Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Succinates”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 991 records · Page 55Linked to original sources
PubMed1985

Functional changes in mitochondrial properties as a result of their membrane cryodestruction. I. Influence of freezing and thawing on succinate-ferricyanide reductase of intact liver mitochondria.

The interaction of the succinate dehydrogenase complex of rat liver mitochondria with an artificial electron acceptor (K3Fe(CN)6), impermeable to the mitochondrial membrane as an index of a cryoinjury is investigated. It is shown that the freeze-thawing stimulates succinate-ferricyanide reductase (SFCR) activity of intact mitochondria. The increase of the freezing and thawing rates leads to a decrease in the released SFCR activity. The released SFCR activity after low-temperature treatment is a consequence of a nonspecific change in membrane ferricyanide permeability. The released SFCR activity decreases as the freezing and thawing rates increase.

Animals↗
PubMed1985

The H+/O ratio of proton translocation linked to the oxidation of succinate by mitochondria. Reply to a commentary.

Costa, L.E., Reynafarje, B. and Lehninger, A.L. [(1984) J. Biol. Chem. 259, 4802-4811] have reported 'second-generation' measurements of the H+/O ratio approaching 8.0 for vectorial H+ translocation coupled to succinate oxidation by rat liver mitochondria. In a Commentary in this Journal [Krab, K., Soos, J. and Wikström, M. (1984) FEBS Lett. 178, 187-192] it was concluded that the measurements of Costa et al. significantly overestimated the true H+/O stoichiometry. It is shown here that the mathematical simulation on which Krab et al. based this claim is faulty and that data reported by Costa et al. had already excluded the criticism advanced by Krab et al. Also reported are new data, obtained under conditions in which the arguments of Krab et al. are irrelevant, which confirm that the H+/O ratio for succinate oxidation extrapolated to level flow is close to 8.

Animals↗
PubMed1985

The prosthetic groups of succinate dehydrogenase: 30 years from discovery to identification.

Recent studies using magnetic circular dichroism at cryogenic temperatures, electron paramagnetic resonance (EPR) and linear electric field effect-EPR (LEFE) of succinate dehydrogenase in membranes and in soluble, homogeneous preparations demonstrated the presence of 3 different Fe-S clusters in the mammalian enzyme, as well as in a similar bacterial enzyme, fumarate reductase from Escherichia coli. There is one each of the 2Fe, 3Fe, and 4Fe clusters. Thus, succinate dehydrogenase is the first enzyme which has been shown to contain all 3 of these Fe-S clusters. The enzyme also contains 1 mol 8 alpha-[N(3)-histidyl]-FAD. It has taken the combined expertise of many laboratories and 15 years of effort to identify the flavin component, and nearly 3 decades to identify the Fe-S clusters. The data from physical methods appear to be internally consistent, in harmony with the results of chemical analysis, and provide a rational explanation for earlier results by the cluster extrusion method. There remains, however, a number of interesting and substantive questions for future investigations. This review traces the tortuous path, the many pitfalls and false leads, which have led us from the discovery of nonheme iron and 'bound' flavin in the enzyme to elucidation of their structures.

Chemistry↗
PubMed1988

Physiological roles of animal succinate thiokinases. Specific association of the guanine nucleotide-linked enzyme with haem biosynthesis.

The discovery of two distinct succinate thiokinases in mammalian tissues, one (G-STK) specific for GDP/GTP and the other (A-STK) for ADP/ATP, poses the question of their differential metabolic roles. Evidence has suggested that the A-STK functions in the citric acid cycle in the direction of succinyl-CoA breakdown (and ATP formation) whereas one role of the G-STK appears to be the re-cycling of succinate to succinyl-CoA (at the expense of GTP) for the purpose of ketone body activation. A third metabolic participation of succinyl-CoA is in haem biosynthesis. This communication shows that in chemically induced hepatic porphyria, when the demand for succinyl-CoA is increased, it is the level of G-STK only which is elevated, that of A-STK being unaffected. The results implicate G-STK in the provision of succinyl-CoA for haem biosynthesis, a conclusion which is further supported by the observation of a high G-STK/A-STK ratio in bone marrow.

Acyl Coenzyme A↗
PubMed1988

Ligands to the 2Fe iron-sulfur center in succinate dehydrogenase.

Membrane-bound succinate oxidoreductases are flavoenzymes containing one each of a 2Fe, a 3Fe and a 4Fe iron-sulfur center. Amino acid sequence homologies indicate that all three centers are located in the Ip (B) subunit. From polypeptide and gene analysis of Bacillus subtilis succinate dehydrogenase-defective mutants combined with earlier EPR spectroscopic data, we show that four conserved cysteine residues in the first half of Ip are the ligands to the [2Fe-2S] center. These four residues have previously been predicted to be the ligands. Our results also suggest that the N-terminal part of B. subtilis Ip constitutes a domain which can incorporate separately the 2Fe center and interact with Fp, the flavin-containing subunit of the dehydrogenase.

Bacillus subtilis↗
PubMed1989

EPR characterization of soluble fragments of succinate dehydrogenase from mutant strains of Bacillus subtilis.

Succinate dehydrogenase is a membrane-bound metallo-flavo-enzyme containing a bi- (S-1), a tri- (S-3) and a tetranuclear (S-2) iron-sulfur cluster. The catalytic portion of the enzyme contains two distinct subunits designated Fp and Ip. Using concentrated extracts from mutant strains of Bacillus subtilis it was demonstrated, by using low temperature EPR, that cluster S-2 can be assembled in a soluble succinate dehydrogenase. In a mutant with a truncated Ip subunit which lacks 7 of the 11 conserved cysteine residues, cluster S-1 lacked the spin relaxation properties attributable to an adjacent cluster S-2. These data are consistent with a model where one or more cysteine residues from the middle set of 4 conserved cysteines in the Ip subunit are ligands to the tetranuclear cluster.

Bacillus subtilis↗
PubMed1992

Evidence for non-cysteinyl coordination of the [2Fe-2S] cluster in Escherichia coli succinate dehydrogenase.

The consequences of replacing Cys65 in the FrdB subunit of Escherichia coli fumarate reductase by Asp or Ala have been investigated in terms of bacterial growth, enzymatic activity, and the ERP/redox properties of the [2Fe-2S] cluster. An aspartic acid residue occupies the equivalent position in E. coli succinate dehydrogenase, and the FrdBCys65Asp mutation has little effect on cell growth, enzyme activity or the physical properties of the Frd [2Fe-2S] cluster. In contrast, the [2Fe-2S] cluster was not observed in the FrdBCys65Ala mutant showing that a coordinating residue is required at this position for assembly of this cluster and significant levels of enzymatic activity. These results support the presence of one non-cysteinyl, oxygenic ligand for the [2Fe-2S] cluster in E. coli succinate dehydrogenase.

Cysteine↗
PubMed1996

A structural model for the membrane-integral domain of succinate: quinone oxidoreductases.

Many succinate:quinone oxidoreductases in bacteria and mitochondria, i.e. succinate:quinone reductases and fumarate reductases, contain in the membrane anchor a cytochrome b whose structure and function is poorly understood. Based on biochemical data and polypeptide sequence information, we show that the anchors in different organisms are related despite an apparent diversity in polypeptide and heme composition. A general structural model for the membrane-integral domain of the anchors is proposed. It is an antiparallel four-helix bundle with a novel arrangement of hexa-coordinated protoheme IX. The structure can be applied to a larger group of membrane-integral cytochromes of b-type and has evolutionary and functional implications.

Amino Acid Sequence↗
PubMed1992

Succinic semialdehyde dehydrogenase from mammalian brain: subunit analysis using polyclonal antiserum.

1. NAD(+)-dependent succinic semialdehyde dehydrogenase was purified to apparent homogeneity from rat brain and highly purified from human brain. 2. Molecular exclusion chromatography of the purified enzymes on Sephadex G-150 and G-200 revealed M(r) values of 203,000 and 191,000 for rat and human, respectively. 3. Electrophoresis on sodium dodecylsulfate polyacrylamide gels revealed a single subunit of M(r) 54,000 for rat and 58,000 for human. Isoelectric focusing of the purified rat enzyme yielded a pI of 6.1. 4. For both proteins, Km values for short-chain aldehydes acetaldehyde and propionaldehyde ranged from 0.33 to 2.5 mM; Km values for succinic semialdehyde were in the 2-4 microM range. 5. The subunit structure of both enzymes was investigated in brain extracts and purified preparations by immunoblotting, using a polyclonal rabbit antiserum against the purified rat brain enzyme. 6. For rat and human extracts, single bands were detected at M(r) 54,000 and 58,000, comparable to findings in the purified preparations. Immunoblotting analyses in other species (guinea pig, hamster, mouse and rabbit) revealed single subunits of M(r) 54,000-56,500.

Aldehyde Oxidoreductases↗
PubMed1995

The effect of electron transport (ET) inhibitors and thiabendazole on the fumarate reductase (FR) and succinate dehydrogenase (SDH) of Strongyloides ratti infective (L3) larvae.

The fumarate reductase (FR) and succinate dehydrogenase (SDH) activities of isolated submitochondrial particles (SMPs) prepared from axenised L3 larvae of S. ratti were characterised with respect to their response to a selected range of inhibitors. Rotenone (a specific inhibitor of electron transport Complex I) inhibited the S. ratti FR (EC50 = 3.0 x 10(-7) M) but not SDH. This strongly suggests that the S. ratti FR is functionally linked with the S. ratti ET-Complex I. 2-Thenoyltrifluoroacetone (TTFA, an inhibitor of ET-Complex II) inhibited FR (EC50 = 2.6 x 10(-5) M) and SDH (EC50 = 2.8 x 10(-5) M) with similar effectiveness. Sodium malonate (substrate analogue of succinate) had a greater affinity for SDH (EC50 = 6.8 x 10(-4) M), than FR (EC50 = 1.9 x 10(-2) M). Sodium fumarate was ca. 8-fold more effective in inhibiting the S. ratti FR (EC50 = 6.0 x 10(-4) M) than SDH (EC50 = 4.8 x 10(-3) M). The S. ratti FR was more sensitive to inhibition by thiabendazole (TBZ; EC50 = 4.6 x 10(-4) M) than SDH (EC50 > 1.0 x 10(-3) M), suggesting that one of the sites-of-action of TBZ to be the FR of S. ratti mitochondria. More potent inhibitors of S. ratti FR, if developed, may prove to be effective chemotherapeutic agents in the management of human strongloidiasis.

Animals↗
PubMed1982

Convulsant action of intracerebroventricularly administered l-kynurenine sulphate, quinolinic acid and other derivatives of succinic acid, and effects of amino acids: structure-activity relationships.

Succinic acid, and the derivatives which have been tested, i.e. phthalic, l-glutamic, l-aspartic, citric and laevulinic acids, in doses of 5,2,5,20,20 and 50 micrograms, respectively, as well as l-kynurenine sulphate and quinolinic acid, injected into the brain ventricles in mice, induced clonic seizures. When administered intraperitoneally or orally they antagonize strychnine-induced seizures. The convulsant effect of l-kynurenine sulphate was observed only when the pH of the solution was 4.0 or lower, while the actions of the other drugs tested were not dependent upon pH. Control intraventricular injections of 5 microliters of 0.06 N sulphuric acid (equivalent to 16.7 micrograms of SO4(2-), the same dose as was injected when a convulsant dose of 50 micrograms of l-kynurenine was administered) induced seizures in 25% of the mice. It is suggested that the convulsant effect of quinolinic acid and l-kynurenine sulphate is related to a moiety of succinic acid (O = C-C-C-C = O). The effect of l-kynurenine sulphate comprises the action of the cation of kynurenine and that of the anion of sulphuric acid. Reduction of the convulsant effect of l-kynurenine sulphate by alpha-amino acids and taurine is presumably related to a "shielding" of both amino- and carbonyl groups of 1-kynurenine. There is no evidence that l-kynurenine sulphate, in small doses, shares the central effects of the inhibitory amino acids.

Amino Acids↗
PubMed1993

Nucleotide sequence of a putative succinate dehydrogenase operon in Thermoplasma acidophilum.

28 amino acids from the N-terminal region of a putative terminal oxidase from the archaebacterium Thermoplasma acidophilum were determined by Edman degradation. On basis of this amino acid sequence a degenerated oligonucleotide was synthesized and used as a radioactive probe for Southern blot analysis of EcoRI digested genomic DNA. A 2.3 kb EcoRI fragment strongly hybridized to the probe and size selected genomic library from genomic DNA was constructed. Several clones scored positive by screening the library with the degenerated oligonucleotide, from which only one clone contained a EcoRI DNA fragment encoding the 28 amino acid sequence determined by protein sequencing. Sequence analysis revealed the presence of three genes in the typical arrangement of an operon. The first gene codes for a protein containing 11 cystein residues in an arrangement typical for Fe/S proteins. Protein sequence comparison revealed significant homologies to the fumarate reductase and succinate dehydrogenase of other bacteria. The two other genes encode small hydrophobic proteins probably serving as membrane anchor for the Thermoplasma acidophilum succinate dehydrogenase.

Amino Acid Sequence↗
PubMed1987

Succinic semialdehyde dehydrogenase activity in bovine adrenal medulla and blood platelets: a comparative study with the brain enzyme.

In the present paper we report the presence of succinic semialdehyde dehydrogenase (SSADH) in bovine adrenal medulla and blood platelets. Both enzymes present some analogies with the brain enzyme in terms of cofactor requirements, optimal pH, mitochondrial localizaton and inhibition by AMP. However, the activity of the platelet enzyme is 100 times lower than that of the brain and affinities of both enzymes for their specific substrate succinic semialdehyde and NAD are different. The presence of SSADH in adrenal medulla and blood platelets allows us to confirm the presence of a complete GABA bypass in these tissues, where the neurotransmitter could have important regulator functions.

Adrenal Medulla↗
PubMed1990

Kinetics of cyclosporine A-induced inhibition of succinate-coenzyme Q dehydrogenase in rat renal cortical mitochondria.

The kinetic mechanism of succinate-coenzyme Q dehydrogenase (Complex II) inhibition by cyclosporine A (CS) on rat renal cortical mitochondria was investigated. CS showed two modes of inhibition of Complex II of the mitochondrial electron transport system: (a) a mixed linear noncompetitive inhibition of resting succinate-limited and ADP-stimulated respirations suggesting that CS binds to Complex II at a different site than the substrate, affecting the dissociation constant for the enzyme-substrate complex and (b) a competitive inhibition of the DNP-stimulated electron transport system suggesting competition with the oxidized form of a component of Complex II. CS action to renal mitochondrial Complex II limits its function, an effect which may be related to CS nephrotoxicity.

Adenosine Diphosphate↗
PubMed2005

A technical feasibility study of surfactant-free drug suspensions using octenyl succinate-modified starches.

Many new drugs exhibit poor wetting behaviour and low aqueous solubility. This is particularly an issue for preclinical studies like toxicological trials, in which considerably higher doses and volumes are being administered compared to clinical studies. Preclinical vehicles typically contain high levels of surfactants that can exert biological effects. However, the biological inertness of vehicles is pivotal for the application in preclinical studies stressing the need in finding new excipients to solve formulation problems of today's drug discovery. The present study investigated the technical feasibility of surfactant-free suspensions using a new poorly soluble drug as model. It was shown that octenyl succinate-modified starches adequately wetted the drug and homogenous tasteless suspensions were obtained. The polymer xanthan gum was identified as macroscopically compatible gelling agent. Concentration effects of xanthan, drug and different modified starches were studied in a D-optimal design with respect to rheological properties. The suspensions were also tested in an analytical centrifuge using NIR transmission profiles to obtain a measure of sedimentation stability under accelerated conditions. The modified starches exhibited only little influence on the viscosity as well as on the yield point in contrast to the rheological effects of xanthan gum. This gelling agent was the main stabilising excipient as the modified starches hindered to a lesser extent sedimentation. The most stable suspensions displayed convenient flow properties. The viscosity at 100 s(-1) and 25 degrees C was in technically acceptable range of 120-140 mPa s in view of a application via gavage or a syringe in animal studies. The results demonstrated that surfactant-free drug suspensions with excellent technical performance can be obtained using octenyl succinate-modified starches. The vehicles were tasteless and based on the experience of modified starches in the food industry, the vehicles should exhibit good tolerability. The future use of such surfactant-free drug suspensions in toxicological, pharmacokinetic and pharmacodynamic studies will have to determine their advantage in terms of biological inertness.

Chemistry, Pharmaceutical↗
PubMed2006

The effect of bovine serum albumin on the membrane potential and reactive oxygen species generation in succinate-supported isolated brain mitochondria.

Characteristics of the succinate-supported H(2)O(2) formation were compared in mitochondria prepared from guinea-pig brain either by Percoll gradient centrifugation or using digitonin. The high rate of H(2)O(2) generation measured in mitochondria prepared with digitonin (600.6+/-26.8pmol/min/mg protein) was inhibited by rotenone, consistently with a reverse flow of electrons via complex I. The rate of H(2)O(2) formation was significantly smaller in Percoll-purified mitochondria (252.6+/-17.3pmol/min/mg protein) and this was stimulated by rotenone. Since bovine serum albumin (BSA) is usually present in the isolation medium used in the digitonin method, systematic study was performed addressing the effect of BSA on H(2)O(2) formation. Mitochondria prepared by the digitonin method (BSA present in the isolation medium) were highly polarized (185+/-3.2mV) and addition of BSA (0.025%) to the assay medium increased H(2)O(2) generation by only 50%. In Percoll-purified mitochondria DeltaPsim was more depolarized (171+/-2mV) and BSA caused hyperpolarization by 10.7+/-1.9mV. H(2)O(2) formation, which was largely independent of DeltaPsim, was stimulated by 400%, became highly dependent on DeltaPsim and could be inhibited by rotenone in the presence of BSA. This shows that in Percoll-purified mitochondria ROS formation via reverse electron flow is preferred only when BSA is present in the assay medium. It is demonstrated that (i) the presence or absence of BSA could determine the mechanism by which ROS is generated in succinate-supported mitochondria and (ii) depolarization by about 10mV eliminates reverse electron flow and the remaining ROS formation, which is smaller but still significant, is no longer dependent on DeltaPsim.

Animals↗
PubMed2003

On the association of succinate dehydrogenase mutations with hereditary paraganglioma.

Hereditary paraganglioma (PGL) is characterized by the development of slow-growing, highly vascularized tumors that can present either as hormonally silent head and neck tumors or as abdominal pheochromocytomas. PGL tumors are caused by germline inactivating heterozygous mutations in the SDHB, SDHC and SDHD genes, which encode three of the four subunits of succinate dehydrogenase (SDH; succinate:ubiquinone oxidoreductase; mitochondrial complex II). Here, potential mechanisms by which SDH mutations could lead to tumor development are discussed. Mechanisms that lead to variations in the prevalence, penetrance and expressivity of SDH subunit mutations remain to be clarified to improve the clinical management of PGL patients. Recently, germline mutations in the FH gene, the product of which (fumarate hydratase) catalyzes the conversion of fumarate to malate in the Krebs cycle, have been detected in a distinct hereditary tumor syndrome, which is characterized by uterine and skin leiomyomatosis and papillary renal cancer. Although the exact mechanisms of tumorigenesis in both disorders are unknown, SDH and FH could be involved in the control of cell proliferation under normal physiological conditions in the affected tissue types. Whereas SDH might be involved in hypoxic proliferation of paraganglia, FH might play an important role in the regulation of ammonium metabolism in smooth muscle cells.

Animals↗
PubMed2005

Development of a metabolic network design and optimization framework incorporating implementation constraints: a succinate production case study.

We have developed a pathway design and optimization scheme that accommodates genetically and/or environmentally derived operational constraints. We express the full set of theoretically optimal pathways in terms of the underlying elementary flux modes and then examine the sensitivity of the optimal yield to a wide class of physiological perturbations. Though the scheme is general it is best appreciated in a concrete context: we here take succinate production as our model system. The scheme produces novel pathway designs and leads to the construction of optimal succinate production pathway networks. The model predictions compare very favorably with experimental observations.

Computer Simulation↗