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PubMed2006

A cost effective fermentative production of succinic acid from cane molasses and corn steep liquor by Escherichia coli.

AIM: Development and optimization of an efficient and inexpensive medium for succinic acid production by Escherichia coli under anaerobic conditions. METHODS AND RESULTS: Initially, 0.8 gl(-1) of succinic acid was produced in 60 h in 300-ml medium. On optimization, glucose and peptone were replaced by cane molasses and corn steep liquor. Three hundred ml of this medium was inoculated with 4% (v/v) of seed inoculum, incubated at 39 degrees C for 72 h, resulted in 7.1 gl(-1) of succinic acid in 36 h. Scale up in a 10-l fermentor under conditions of controlled pH and continuous CO2 supply in this medium resulted in 17 gl(-1) of succinic acid in 30 h. CONCLUSIONS: A ninefold increase in succinic acid production was obtained in 500-ml anaerobic bottles with optimized medium having cane molasses and corn steep liquor as against initial medium containing glucose and peptone. However, a subsequent scale up in a 10-l fermentor resulted in a 2.5-fold increase in succinic acid production as against optimized medium used in 500-ml anaerobic bottles. SIGNIFICANCE AND IMPACT OF THE STUDY: Succinic acid production was enhanced in medium consisting of inexpensive carbon and nitrogen sources in a shorter span of time.

Animals↗

PubMed1989

[Determining the conditions for stimulation of levorin biosynthesis in the presence of succinic acid].

Conditions promoting the stimulating effect of succinic acid on biosynthesis of levorin were determined. The optimal concentration of succinate was shown to be equal to 0.05-0.3 per cent and the best time for the addition was before inoculation. The most pronounced stimulating effect was observed when the initial pH value of the fermentation medium was equal to 7.0. The important role of ammonium nitrogen in manifestation of the succinic acid stimulating effect on biosynthesis of levorin was suggested.

Anti-Bacterial Agents↗

PubMed1986

Assay of prolyl 4-hydroxylase by the chromatographic determination of [14C]succinic acid on ion-exchange minicolumns.

An assay for prolyl 4-hydroxylase (EC 1.14.11.2) is described which measures succinic acid produced during the decarboxylation of 2-oxoglutaric acid in the presence of poly(L-Pro-Gly-L-Pro). [1-14C]Succinic acid was separated from its precursor 2-oxo[5-14C]glutaric acid by using ion-exchange minicolumns. The contamination of succinic acid by 2-oxoglutaric acid was approx. 1%, and the recovery of succinic acid was 100%. Kinetic parameters of prolyl 4-hydroxylase measured by the assay showed good agreement with published values. Our experience indicates that the measurement of prolyl 4-hydroxylase by the production of succinic acid is especially suited to investigations involving large numbers of assays.

Carbon Radioisotopes↗

PubMed2004

Succinic acid adsorption from fermentation broth and regeneration.

More than 25 sorbents were tested for uptake of succinic acid from aqueous solutions. The best resins were then tested for successive loading and regeneration using hot water. The key desired properties for an ideal sorbent are high capacity, complete stable regenerability, and specificity for the product. The best resins have a stable capacity of about 0.06 g of succinic acid/g of resin at moderate concentrations (1-5 g/L) of succinic acid. Several sorbents were tested more exhaustively for uptake of succinic acid and for successive loading and regeneration using hot water. One resin, XUS 40285, has a good stable isotherm capacity, prefers succinate over glucose, and has good capacities at both acidic and neutral pH. Succinic acid was removed from simulated media containing salts, succinic acid, acetic acid, and sugar using a packed column of sorbent resin, XUS 40285. The fermentation byproduct, acetate, was completely separated from succinate. A simple hot water regeneration successfully concentrated succinate from 10 g/L (inlet) to 40-110 g/L in the effluent. If successful, this would lower separation costs by reducing the need for chemicals for the initial purification step. Despite promising initial results of good capacity (0.06 g of succinic/g of sorbent), 70% recovery using hot water, and a recovered concentration of >100 g/L, this regeneration was not stable over 10 cycles in the column. Alternative regeneration schemes using acid and base were examined. Two (XUS 40285 and XFS-40422) showed both good stable capacities for succinic acid over 10 cycles and >95% recovery in a batch operation using a modified extraction procedure combining acid and hot water washes. These resins showed comparable results with actual broth.

Adsorption↗

PubMed2001

Metabolic flux analysis for succinic acid production by recombinant Escherichia coli with amplified malic enzyme activity.

A pfl ldhA double mutant Escherichia coli strain NZN111 was used to produce succinic acid by overexpressing the E. coli malic enzyme. Escherichia coli strain NZN111 harboring pTrcML produced 6 and 8 g/L of succinic acid from 20 g/L of glucose in flask culture at 37 degrees C and 30 degrees C, respectively. When NZN111(pTrcML) was cultured at 30 degrees C with intermittent glucose feeding the final succinic acid concentration obtained was 9.5 g/L and the ratio of succinic acid to acetic acid was 13:1. This system could not be analyzed by conventional metabolic flux analysis techniques, since some pyruvate and succinic acid were accumulated intracellularly. Therefore, a new flux analysis method was proposed by introducing intracellular pyruvate and succinic acid pools. By this new method the concentrations of intracellular metabolites were successfully predicted and the differences between the measured and calculated reaction rates could be considerably reduced.

Acetyltransferases↗

PubMed1994

Metabolic effects and fate of succinic acid methyl esters in rat hepatocytes.

The metabolic fate and metabolic effects of succinic acid methyl esters were examined in rat isolated hepatocytes. Both the monomethyl ester (SAM) and dimethyl ester (SAD) of succinic acid inhibited D-glucose metabolism. Such an inhibition affected, in order of increasing severity, the direct incorporation of D-glucose into glycogen and futile cycling between the hexose and its 6-phosphate ester, the phosphorylation of D-glucose, the generation of triose phosphates from the hexose, and the production of 14C-labeled lactate, pyruvate, and amino acids from D-[U-14C]glucose and its oxidation. The dimethyl ester of [1,4-14C]succinic acid ([1,4-14C]SAD) or [2,3-14C]-succinic acid ([2,3-14C]SAD) was efficiently converted to acidic metabolites. The oxidation of [1,4-14C]SAD largely exceeded that of [2,3-14C]SAD. Inversely the generation of newly formed radioactive D-glucose and glycogen appeared higher in cells exposed to [2,3-14C]SAD, rather than [1,4-14C]SAD. It is proposed that SAM and SAD are suitable nutrients both to cover the energy need of hepatocytes and to act as gluconeogenic precursors.

Amino Acids↗

PubMed2003

Batch and continuous cultures of Mannheimia succiniciproducens MBEL55E for the production of succinic acid from whey and corn steep liquor.

Mannheimia succiniciproducens MBEL55E isolated from bovine rumen is able to produce a large amount of succinic acid in a medium containing glucose, peptone, and yeast extract. In order to reduce the cost of the medium, whey and corn steep liquor (CSL) were used as substrates for the production of succinic acid by M. succiniciproducens MBEL55E. Anaerobic batch cultures of M. succiniciproducens MBEL55E in a whey-based medium containing CSL resulted in the production of succinic acid with a yield of 71% and productivity of 1.18 g/l/h, which are similar to those obtained in a whey-based medium containing yeast extract (72% and 1.21 g/l/h). Anaerobic continuous culture of M. succiniciproducens MBEL55E in a whey-based medium containing CSL resulted in a succinic acid yield of 69% and a succinic acid productivity as high as 3.90 g/l/h. These results show that succinic acid can be produced efficiently and economically by M. succiniciproducens MBEL55E from whey and CSL.

Animals↗

PubMedDate not supplied

Insulinotropic action of novel succinic acid esters.

The insulinotropic action of several new esters of succinic acid was assessed in isolated rat islets incubated in the presence of 7 mM D-glucose. An efficient secretory response was observed with the monobenzyl, monoisopropyl, monoallyl, monopropyl, monoethyl, monobutyl, dibutyl, dipropyl and diallyl esters of succinic acid. This indicates that it is possible to design esters of succinic acid which act as insulin secretagogues, while avoiding the undesirable generation of methanol that otherwise results from the use of either the monomethyl or dimethyl ester of this dicarboxylic acid.

Animals↗

PubMed1984

An enzymatic method for the determination of enantiomeric composition and absolute configuration of deuterated or tritiated succinic acid.

The distribution of hydrogen isotope between pro-R and pro-S positions of succinic acid has been determined by comparison of its isotopic content before and after incubation with isocitrate lyase. This enzyme, in the presence of glyoxylate, exchanges exclusively the pro-S protons of succinate with water (M. Sprecher, R. Berger, and D. B. Sprinson (1964) J. Biol. Chem. 239, 4268-4271). With [1-14C,2(R,S)-3H]succinate as substrate, the exchange was easily followed by the decrease of 3H/14C ratio (dried aliquots), which accounted for the high isotopic effect of this reaction. The final ratio was within +/- 5% of the theoretical one. The evolution of the exchange of deuterated succinate added with [1-14C,2(R,S)-3H]succinate acid was again followed by 3H/14C ratio. The deuterium content of [2,3-2H2]succinic acid, [2-2H2]succinic acid (derived from L-[4-2H2]glutamic acid by oxidation) and of the corresponding succinates isolated after incubation with isocitrate lyase was determined by gas chromatography-mass spectroscopy of their dimethylester under NH4+ chemical ionization. This method provides the basis for a quantitative measurement of the distribution of hydrogen isotopes in unsymmetrically 2-labeled succinate or 4-labeled glutamate.

Deuterium↗

PubMed1998

Simultaneous quantification of released succinic acid and a weakly basic drug compound in dissolution media.

A HPLC-method was developed to determine both fenoldopam, a weakly basic drug and succinic acid, a pH-adjuster for this drug in dissolution media. The usual assays for succinic acid were not applicable due to its low UV-absorption, the low pH-value of samples or the presence of buffer salts and fenoldopam. The described method is a simple non-ion-pair reversed phase HPLC-method using a fast scanning UV-detector and a PC software program for the quantification of both components. Succinic acid is detected at 205 nm and fenoldopam at 225 nm. The UV-spectrum is used to determine peak purity and to identify peaks (carried out at a 99.9% match). This is especially important as in some of the investigated samples an unknown peak elutes immediately after succinic acid, resulting in spurious high contents, if mistaken for succinic acid. The simple method accomplished the simultaneous quantification of both, succinic acid and fenoldopam, by an accurate, precise, specific and reproducible assay, with a linear range covering all concentrations relevant for dissolution testing. The method is stability indicating and can also be used for the quantification of fumaric acid, another pH-adjuster in dissolution media together with fenoldopam.

Chemistry, Pharmaceutical↗

PubMed2000

Batch and continuous cultivation of Anaerobiospirillum succiniciproducens for the production of succinic acid from whey.

Batch and continuous cultivation of Anaerobiospirillum succiniciproducens were systematically studied for the production of succinic acid from whey. Addition of 2.5 g l(-1) yeast extract and 2.5 g l(-1) polypeptone per 10 g l(-1) whey was most effective for succinic acid production from both treated and nontreated whey. When 20 g l(-1) nontreated whey and 7 g l(-1) glucose were used as cosubstrates, the yield and productivity of succinic acid reached at the end of fermentation were 95% and 0.46 g (1 h)(-1), respectively. These values were higher than those obtained using nontreated whey alone [93% and 0.24 g (1 h)(-1) for 20 g l(-1) whey]. Continuous fermentation of A. succiniciproducens at an optimal dilution rate resulted in the production of succinic acid with high productivity [1.35 g (1 h)(-1)], high conversion yield (93%), and higher ratio of succinic acid to acetic acid (5.1:1) from nontreated whey.

Bacteria, Anaerobic↗

PubMed1988

Evaluation of 99mtechnetium-dimercapto-succinic acid renal scans in experimental acute pyelonephritis in piglets.

We evaluated the sensitivity and specificity of 99mtechnetium-dimercapto-succinic acid renal scans in the detection and localization of experimental acute pyelonephritis in piglets. To create pyelonephritis vesicoureteral reflux of infected urine was surgically induced in 22 piglets. Nine animals were evaluated with a dimercapto-succinic acid renal scan at 1 week and 13 at 2 weeks. Autopsy and histopathological examination of the kidneys were performed subsequently. The location and extent of the inflammatory response found on histopathological examination were compared to dimercapto-succinic acid renal scan findings in a blinded fashion. Of the 22 kidneys subjected to vesicoureteral reflux 15 had positive histopathological findings of acute pyelonephritis, including 13 detected by the dimercapto-succinic acid renal scan findings. The 2 kidneys in which inflammation was not detected had only minimal grade I lesions and were grossly normal. There were no false positive scans in any of these kidneys. The sensitivity of the scan for detection of acute pyelonephritis in the kidneys subjected to reflux was 87 per cent and the specificity was 100 per cent. Furthermore, in these same kidneys the dimercapto-succinic acid renal scan findings correctly predicted the presence or absence of individual pyelonephritic lesions in 62 of 66 poles for an over-all agreement rate of 94 per cent. Thus, dimercapto-succinic acid renal cortical imaging is a highly sensitive and reliable imaging modality to detect and localize experimental acute pyelonephritis in piglets.

Acute Disease↗

PubMed2002

Effects of growth mode and pyruvate carboxylase on succinic acid production by metabolically engineered strains of Escherichia coli.

Escherichia coli NZN111, which lacks activities for pyruvate-formate lyase and lactate dehydrogenase, and AFP111, a derivative which contains an additional mutation in ptsG (a gene encoding an enzyme of the glucose phophotransferase system), accumulate significant levels of succinic acid (succinate) under anaerobic conditions. Plasmid pTrc99A-pyc, which expresses the Rhizobium etli pyruvate carboxylase enzyme, was introduced into both strains. We compared growth, substrate consumption, product formation, and activities of seven key enzymes (acetate kinase, fumarate reductase, glucokinase, isocitrate dehydrogenase, isocitrate lyase, phosphoenolpyruvate carboxylase, and pyruvate carboxylase) from glucose for NZN111, NZN111/pTrc99A-pyc, AFP111, and AFP111/pTrc99A-pyc under both exclusively anaerobic and dual-phase conditions (an aerobic growth phase followed by an anaerobic production phase). The highest succinate mass yield was attained with AFP111/pTrc99A-pyc under dual-phase conditions with low pyruvate carboxylase activity. Dual-phase conditions led to significant isocitrate lyase activity in both NZN111 and AFP111, while under exclusively anaerobic conditions, an absence of isocitrate lyase activity resulted in significant pyruvate accumulation. Enzyme assays indicated that under dual-phase conditions, carbon flows not only through the reductive arm of the tricarboxylic acid cycle for succinate generation but also through the glyoxylate shunt and thus provides the cells with metabolic flexibility in the formation of succinate. Significant glucokinase activity in AFP111 compared to NZN111 similarly permits increased metabolic flexibility of AFP111. The differences between the strains and the benefit of pyruvate carboxylase under both exclusively anaerobic and dual-phase conditions are discussed in light of the cellular constraint for a redox balance.

Aerobiosis↗

PubMed1997

Potentiation of the insulinotropic and hypoglycemic action of gliquidone by succinic acid esters.

The monoethyl, monopropyl and monoisopropyl esters of succinic acid, administered intravenously at the dose of 2 micromol/g body weight, were found to increase the insulinotropic action of gliquidone (0.2 nmol/g body weight) in anaesthetized rats. The monoisopropyl ester of succinic acid also doubled the hypoglycemic action of gliquidone. These findings indicate that it is possible to design esters of succinic acid that are devoid of the risk of generating methanol by intracellular hydrolysis, and yet susceptible to increase both the insulinotropic and hypoglycemic responses to antidiabetic agents.

Animals↗

PubMed2005

Direct high-performance liquid chromatographic analysis of D-tocopheryl acid succinate and derivatives.

A method of analysis of a Vitamin E derivative D-tocopheryl acid succinate (TS) in biological fluids and commercially available products is necessary to study the kinetics of in vitro and in vivo metabolism, tissue distribution, and content uniformity. A simple and inexpensive high-performance liquid chromatographic method was developed for the direct determination of D-tocopheryl acid succinate in commercially available products, rat serum, and rat tissues. This method can also be applied to the determination of 15 Vitamin E derivatives. Rat serum (0.1 ml) was extracted with sodium dodecyl sulfate, ethanol, hexane, and then dried under nitrogen gas after addition of the internal standard, DL-alpha-tocopherol acetate. Separation was achieved on a C18 column with UV detection at 205 nm. The calibration curve for D-tocopheryl acid succinate was linear ranging from 0.025 to 100 microg/ml. The mean extraction efficiency was >92%. Precision of the assay was <5% (CV), and was within 5% at the limit of quantitation (0.025 microg/ml). Bias of the assay was lower than 5%, and was within 5% at the limit of quantitation. The assay was applied successfully to the serum and tissue distribution of D-tocopheryl acid succinate in rats, various Vitamin E derivatives, and content uniformity in commercially available products containing D-tocopheryl acid succinate.

Animals↗

PubMed2002

In silico metabolic pathway analysis and design: succinic acid production by metabolically engineered Escherichia coli as an example.

The intracellular metabolic fluxes can be calculated by metabolic flux analysis, which uses a stoichiometric model for the intracellular reactions along with mass balances around the intracellular metabolites. In this study, we have constructed in silico metabolic pathway network of Escherichia coli consisting of 301 reactions and 294 metabolites. Metabolic flux analyses were carried out to estimate flux distributions to achieve the maximum in silico yield of succinic acid in E. coli. The maximum in silico yield of succinic acid was only 83% of its theoretical yield. The lower in silico yield of succinic acid was found to be due to the insufficient reducing power, which could be increased to its theoretical yield by supplying more reducing power. Furthermore, the optimal metabolic pathways for the production of succinic acid could be proposed based on the results of metabolic flux analyses. In the case of succinic acid production, it was found that pyruvate carboxylation pathway should be used rather than phosphoenolpyruvate carboxylation pathway for its optimal production in E. coli. Then, the in silico optimal succinic acid pathway was compared with conventional succinic acid pathway through minimum set of wet experiments. The results of wet experiments indicate that the pathway predicted by in silico analysis is more efficient than conventional pathway.

Computational Biology↗

PubMed1991

X-ray studies on crystalline complexes involving amino acids and peptides. XXIII. Variability in ionization state, conformation and molecular aggregation in the complexes of succinic acid with DL- and L-lysine.

Crystalline complexes of succinic acid with DL- and L-lysine have been prepared and analysed by X-ray diffraction. DL-Lysine complex: C6H15N2O2+.-1/2C4H4O4(2-).1/2C4H6O4, Mr = 264.2, P1, a = 5.506 (4), b = 8.070 (2), c = 14.089 (2) A, alpha = 92.02 (1), beta = 100.69 (3), gamma = 95.85 (3) degrees, Z = 2, Dx = 1.44 g cm-3, R = 0.059 for 2546 observed reflections. Form I of the L-lysine complex: C6H15N2O2+.C4H5O4-, Mr = 264.2, P1, a = 5.125 (2), b = 8.087 (1), c = 8.689 (1) A, alpha = 112.06 (1), beta = 99.08 (2), gamma = 93.77 (2) degrees, Z = 1, Dm = 1.34 (3), Dx = 1.34 g cm-3, R = 0.033 for 1475 observed reflections. Form II of the L-lysine complex: C6H15N2O2+.1/4C4H4O4(2-).-1/4C4H6O4.1/4(C4H5O4.. .H...C4H4O4)2-, Mr = 264.2, P1, a = 10.143 (4), b = 10.256 (2), c = 12.916 (3) A, alpha = 105.00 (2), beta = 99.09 (3), gamma = 92.78 (3) degrees, Z = 4, Dm = 1.37 (4), Dx = 1.38 g cm-3, R = 0.067 for 2809 observed reflections. The succinic acid molecules in the structures exhibit a variety of ionization states. Two of the lysine conformations found in the complexes have been observed for the first time in crystals containing lysine. Form II of the L-lysine complex is highly pseudosymmetric. In all the complexes, unlike molecules aggregate into separate alternating layers. The basic element of aggregation in the lysine layer in the complexes is an S2-type head-to-tail sequence.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1982

Effects of tocopherol (vitamin E) acid succinate on morphological alterations and growth inhibition in melanoma cells in culture.

The effects of various forms of tocopherol (vitamin E) on the growth and differentiation of mouse melanoma (B-16) and mouse fibroblast (L-cells) cells in culture were studied. D-alpha-tocopherol acid succinate induced morphological alterations and growth inhibition in melanoma cells. When vitamin E acid succinate was removed 4 days after treatment, the above changes remained irreversible for a period of 24 hr, after which resistant cells and partially affected cells renewed cell division and eventually reached confluency. The relative efficacy of D and DL forms of vitamin E acid succinate remains to be evaluated. However, other forms of vitamin E such as DL-alpha-tocopherol free alcohol, Aquasol DL-alpha-tocopherol acetate, DL-alpha-tocopherol nicotinate, or sodium succinate with an equivalent volume of ethanol, at similar concentrations, were ineffective. Vitamin E acid succinate at similar concentrations did not induce morphological changes in fibroblasts. Melanoma cells were about 2-fold more sensitive to vitamin E acid succinate than were fibroblasts for the criterion of growth inhibition. Vitamin E acid succinate-induced morphological changes and growth inhibition in melanoma cells were expressed in hormone-supplemented serum-free medium, but the concentration requirement was about 5 times less than that needed in serum-supplemented medium. Although cyclic adenosine 3': 5'-monophosphate-stimulating agents are known to cause growth inhibition and morphological changes in melanoma cells in culture, vitamin E acid succinate-induced morphological alterations in melanoma cells are no mediated by a rise in cellular cyclic adenosine 3':5'-monophosphate. Ethanol was sufficient to increase the melanin content in melanoma cells. These data show that vitamin E acid succinate may be a potentially useful tumor therapeutic agent.

Animals↗