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PubMed2002

Structure of human succinic semialdehyde dehydrogenase gene: identification of promoter region and alternatively processed isoforms.

Mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase (ALDH5A1, SSADH) represents the last enzyme in the GABA catabolism and irreversibly oxidizes SSA to succinate. In human, SSADH deficiency results in 4-hydroxybutyric aciduria, an autosomal recessive disorder due to an accumulation of GABA and 4-hydroxybutyric acid in the CNS. We already identified SSADH gene on human chromosome 6p22 and characterized the coding region. Furthermore, we described the first two mutations causing the disease. We report here the complete cDNA and genomic structure of the gene. A single transcription start site was identified by RNase protection 122 bp upstream of the ATG. EST database search and reporter gene constructs of the 3(') genomic region showed that the two major SSADH mRNA isoforms are due to alternative polyadenylation sites. The two mRNAs of 1827 and 5225 nt were analyzed for differential stability and translation efficiency. The analysis of mRNA turnover showed that both SSADH transcripts are equally stable. Similarly, a measurement of polysomal association capability of the two GFP-SSADH reporter mRNAs (containing the 3' UTR regions of the two SSADH mRNAs) did not reveal any difference. However, we cannot exclude the fact that differential properties could be restricted to particular physiological conditions and/or specific tissues. We have also identified an alternatively spliced small exon, which may lead to a novel isoform of the enzyme. Furthermore, we report here on naturally occurring missense variants, which may significantly contribute to inter-individual variation of SSADH activity, possibly influencing GABA and GHB endogenous levels.

3' Untranslated Regions↗
PubMed1985

A comparative study of the succinate dehydrogenase-fumarate reductase complex in the genus Trichinella.

Succinate dehydrogenase and fumarate reductase activities from a particulate fraction of 4 isolates of the supposed 'species' of Trichinella, T. spiralis, T. pseudospiralis, T. nativa and T. nelsoni have been determined using spectrophotometric methods. The 'in vitro' effect of the anthelmintics thiabendazole, mebendazole and ivermectin on succinate dehydrogenase and fumarate reductase activities from the above isolates is also described. The significance of the results is discussed in the context of the controversy that surrounds speciation of the genus Trichinella.

Animals↗
PubMed2006

Fascination with the conformational analysis of succinic acid, as evaluated by NMR spectroscopy, and why.

A serendipitous effort to use NMR spectroscopy to determine the conformational preferences of succinate monoanion opened a Pandora's box of unexpected uncertainties as to what influences such preferences of succinic acid in its various ionization states, not only in water but also in other less polar protic solvents, as well as a range of aprotic solvents. The dianion in aprotic solvents shows substantial gauche preferences, which give the appearance of violating Coulomb's law.

Magnetic Resonance Spectroscopy↗
PubMed1995

Transmembrane topology and axial ligands to hemes in the cytochrome b subunit of Bacillus subtilis succinate:menaquinone reductase.

The membrane-anchoring subunit of Bacillus subtilis succinate:menaquinone reductase is a protein of 202 residues containing two protoheme IX groups with bis-histidine axial ligation. Residues His13, His28, His70, His113, and His155 are the possible heme ligands. The transmembrane topology of this cytochrome was analyzed using fusions to alkaline phosphatase. The results support a proposed model with five transmembrane polypeptide segments and the N-terminus exposed to the cytoplasm. Mutant B. subtilis cytochromes containing a His13-->Tyr, a His28-->Tyr, and a His113-->Tyr mutation, respectively, were produced in Escherichia coli, partially purified, and analyzed. In addition, succinate: menaquinone reductase containing the His13-->Tyr mutation in the anchor subunit was overproduced in B. subtilis, purified, and characterized. The data demonstrate that His13 is not an axial heme ligand. Thermodynamic and spectroscopic properties of the cytochrome are, however, affected by the His13-->Tyr mutation; compared to wild type, the redox potentials of both hemes are negatively shifted and the gmax signal in the EPR spectrum of the high-potential heme is shifted from 3.68 to 3.50. From the combined results we conclude that His28 and His113 function as axial ligands to the low-potential heme, which is located in the membrane near the outer surface of the cytoplasmic membrane. Residues His70 and His155 ligate the high-potential heme, which is positioned close to His13 in the protein, near the inner surface of the membrane.

Alkaline Phosphatase↗
PubMed1986

Bacillus subtilis mutant succinate dehydrogenase lacking covalently bound flavin: identification of the primary defect and studies on the iron-sulfur clusters in mutated and wild-type enzyme.

Succinate dehydrogenase consists of two protein subunits and contains one FAD and three iron-sulfur clusters. The flavin is covalently bound to a histidine in the larger, Fp, subunit. The reduction oxidation midpoint potentials of the clusters designated S-1, S-2, and S-3 in Bacillus subtilis wild-type membrane-bound enzyme were determined as +80, -240, and -25 mV, respectively. Magnetic spin interactions between clusters S-1 and S-2 and between S-1 and S-3 were detected by using EPR spectroscopy. The point mutations of four B. subtilis mutants with defective Fp subunits were mapped. The gene of the mutant specifically lacking covalently bound flavin in the enzyme was cloned. The mutation was determined from the DNA sequence as a glycine to aspartate substitution at a conserved site seven residues downstream from the histidine that binds the flavin in wild-type enzyme. The redox midpoint potential of the iron-sulfur clusters and the magnetic spin interactions in mutated succinate dehydrogenases were indistinguishable from the those of the wild type. This shows that flavin has no role in the measured magnetic spin interactions or in the structure and stability of the iron-sulfur clusters. It is concluded from sequence and mutant studies that conserved amino acid residues around the histidyl-FAD are important for FAD binding; however, amino acids located more than 100 residues downstream from the histidyl in the Fp subunit can also effect flavinylation.

Bacillus subtilis↗
PubMed1981

Evidence for the existence of two classes of sulfhydryl groups essential for membrane-bound succinate dehydrogenase activity.

Kinetics of the inhibition of activated membrane-bound dehydrogenase by N-substituted maleimides were studied. Three maleimide derivatives having a different hydrophobic character (N-ethyl-, N-butyl-, and N-benzylmaleimide) were tested. The method developed by Ray & Koshland (Ray, W. J., Jr., & Koshland, D. E., Jr. (1961) J. Biol, Chem. 236, 1973-1979) was used for analyzing experimental data. The results showed that two classes of sulfhydryl groups, with quite different reactivities, were essential for catalytic activity. The most reactive sulfhydryl groups were located in the substrate site as revealed by the fact that they were protected against alkylation in the presence of succinate or a competitive inhibitor, malonate. However, ligands of the catalytic site did not completely prevent inactivation of succinate dehydrogenase. Analysis of the kinetics of the inhibition observed in the presence of substrate indicated that the slow-reacting sulfhydryl groups did not belong to the active site. Rate constant values of the reaction of each set of sulfhydryl groups with the three maleimide derivatives showed that the most reactive thiols were probably located in a hydrophobic microenvironment since alkylation of this set of sulfhydryl groups was sensitive to the hydrophobic character of the thiol reagent. The reactivity of the other class of sulfhydryl groups was not influenced by the nature of the substituent. When the enzyme was deactivated by oxaloacetate, the two classes of sulfhydryl groups became unreactive with the alkylating agents. Masking of these groups may reflect a conformational change of the enzyme.

Animals↗
PubMed1976

The effect of opposing effectors on activation level of succinate dehydrogenase: equilibrium and kinetic studies.

The activation of mitochondrial succinate dehydrogenase by various activators is a result of dissociation of oxaloacetate tightly bound to the nonactive enzyme. But, quantitative correlation between the effector concentrations and the active fraction of the enzyme was not at hand. In this study we measured the level of active succinate dehydrogenase equilibrated with a wide range of opposing effectors: oxaloacetate (1-500 muM) and activator (0.02-1.5 M NaBr). The results are compatible with a model assuming two stable forms of the enzyme: a nonactive enzyme-oxaloacetate complex and an active enzyme free of oxaloacetate. The active form is stabilized by binding two Br- and one H+. The rate of activation (ka) and exchange between enzyme bound and free oxaloacetate k(ex) were measured. Both ka and kex are hyperbolically dependent on Br- concentration but differ in magnitude and pH dependence. kex at infinite Br- concentration is pH dependent but ka is not. The two reactions, activation and exchange, also differ in their activation energy bein 32 and 21.5 kcal/mol, respectively. It is concluded that, in the course of activation, Br- interacts at two distinct steps. First to produce a ternary, nonactive [enzyme-oxaloacetate-Br-] complex. From this complex, oxaloacetate dissociates and the oxaloacetate-free enzyme assumes its active form. Finally, the active enzyme is stabilized by binding another Br-. The rate-limiting step in deactivation is binding of oxaloacetate to active enzyme. The complex formed undergoes a very rapid transformation to the stable nonactive form. This pathway, under certain conditions, can reverse its direction and contribute to the overall rate of activation. It is suggested that the equilibrium between the two stable forms of the enzyme can be reached by two parallel pathways, each contributing independently to the observed rate of activation, while the final equilibrium is determined by the free energy between the products and the reactants.

Animals↗
PubMed2000

Discovering new enzymes and metabolic pathways: conversion of succinate to propionate by Escherichia coli.

The Escherichia coli genome encodes seven paralogues of the crotonase (enoyl CoA hydratase) superfamily. Four of these have unknown or uncertain functions; their existence was unknown prior to the completion of the E. coli genome sequencing project. The gene encoding one of these, YgfG, is located in a four-gene operon that encodes homologues of methylmalonyl CoA mutases (Sbm) and acyl CoA transferases (YgfH) as well as a putative protein kinase (YgfD/ArgK). We have determined that YgfG is methylmalonyl CoA decarboxylase, YgfH is propionyl CoA:succinate CoA transferase, and Sbm is methylmalonyl CoA mutase. These reactions are sufficient to form a metabolic cycle by which E. coli can catalyze the decarboxylation of succinate to propionate, although the metabolic context of this cycle is unknown. The identification of YgfG as methylmalonyl CoA decarboxylase expands the range of reactions catalyzed by members of the crotonase superfamily.

Amino Acid Sequence↗
PubMedDate not supplied

Lipase-catalyzed transformation of poly(butylene adipate) and poly(butylene succinate) into repolymerizable cyclic oligomers.

The enzymatic degradation and repolymerization were carried out with the objectives of developing the chemical recycling of aliphatic polyester-type plastics, such as the poly(butylene adipate) (PBA), poly(butylene succinate), and poly(butylene adipate-co-succinate) copolymers which are typical biodegradable plastics. They were degraded by lipase in an organic solvent solution containing a small amount of water to produce cyclic oligomers mainly consisting of the cyclic diester. The produced cyclic oligomer was readily repolymerized by lipase to produce a polyester having an equal or higher molecular weight compared to the parent polymer. As an example, PBA having an Mw of 22,000 was almost quantitatively transformed by lipase CA (Novozym 435) in water-containing toluene at 50 degrees C into the corresponding cyclic oligomers mainly consisting of dimers. Thus, the obtained oligomers were readily polymerized by lipase CA to produce the PBA with an Mw of 52,000.

Adipates↗
PubMedDate not supplied

Novel biodegradable aliphatic poly(butylene succinate-co-cyclic carbonate)s with functional carbonate building blocks. 1. Chemical synthesis and their structural and physical characterization.

This study presents chemical synthesis, structural, and physical characterization of novel biodegradable aliphatic poly(butylene succinate-co-cyclic carbonate)s P(BS-co-CC) bearing functional carbonate building blocks. First, five kinds of six-membered cyclic carbonate monomers, namely, trimethylene carbonate (TMC), 1-methyl-1,3-trimethylene carbonate (MTMC), 2,2-dimethyl-1,3-trimethylene carbonate (DMTMC), 5-benzyloxytrimethylene carbonate (BTMC), and 5-ethyl-5-benzyloxymethyl trimethylene carbonate (EBTMC), were well prepared from ethyl chloroformate and corresponding diols at 0 degrees C in THF solution with our modified synthetic strategies. Then, a series of new P(BS-co-CC)s were synthesized at 210 degrees C through a simple combination of poly-condensation and ring-opening-polymerization (ROP) of hydroxyl capped PBS macromers and the prepared carbonate monomers, and titanium tetra-isopropoxide Ti(i-OPr)4 was used as a more suitable catalyst of 5 candidate catalysts which could concurrently catalyze poly-condensation and ROP. By means of NMR, GPC, FTIR, and thermal analytical instruments, macromolecular structures and physical properties have been characterized for these aliphatic poly(ester carbonate)s. The experimental results indicated that novel biodegradable P(BS-co-CC)s were successfully synthesized with number average molecular weight Mn ranging from 24.3 to 99.6 KDa and various CC molar contents without any detectable decarboxylation and that the more bulky side group was attached to a cyclic carbonate monomer, the lower reactivity for its copolymerization would be observed. The occurrences of 13C NMR signal splitting of succinyl carbonyl attributed to the BS building blocks could be proposed due to the randomized sequences of BS and CC building blocks. FTIR characterization indicated two distinct absorption bands at 1716 and 1733 approximately 1735 cm(-1), respectively, stemming from carbonyl stretching modes for corresponding BS and CC units. With regard to their thermal properties, it is seen that the synthesized P(BS-co-CC)s exhibited thermal degradation temperatures 10 approximately 20 degrees C higher than that of PBS. On the basis of the synthesized P(BS-co-BTMC)s, new aliphatic poly(butylene succinate-co-5-hydroxy trimethylene carbonate)s were further synthesized, bearing hydrophilic hydroxyl pendant functional groups through an optimized Pd/C catalyzed hydrogenation. These semi-crystalline new biodegradable aliphatic copolymers with tunable physical properties and functional carbonate building blocks might be expected as potential new biomaterials.

Biocompatible Materials↗
PubMed2006

Syntheses, crystal structures, and magnetic properties of [Ln(III)2(Succinate)3(H2O)2].0.5H2O [Ln = Pr, Nd, Sm, Eu, Gd, and Dy] polymeric networks: unusual ferromagnetic coupling in Gd derivative.

Lanthanide-organic coordination polymeric networks of [Ln(III)2(suc)3(H2O)2].0.5H2O [suc = succinate dianion, Ln = Pr (1), Nd (2), Sm (3), Eu (4), Gd (5), and Dy (6)] have been synthesized and characterized by single-crystal X-ray diffraction analyses. The structural determination reveals that complexes are isomorphous, all crystallizing in monoclinic system, space group I2/a(.) The complexes possess a 3D architecture with Ln ion in a nine-coordination geometry attained by eight oxygen atoms from succinate and one oxygen atom from an aqua ligand. Low-temperature magnetic study indicates that ferromagnetic interaction is present in case of Gd(III) and Dy(III). Antiferromagnetic interaction is observed for the rest of the complexes. Density functional theory calculations are performed which support the existence of a superexchange ferromagnetic coupling in Gd(III) ions, whereas classical crystal field model has been applied to study the complexes 1, 2, 3, and 6.

Crystallography, X-Ray↗
PubMed2002

Nonactin biosynthesis: the initial committed step is the condensation of acetate (malonate) and succinate.

Nonactin is a macrotetrolide antibiotic produced by Streptomyces griseus subsp. griseus ETH A7796 that has shown activity against the P170-glycoprotein efflux pump associated with multiple drug resistant cancer cells. Nonactin is a polyketide, albeit a highly atypical one. The structure is composed of two units of each of the enantiomers of nonactic acid, arranged in a macrocycle, so that the molecule has S4 symmetry and is achiral. The monomer units, (+)- and (-)-nonactic acid, are derived from acetate, succinate, and propionate, although the exact details of the assembly process are quite unclear. We have used feeding experiments with a series of multiple stable isotope labeled precursors to elucidate the details of the first committed step of nonactic acid biosynthesis. We have found that the (13)C label from 3-ketoadipate is incorporated specifically into both nonactic acid and its homologue, homononactic acid. The data conclusively show that the first committed step of nonactin biosynthesis is the coupling of a succinate derivative with either acetate or malonate. The differentiation into either nonactate or homononactate occurs after the initial condensation; the homologues are not derived from use of a different "starter unit" by the nonactate polyketide synthase. The first step of nonactin biosynthesis involves achiral intermediates; differentiation between the known enantiocomplementary biosynthesis pathways to form each enantiomer of the precursor monomer units likely occurs after the initial condensation reaction.

Anti-Bacterial Agents↗
PubMed2004

Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids.

A crystal engineering strategy for designing cocrystals of pharmaceuticals is presented. The strategy increases the probability of discovering useful cocrystals and decreases the number of experiments that are needed by selecting API:guest combinations that have the greatest potential of forming energetically and structurally robust interactions. Our approach involves multicomponent cocrystallization of hydrochloride salts, wherein strong hydrogen bond donors are introduced to interact with chloride ions that are underutilized as hydrogen bond acceptors. The strategy is particularly effective in producing cocrystals of amine hydrochlorides with neutral organic acid guests. As an example of the approach, we report the discovery of three cocrystals containing fluoxetine hydrochloride (1), which is the active ingredient in the popular antidepressant Prozac. A 1:1 cocrystal was prepared with 1 and benzoic acid (2), while succinic acid and fumaric acid were each cocrystallized with 1 to provide 2:1 cocrystals of fluoxetine hydrochloride:succinic acid (3) and fluoxetine hydrochloride:fumaric acid (4). The presence of a guest molecule along with fluoxetine hydrochloride in the same crystal structure results in a solid phase with altered physical properties when compared to the known crystalline form of fluoxetine hydrochloride. On the basis of intrinsic dissolution rate experiments, cocrystals 2 and 4 dissolve more slowly than 1, and 3 dissolves more quickly than 1. Powder dissolution experiments demonstrated that the solid present at equilibrium corresponds to the cocrystal for 2 and 4, while 3 completely converted to 1 upon prolonged slurry in water.

Benzoic Acid↗
PubMed2004

Identification of monomenthyl succinate, monomenthyl glutarate, and dimenthyl glutarate in nature by high performance liquid chromatography-tandem mass spectrometry.

Menthol, menthone, and other natural compounds provide a cooling effect and a minty flavor and have found wide application in chewing gum and oral care products. Monomenthyl succinate, monomenthyl glutarate, and dimenthyl glutarate provide a cooling effect without the burning sensation associated with menthol. Additionally, because they do not have a distinct flavor, they can be used in applications other than mint flavors. Because these menthyl esters have not been reported in nature, we undertook to identify a natural source for these cooling compounds. Using high performance liquid chromatography-tandem mass spectrometry, monomenthyl succinate was identified in Lycium barbarum and Mentha piperita, and monomenthyl glutarate and dimenthyl glutarate were identified in Litchi chinesis. The identifications were based on the correlation of mass spectrometric and chromatographic retention time data for the menthyl esters in the extracts with authentic standards which resulted in a 99.980% confidence in the identifications.

Chromatography, High Pressure Liquid↗
PubMed2006

Identification of monomenthyl succinate in natural mint extracts by LC-ESI-MS-MS and GC-MS.

Fresh and dried mint leaves Mentha piperita (peppermint) and Mentha spicata (spearmint) were extracted in two different ways and the extracts investigated by high performance liquid chromatography-tandem mass spectrometry. All the ethanolic extracts prepared with Soxhlet apparatus were used in the identification of monomenthyl succinate as previously reported. The highest level was found in fresh spearmint leaves. The analysis of the extractions, prepared under mild conditions using a fluorinated solvent (HFC 134-a), confirmed the natural occurrence of monomenthyl succinate in the leaves, ruling out the hypothesis that this constituent could be an artifact of the Soxhlet extraction process. A method for identifying this compound in such a fluorinated solvent extract of mint leaf using preliminary esterification with diazomethane and then GC-MS is described.

Chromatography, High Pressure Liquid↗
PubMed1999

New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors.

Tumor necrosis factor alpha convertase (TACE), the enzyme responsible for the processing of pro-TNFalpha to TNFalpha, has been reported to be a metalloproteinase closely related to matrix metalloproteinases (MMPs). Current inhibitors of TACE such as succinate-based hydroxamic acids exemplified by Marimastat (TACE IC(50): 3.8 nM; blood IC(50): 7 microM) and BB1101 (TACE IC(50): 0.2 nM; blood IC(50): 2.3 microM) suffer from modest potency in blood and poor in vivo properties. The introduction of new bulky alpha-substituents into these succinate-based hydroxamic acids was studied. Substituents such as thioethers, sulfonamides, and ethers showed improved potency against TACE when compared with Marimastat. Although this improvement did not translate into better blood potency for thioether or ether substituents, the sulfonamide series exhibited improved potency both against TACE and in blood when compared with Marimastat. Optimization of this sulfonamide series has culminated in the identification of heterocyclic bicyclic sulfonamides such as 3t (TACE IC(50): 0.57 nM; blood IC(50): 0.28 microM).

ADAM Proteins↗
PubMed2002

An efficient method for synthesis of succinate-based MMP inhibitors.

A differentially protected fumarate undergoes radical addition followed by allylstannane trapping to provide disubstituted succinates in good yields and high anti diastereoselectivity. The conversion of the succinate to a known MMP inhibitor has been accomplished. [reaction: see text]

Enzyme Inhibitors↗
PubMed2000

Effect of cisplatin on mitochondrial protein, glutathione, and succinate dehydrogenase in Dalton lymphoma-bearing mice.

Cisplatin treatment of tumor-bearing mice resulted a significant decrease of protein in the tissues studied (liver, kidney, and Dalton lymphoma) and also in their mitochondrial fractions. As compared to respective tissues, the protein decrease was noted to be more conspicuous in their mitochondrial fractions. Similarly, mitochondrial glutathione also decreased significantly in the tissues. However, succinate dehydrogenase activity was selectively decreased in the kidney and Dalton lymphoma cells, whereas in liver it remained almost unchanged. An increase in serum urea concentration and kidney mitochondrial lipid peroxidation was also observed after cisplatin treatment. It is suggested that the cisplatin-induced biochemical changes in mitochondria involving mitochondrial protein, glutathione, and succinate dehydrogenase could be the important potent cellular sites contributing to toxicity/cytotoxicity after cisplatin treatment.

Animals↗