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PubMed2002

The Saccharomyces cerevisiae mitochondrial succinate:ubiquinone oxidoreductase.

The Saccharomyces cerevisiae succinate dehydrogenase (SDH) provides an excellent model system for studying the assembly, structure, and function of a mitochondrial succinate:quinone oxidoreductase. The powerful combination of genetic and biochemical approaches is better developed in yeast than in other eukaryotes. The yeast protein is strikingly similar to other family members in the structural and catalytic properties of its subunits. However, the membrane domain and particularly the role of the single heme in combination with two ubiquinone-binding sites need further investigation. The assembly of subunits and cofactors that occurs to produce new holoenzyme molecules is a complex process that relies on molecular chaperones. The yeast SDH provides the best opportunity for understanding the biogenesis of this family of iron-sulfur flavoproteins.

Amino Acid Sequence↗
PubMed2002

Spectroscopy of succinate dehydrogenases, a historical perspective.

An attempt is made to retrace, from personal experience, the discovery of redox-reactive non-heme iron in living matter, which turned out to occur in the form of iron-sulfur (Fe-S) clusters, and then to recount the immediate application of this knowledge in exploring the composition of the mitochondrial respiratory chain, and in the rather detailed description of the workings of its components and, for the purposes of the present volume, of succinate dehydrogenase. The relationship of these events to the general status of technology and the available methodology and instrumentation is considered in some detail, with the conclusion that there scarcely was a way that these discoveries could have been made earlier. It is then shown how methods, techniques and interpretations of results were developed and evolved during the applications that were made to a complex problem such as that of the composition, structure and functioning of succinate dehydrogenase. A tabulation of the most significant events--concerning specifically spectroscopy and its interpretations--in this development is given up to the year 2000.

Animals↗
PubMed1998

Reconstitution of cytochrome b-560 (QPs1) of bovine heart mitochondrial succinate-ubiquinone reductase.

The QPs1 subunit of bovine heart mitochondrial succinate-ubiquinone reductase was overexpressed in Escherichia coli DH5 alpha cells as a glutathione S-transferase fusion protein (GST-QPs1) using the expression vector, pGEX/QPs1. The yield of soluble active recombinant GST-QPs1 fusion protein depends on the IPTG concentration, induction growth time, temperature, and medium. Maximum yield of recombinant fusion protein was obtained from cells harvested 3 h postinduction of growth with 0.5 mM IPTG at 27 degrees C in an enriched medium containing betaine and sorbitol. QPs1 is released from the fusion protein by proteolytic cleavage with thrombin. Isolated recombinant QPs1 shows one protein band in SDS-polyacrylamide gel electrophoresis corresponding to subunit III of mitochondrial succinate-ubiquinone reductase. However, partial N-terminal amino acid sequence analysis of recombinant QPs1 shows two extra amino acid residues, glycine and serine, at the N-terminus of mature QPs1, resulting from the recombinant manipulation. When isolated recombinant QPs1 is dispersed in 0.01% dodecyl maltoside, it is in a highly aggregated form with an apparent molecular mass of over 1 million. Recombinant GST-QPs1 contains little cytochrome b-560 heme. However, addition of hemin chloride restores the spectral characteristics of cytochrome b-560. Cytochrome b-560 restoration varies with the amount of hemin used. Maximum reconstitution is obtained when the molar ratio of heme to fusion protein used in the system is 0.6. Reconstituted cytochrome b-560 shows a EPR signal at g = 2.91 which corresponds to one of the EPR signals of cytochrome b-560 in a QPs preparation. When GST-QPs1 with reconstituted cytochrome b-560 is treated with thrombin to cleave GST from QPs1, no change in the absorption and EPR characteristics of cytochrome b-560 is observed, indicating that the bis-histidine ligands of reconstituted cytochrome b-560 are provided by QPs1.

Amino Acid Sequence↗
PubMed1998

Structural and functional comparison of agents interfering with dihydroorotate, succinate and NADH oxidation of rat liver mitochondria.

Mitochondrially bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyses the fourth sequential step in the de novo synthesis of uridine monophosphate; this enzyme uses ubiquinone as the proximal and cytochrome oxidase as is the ultimate electron transfer system. Here, seven compounds with proven antiproliferative activity and in vitro antipyrimidine effects were investigated with isolated functional mitochondria of rat tissues in order to differentiate their anti-dihydroorotate dehydrogenase potency versus putative effects on the respiratory chain enzymes. Ten microM of brequinar sodium, the leflunomide derivatives A77-1726, [2-cyano-3-cyclopropyl-3-hydroxy-enoic acid (4-trifluoromethylphenyl)-amide], MNA 279, (2-cyano-N-(4-cyanophenyl)-3-cyclopropyl-3-oxo-propanamide), MNA715 (2-cyano-3-hydroxy-N-(4-(trifluoromethyl)-phenyl-6-heptanamide), HR325 (2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl ]-propenamide), and the diazine toltrazuril completely inhibited the dihydroorotate-induced oxygen consumption of liver mitochondria. Succinate and NADH oxidation were found to be influenced only at elevated drug concentration (100 microM), with the exception of HR325, 10 microM of which caused a 70% inhibition of NADH and 50% inhibition of succinate oxidation. This was comparable to the effects of toltrazuril, which caused an approximate 75% inhibition of NADH oxidation. Ciprofloxacin was shown here to have only marginal effects on the redox activities of the inner mitochondrial membrane. This differentiation of drug effects on mitochondrial functions will contribute to a better understanding of the in vivo pharmacological activity of these drugs, which are presently in clinical trials because of their immunosuppressive, cytostatic or anti-parasitic activity. A comparison of the influence of A77-1726, HR325, brequinar and 2,4-dinitrophenol on energetically coupled rat liver mitochondria revealed only a weak uncoupling potential of A77-1726 and brequinar. In addition, a modeling study was raised to search for common spatial arrangements of functional groups essential for binding of inhibitors to dihydroorotate dehydrogenase. From the structural comparison of different metabolites and inhibitors of pyrimidine metabolism, a 6-point model was obtained by conformational analysis for the drugs tested on mitochondrial functions, pharmacophoric perception and mapping. We propose our model in combination with kinetic data for a rational design of highly specific inhibitors of dihydroorotate dehydrogenase.

Aniline Compounds↗
PubMed1999

A novel trisaccharide glycolipid biosurfactant containing trehalose bears ester-linked hexanoate, succinate, and acyloxyacyl moieties: NMR and MS characterization of the underivatized structure.

A Gram-positive actinomycete growing on n-hexadecane secreted a family of anionic glycolipid surfactant homologs. The major homolog, with a molecular weight of 1210.6347, had the formula C58H98O26. Following mild alkaline saponification, 1H and 13C NMR spectroscopy were used to characterize the non-reducing trisaccharide backbone: beta-Glcp-(1-->3)-alpha-Glcp-(1<-->1)-alpha-Glcp ('laminaratrehalose'). Hexanoate, succinate, 3-hydroxyoctanoate, and 3-hydroxydecanoate were found in 3:1:1:1 molar ratio using GC-EIMS analysis of fatty acid methyl esters (FAME) prepared by transesterification. We found that the beta-hydroxy acids bore secondary hexanoate chains in 3-O-ester linkage, giving acyloxyacyl anions of appropriate m/z in FABMS and FABMS/MS spectra. COSY, HETCOR, HMBC, and HMQC NMR experiments established the acylation pattern: succinate at C-2 of the terminal alpha-glucopyranose ring; hexanoate at C-3" of the beta-glucopyranose ring; 3-hexanoyloxyoctanoate and 3-hexanoyloxydecanoate at the 2'- and 4-positions. In FABMS spectra, the homologs flanked the molecular ion by +/- 14 and +/- 28 amu, suggesting heterogeneity in acyl chain length.

Acylation↗
PubMed2003

Variation in proton donor/acceptor pathways in succinate:quinone oxidoreductases.

The anaerobically expressed fumarate reductase and aerobically expressed succinate dehydrogenase from Escherichia coli comprise two different classes of succinate:quinone oxidoreductases (SQR), often termed respiratory complex II. The X-ray structures of both membrane-bound complexes have revealed that while the catalytic/soluble domains are structurally similar the quinone binding domains of the enzyme complexes are significantly different. These results suggest that the anaerobic and aerobic forms of complex II have evolved different mechanisms for electron and proton transfer in their respective membrane domains.

Benzoquinones↗
PubMed1997

Identification of the yeast ACR1 gene product as a succinate-fumarate transporter essential for growth on ethanol or acetate.

The protein encoded by the ACR1 gene in Saccharomyces cerevisiae belongs to a family of 35 related membrane proteins that are encoded in the fungal genome. Some of them are known to transport various substrates and products across the inner membranes of mitochondria, but the functions of 28 members of the family are unknown. The yeast ACR1 gene was introduced into Escherichia coli on an expression plasmid. The protein was over-produced as inclusion bodies, which were purified and solubilised in the presence of sarkosyl. The solubilised protein was reconstituted into liposomes and shown to transport fumarate and succinate. Its physiological role in S. cerevisiae is probably to transport cytoplasmic succinate, derived from isocitrate by the action of isocitrate lyase in the cytosol, into the mitochondrial matrix in exchange for fumarate. This exchange activity and the subsequent conversion of fumarate to oxaloacetate in the cytosol would be essential for the growth of S. cerevisiae on ethanol or acetate as the sole carbon source.

Acetates↗
PubMed1999

The Saccharomyces cerevisiae succinate-ubiquinone reductase contains a stoichiometric amount of cytochrome b562.

The Saccharomyces cerevisiae succinate-ubiquinone reductase or succinate dehydrogenase (SDH) is a tetramer of non-equivalent subunits encoded by the SDH1, SDH2, SDH3, and SDH4 genes. In most organisms, SDH contains one or two endogenous b-type hemes. However, it is widely believed that the yeast SDH does not contain heme. In this report, we demonstrate the presence of a stoichiometric amount of cytochrome b562 in the yeast SDH. The cytochrome is detected as a peak present in fumarate-oxidized, dithionite-reduced mitochondria. The peak is centered at 562 nm and is present at a heme:covalent FAD molar ratio of 0.92+/-0.11. The cytochrome is not detectable in mitochondria isolated from SDH3 and SDH4 deletion strains. These observations strongly support our conclusion that cytochrome b562 is a component of the yeast SDH.

Animals↗
PubMed1978

Calcium oxalate stone disease: effects and side effects of cellulose phosphate and succinate in long-term treatment of absorptive hypercalciuria or hyperoxaluria.

Absorptive hypercalciuria was treated in 27 patients with cellulose phosphate. In all patients urinary calcium decreased and stone formation virtually ceased. The most striking side effect was an excessive hyperoxaluria, necessitating withdrawal of the drug in 8 patients. Succinate decreased the hyperoxaluria in 14 of 19 patients. All patients had mild hypercalciuria and hypermagnesiuria. This study was done to determine the therapeutic value and the side effects in the treatment of absorptive hypercalciuria with sodium cellulose phosphate and of hyperoxaluria with succinate.

Adult↗
PubMed1999

Opposite effects of D-glucose pentaacetate and D-galactose pentaacetate anomers on insulin release evoked by succinic acid dimethyl ester in rat pancreatic islets.

Both alpha- and beta-D-glucose pentaacetate (1.7 mM each) augmented, to almost the same extent, insulin release caused by succinic acid dimethyl ester (10.0 mM) in rat pancreatic islets. The secretory response to these hexose esters largely exceeded that evoked by unesterified D-glucose tested at the same concentration (1.7 mM). The release of insulin provoked by succinic acid dimethyl ester was inhibited, however, by alpha-D-galactose pentaacetate, whilst being unaffected by beta-D-galactose pentaacetate (each also 1.7 mM). It appears, therefore, that the insulinotropic action of hexose esters is not attributable solely to the catabolism of their carbohydrate moiety, but may also involve a receptor system that displays anomeric specificity and can be directly activated or inhibited by the esters themselves. Hence, it is proposed that selected esters of non-nutrient monosaccharides may represent new tools to either stimulate insulin release in diabetes or prevent excessive hormonal secretion in situations of hyperinsulinemia.

Animals↗
PubMed1999

Effects of starvation and diabetes on the metabolism of [2,3-13C]succinic acid dimethyl ester in rat hepatocytes.

The metabolism of [2,3-13C]succinic acid dimethyl ester ([2,3-13C]-SAD) 10 mmol/L was examined in hepatocytes from overnight-fasted normal rats, 3-day starved rats, and overnight-fasted hereditarily diabetic Goto-Kakizaki (GK) rats. The amount of 13C-labeled succinate, fumarate, malate, lactate, alanine, and aspartate released by the hepatocytes was much higher in fasted normal rats than in starved or diabetic animals. Although the integrated areas of the 13C2 and 13C3 signals assigned to double-labeled malate, lactate, or alanine were not significantly different, the amount of single-labeled malate, lactate, alanine, and aspartate was higher in C3- versus C2-labeled isotopomers. The release of 13C-labeled glucose by the hepatocytes was lower in fasted versus starved or diabetic rats. Virtually all hexose molecules double-labeled in the C1-C2-C3 and/or C6-C5-C4 moieties corresponded to the [1,2-13C] and/or [5,6-13C] isotopomers. However, in the case of the single-labeled species, 13C-labeling of C1 (or C6) exceeded that of C2 (or C5). Both the single- and double-labeled molecules enriched with 13C in the C1-C2-C3 moiety were less abundant than those labeled in the C6-C5-C4 moiety, with such asymmetry being most marked in overnight-fasted normal rats, less pronounced in diabetic animals, and virtually absent in starved rats. These findings document that SAD is efficiently metabolized in hepatocytes, with its use as a gluconeogenic precursor being influenced by the nutritional and hormonal status of the animals. The present experiments also reinforce the view that asymmetrical labeling of glucose by 13C-labeled precursors is modulated by the relative contribution of exogenous and endogenous nutrients to the production of triose phosphates incorporated into the hexose.

Animals↗
PubMed1977

A comparative study of histoenzymological mapping on the distribution of acid and alkaline phosphatases and succinic dehydrogenase in the spinal cord and medulla oblongata of mouse.

The present contribution deals with the histochemical mapping of the distribution of acid and alkaline phosphatases and succinic dehydrogenase in the medulla oblongata and spinal cord of mouse. The acid phosphatase is observed in neurons of all the nuclei except nucleus cervicalis lateralis (NC), though the activity varies from intense to moderate. Only one nucleus, i.e., nucleus parvocellularis compactus (NPC) is midly positive. In alkaline phosphatase preparations most of the nuclei are either intensely positive or moderately positive. Few nuclei are midly positive. It is interesting to note that only two nuclei, i.e., area postrema (AP) and nucleus cervicalis lateralis (NC) are negative for this enzyme. Further the reaction in most of the nuclei is diffused. In the case of succinic dehydrogenase out of 36 nuclei studied, 9 nuclei are intensely positive, 11 areas are moderately positive, 7 are mildly positive and 9 are completely devoid of enzymatic activity. Nucleus reticularis superior demonstrates activity of very high order. The distribution of the above enzyme has been co-related with the functional significance of the various nuclei.

Acid Phosphatase↗
PubMed2000

Succinate dehydrogenase in Plasmodium falciparum mitochondria: molecular characterization of the SDHA and SDHB genes for the catalytic subunits, the flavoprotein (Fp) and iron-sulfur (Ip) subunits.

Mitochondria of malaria parasites generate a membrane potential through an electron transport system that is a possible target of primaquine and a new anti-malarial drug, atovaquone. However, little information is available for conclusive understanding of the respiratory chain in Plasmodium mitochondria. In the present study, we cloned and characterized from Plasmodium falciparum the genes for the catalytic subunits, SDHA for the flavoprotein (Fp) and SDHB for iron-sulfur protein (Ip), of succinate-ubiquinone oxidoreductase (complex II), which is a marker enzyme for mitochondria and links the TCA cycle and respiratory chain directly. Each of the two genes contains a single open reading frame (ORF), which are located on different chromosomes, 1860 nucleotides on chromosome 10 for SDHA and 963 nucleotides on chromosome 12 for SDHB. The expression of these genes in asynchronous erythrocytic stage cells was confirmed by observation of 3.3 and 2.4 kb transcripts from the SDHA and SDHB genes, respectively. The SDHA and SDHB genes encode proteins of 620 (Fp) and 321 (Ip) amino acids with molecular masses of 69.2 and 37.8 kDa, respectively. A mitochondrial presequence essential for the import of mitochondrial proteins encoded by nuclear DNA, as well as almost all the conserved amino acids indispensable for substrate binding and the catalytic reaction were found in these peptides, indicating the functional importance of this enzyme in the parasite. Interestingly, a P. falciparum-specific insertion and a unicellular organism-specific deletion were found in the amino acid sequence of Fp. This is the first report of the primary structure of the protozoan succinate dehydrogenase.

Amino Acid Sequence↗
PubMed2003

Inhibition of succinic semialdehyde dehydrogenase activity by alkenal products of lipid peroxidation.

Lipid peroxidation causes the generation of the neurotoxic aldehydes acrolein and 4-hydroxy-trans-2-nonenal (HNE). These products are elevated in neurodegenerative diseases and acute CNS trauma. Previous studies demonstrate that mitochondrial class 2 aldehyde dehydrogenase (ALDH2) is susceptible to inactivation by these alkenals. In the liver and brain another mitochondrial aldehyde dehydrogenase, succinic semialdehyde dehydrogenase (SSADH/ALDH5A1), is present. In this study, we tested the hypothesis that aldehyde products of lipid peroxidation inhibit SSADH activity using the endogenous substrate, succinic semialdehyde (SSA, 50 microM). Acrolein potently inhibited SSADH activity (IC(50)=15 microM) in rat brain mitochondrial preparations. This inhibition was of an irreversible and noncompetitive nature. HNE inhibited activity with an IC(50) of 110 microM. Trans-2-hexenal (HEX) and crotonaldehyde (100 microM each) did not inhibit activity. These data suggest that acrolein and HNE disrupt SSA metabolism and may have subsequent effects on CNS neurochemistry.

Acrolein↗
PubMed2003

Reversible and irreversible inhibitory activity of succinic and maleic acid derivatives on acetylcholinesterase.

Aryl succinic and maleic acid derivatives are potent inhibitors of bovine acetylcholinesterase in vitro. Succinic acid aminophenol derivatives 1b-e and 2b-d act as reversible inhibitors of acetylcholinesterase, while maleic acid aminophenol derivatives 3b-d and 4c-e act as choline subsite-directed irreversible inhibitors, detected by dialysis in the presence of edrophonium. Linear relationships between the logarithm of the velocity of hydrolysis of acetylcholine plotted against the time of incubation at several different inhibitor concentrations were determined. The K(i) for reversible competitive inhibitors was determined. For irreversible inhibitors the K(i) for the dissociation constant of the enzyme-inhibitor complex at the beginning of the recognition process was also determined as well as the inactivation constant of the enzyme-inhibitor adduct formation k(+2) and the bimolecular inhibition constant k(i) for the inhibition of acetylcholinesterase by aminophenol derivatives 3b-d and 4c-e. The conclusions of this study can be summarized as follows for both families: (a) the aromatic moiety played a critical role in the recognition of the active site; (b) in case of the reversible inhibitor, when the ester function took the place of the hydroxyl fragment, there was an important increase in the affinity; and (c) the distance between phenolic hydroxyl and nitrogen was critical because the inhibition is ortho<<meta<para.

Acetylcholinesterase↗
PubMed2003

Enhanced film-forming properties for ethyl cellulose and starch acetate using n-alkenyl succinic anhydrides as novel plasticizers.

PURPOSE: The aim of this study was to investigate the ability of n-alkenyl succinic anhydrides (n-ASAs) to improve the film-forming characteristics of a novel coating polymer, potato starch acetate degree of substitution 2.8 (SA). n-ASAs were also applied to improve the otherwise brittle properties of ethyl cellulose (EC) aqueous dispersion (Aquacoat) and EC solvent-based films. METHODS: The effectiveness of two n-ASAs, 2-octenyl succinic anhydride (OSA) and 2-dodecen-1-ylsuccinic anhydride were evaluated as plasticizers. Mechanical properties, both water vapor and drug permeabilities, and glass transition temperatures of the cast free films were measured. Triethyl citrate and dibutyl sebacate were used as reference plasticizers. RESULTS: The long hydrocarbon chain of n-ASA, with its accessible carbonyl groups, enabled a strong plasticization effect on the tested polymers. Due to the excellent mechanical properties (i.e., a tough film structure with considerable flexibility) and low permeability of the plasticized films, n-ASAs, and especially OSA proved to be an ideal plasticizer particularly for EC based coatings. Also, the EC aqueous dispersion plasticized with n-ASAs resulted in a markedly enhanced coalescence of the colloidal polymer particles, even at low drying temperatures. CONCLUSIONS: In applications where a coating with high flexibility is required, n-ASAs can be used as plasticizers at moderately high concentrations (up to 60-70%, w/w) without losing the high tensile strength, excellent toughness and low permeability of EC and SA films.

Algorithms↗
PubMed1999

[Leigh syndrome and leukodystrophy due to partial succinate dehydrogenase deficiency: regression with riboflavin].

UNLABELLED: Succinate dehydrogenase (SDH) deficiency is rare. Clinical manifestations can appear in infancy with a marked impairment of psychomotor development with pyramidal signs and extrapyramidal rigidity. CASE REPORT: A 10-month-old boy developed severe neurological features, evoking a Leigh syndrome; magnetic resonance imaging showed features of leukodystrophy. A deficiency in the complex II respiratory chain (succinate dehydrogenase [SDH]) was shown. The course was remarkable by the regression of neurological impairment under treatment by riboflavin. The delay of psychomotor development, mainly involving language, was moderate at the age of 5 years. CONCLUSION: The relatively good prognosis of this patient, despite severe initial neurological impairment, may be due to the partial enzyme deficiency and/or riboflavin administration.

Basal Ganglia Diseases↗
PubMed1998

Alkylation of succinates: synthesis of Ro 32-3555.

A short synthesis, based on a succinate acylation-alkylation-decarboxylation approach, of the clinical compound Ro 32-3555 is reported. The nature of the selectivity in the mono-alkylation of succinates was examined under varying enolization conditions and in the presence of chaotropic additives.

Alkylation↗