quinone reactions and the higher level of side reactions in the prokaryotic enzymes has hampered the elucidation of the mechanism of quinone oxidation/reduction in E. coli Complex II. In this communication DT-diaphorase and an appropriate quinone are used to measure quinol-fumarate reductase activity and E. coli bo-oxidase and quinones are used to determine succinate-quinone reductase activity. Simple Michaelis kinetics are observed for both enzymes with ubiquinones and menaquinones in the succinate oxidase (forward) and fumarate reductase (reverse) reactions. The comparison of E. coli SQR and QFR demonstrates that 2-n-heptyl 4-hydroxyquinoline-N-oxide (HQNO) is a potent inhibitor of QFR in both assays; however, SQR is not sensitive to HQNO. A series of 2-alkyl-4,6-dinitrophenols and pentachlorophenol were found to be potent competitive inhibitors of both SQR and QFR. In addition, the isolated E. coli SQR complex demonstrates a mixed-type inhibition with carboxanilides, whereas the QFR complex is resistant to this inhibitor. The kinetic properties of SQR and QFR suggest that either ubiquinone or menaquinone operates at a single exchangeable site working in forward or reverse reactions. The pH activity profiles for E. coli QFR and SQR are similar showing maximal activity between pH 7.4 and 7.8, suggesting the importance of similar catalytic groups in quinol deprotonation and oxidation.

Anilides↗
PubMed1986

Distinct physiological roles of animal succinate thiokinases. Association of guanine nucleotide-linked succinate thiokinase with ketone body utilization.

Two distinct succinate thiokinases have recently been shown to exist in animal tissues, one specific for guanine nucleotide and the other for adenine nucleotide. Their physiological roles have here been investigated by comparing the levels of the two enzymes in liver and brain of normal and diabetic rats. A marked rise in the level of brain guanine nucleotide-linked succinate thiokinase in the diabetic condition is consistent with an enhanced utilization of ketone bodies and hence with the associated elevated demand for succinyl-CoA for the activation of acetoacetate. Taken together with the reported mitochondrial values of the ATP/ADP and GTP/GDP ratios, the results are interpreted to indicate that the adenine nucleotide-linked enzyme functions as a component of the citric acid cycle whereas the guanine nucleotide-linked enzyme functions in the opposite metabolic direction to produce succinyl-CoA from succinate.

Adenosine Triphosphate↗
PubMed1975

The effect of succinic semialdehyde and sodium succinate on the higher nervous activity in normal subjects.

In 15 normal volunteers the action of succinic semialdehyde (SSA), and in 24 volunteers the effect of sodium succinate (SS), on the HNA have been investigated. As a result it was found that SSA brings about some enhancement of the excitatory process in cortical - mainly verbal -activities, accompanied by subjective improvement of memory and concentration. In the other hand, the administration of SS improves the stability of cortical excitatory process and its equilibrium with cortical inhibition; and enhances the connecting activity of the verbal system. These changes parallel the subjective elevation of mood and of general tone. In the basis of this study, one may suggest that succinic acid may be a psychoenergizer. The task of further investigations is to establish the range of therapeutic activity of these compounds.

Adult↗
PubMed1986

Studies on the succinate dehydrogenating system. Interaction of the mitochondrial succinate-ubiquinone reductase with pyridoxal phosphate.

The inhibitory effect of pyridoxal phosphate on the Triton X-100 solubilized purified bovine heart succinate-ubiquinone reductase (Choudhry, Z.M., Gavrikova, E.V., Kotlyar, A.B., Tushurashvilli, P.R. and Vinogradov, A.D. (1985) FEBS Lett. 182, 171-175) was studied. The kinetics of the enzyme inactivation by pyridoxal phosphate was found to be strongly dependent both qualitatively and quantitatively on the concentration of the protein-detergent complexes. In the diluted system the inactivation of the ubiquinone-depleted enzyme was completely prevented by the saturating concentrations of Q2, carboxin, thenoiltrifluoroacetone and pentachlorophenol, i.e., by the substrate and specific inhibitors of the enzyme. The protective effects of Q2 and the inhibitors was employed to quantitate the affinities of the ligands to their specific binding sites. Strong difference in the affinity of Q2 to the reduced and oxidized enzyme was found. When the soluble reconstitutively active succinate dehydrogenase was treated with pyridoxal phosphate, the reactivity of the enzyme towards low ferricyanide concentrations and its reconstitutive activity was significantly protected against aerobic inactivation.

Animals↗