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PubMed2004

Use of 8-substituted-FAD analogues to investigate the hydroxylation mechanism of the flavoprotein 2-methyl-3-hydroxypyridine-5-carboxylic acid oxygenase.

2-Methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) oxygenase (MHPCO) is a flavoprotein that catalyzes the oxygenation of MHPC to form alpha-(N-acetylaminomethylene)-succinic acid. Although formally similar to the oxygenation reactions catalyzed by phenol hydroxylases, MHPCO catalyzes the oxygenation of a pyridyl derivative rather than a simple phenol. Therefore, in this study, the mechanism of the reaction was investigated by replacing the natural cofactor FAD with FAD analogues having various substituents (-Cl, -CN, -NH(2), -OCH(3)) at the C8-position of the isoalloxazine. Thermodynamic and catalytic properties of the reconstituted enzyme were investigated and found to be similar to those of the native enzyme, validating that these FAD analogues are reasonable to be used as mechanistic probes. Dissociation constants for the binding of MHPC or the substrate analogue 5-hydroxynicotinate (5HN) to the reconstituted enzymes indicate that the reconstituted enzymes bind well with ligands. Redox potential values of the reconstituted enzymes were measured and found to be more positive than the values of free FAD analogues, which correlated well with the electronic effects of the 8-substituents. Studies of the reductive half-reaction of MHPCO have shown that the rates of flavin reduction by NADH could be described as a parabolic relationship with the redox potential values of the reconstituted enzymes, which is consistent with the Marcus electron transfer theory. Studies of the oxidative half-reaction of MHPCO revealed that the rate of hydroxylation depended upon the different analogues employed. The rate constants for the hydroxylation step correlated with the calculated pK(a) values of the 8-substituted C(4a)-hydroxyflavin intermediates, which are the leaving groups in the oxygen transfer step. It was observed that the rates of hydroxylation were greater when the pK(a) values of C(4a)-hydroxyflavins were lower. Although these results are not as dramatic as those from analogous studies with parahydroxybenzoate hydroxylase (Ortiz-Maldonado et al., (1999) Biochemistry 38, 8124-8137), they are consistent with the model that the oxygenation reaction of MHPCO occurs via an electrophilic aromatic substitution mechanism analogous to the mechanisms for parahydroxybenzoate and phenol hydroxylases.

Apoenzymes↗
PubMed1994

The use of tetrazolium salts to determine sites of damage to the mitochondrial electron transport chain in intact cells following in vitro photodynamic therapy with Photofrin II.

A method is described utilizing the tetrazolium salts neotetrazolium chloride (NTC), triphenyltetrazolium chloride (TTC), C,N-diphenyl-N'-4,5-dimethylthiazol-2-yltetrazolium bromide (MTT) and various substrates to elucidate damage to the mitochondrial electron transport chain of intact cells following in vitro photodynamic therapy (PDT). Using this methodology, a portion of the dark toxicity manifested by Photofrin II (PII) was found to occur prior to entry of electrons into the transport chain through Complex I, as evidenced by the fact that the inhibition of MTT reduction was reversible by the addition of malic acid to the culture media. A second site of dark toxicity was found to be Complex IV (cytochrome oxidase). After photoirradiation of the cells, Complex I was found to be affected since malic acid could no longer reverse the inhibition of MTT reduction but it could be reversed by the addition of succinic acid, whose electrons enter the transport chain at Complex II. A second and more sensitive site of photoirradiation damage was found to be Complex IV. A region near cytochrome C was also affected by photoirradiation but appreciably less so than noted for Complexes I and IV. A kinetic analysis of MTT and TTC reduction following photoirradiation indicated that MTT reduction was sustained at a normal rate for 1 h after which it slowed down and eventually plateaued. In contrast, TTC reduction was found to be inhibited almost immediately indicating Complex IV is extremely susceptible to photoirradiation damage. Compared to other assays of mitochondrial function requiring subcellular fractionation, the use of tetrazolium salts is simpler to perform and can be done using physiologically relevant conditions.

Animals↗
PubMed2003

[Study on chemical constituents in rhizome of Smilax perfoliate].

OBJECTIVE: To investigate the components of Smilax perfoliate. METHOD: The chemical components were isolated by solvent extraction and column chromatography. The chemical structures were identified on the base of physical and spectral data. RESULT: Nine compounds were isolated and identified as palmitic acid(I), beta-sitosterol(II), delta 7-5 alpha-cholesten-3-beta-ol(III), naringenin(IV), succinic acid(V), apigenin(VI), resveratrol(VII), daucosterol(VIII) and juncusyl ester B(IX). CONCLUSION: Compound(I), (III), (IV), (VI) and (IX) were obtained from the genus Smilax for the first time.

Apigenin↗
PubMed1985

[Isolation and identification of Gardnerella vaginalis].

Thirty-four strains of Gardnerella vaginalis were studied. They were isolated from non specific vaginitis. A presumptive identification can be based on colonial morphology, Gram stain characteristics, negative catalase and oxidase test. The differentiation of Gardnerella vaginalis from other negative catalase coccobacilli is based on the acid formation of carbohydrates, enzymatic test, analysis of short chain volatile and non volatile end products of fermentation in GLC. All Gardnerella strains produce acid from glucose, maltose, starch and are hippurate and alpha glucosidase positive. They are sulfonamide resistant, acetic, lactic and succinic acids are detected by gas liquid chromatography.

Actinomyces↗
PubMed1977

GC-MS measurement of deuterium in succinic anhydride and TMS-succinate. An isotope memory effect with succinic anhydride.

Direct GC-MS of succinic and glutaric anhydrides has been investigated, and shown to be feasible. In the GC-MS determination of deuterium in succinic anhydride, an isotope memory effect was observed, shown to be due to strong adsorption of solute onto the column. This phenomenon was investigated, together with possible methods for its suppression. Succinate TMS ester also was found to be a suitable derivative for direct GC-MS of deutero-succinic acid.

Anhydrides↗
PubMed1998

The study of water uptake in degradable polymers by thermally stimulated depolarization currents.

Poly(DTH succinate) is a new, degradable polymer with potential applications as a medical implant material. This polymer can be classified as an alternating copolymer of succinic acid and desaminotyrosyl-tyrosine hexyl ester (DTH), a diphenolic monomer derived from the natural amino acid L-tyrosine. In this study, the effects of water uptake (hydration) on the secondary relaxations of poly(DTH succinate) were investigated using the technique of thermally stimulated depolarization currents (TDSC). Four relaxation peaks were precisely characterized by means of Gaussian activation energy distributions. Drying and rehydration treatments show that only small amounts of water, at most 0.5% (w/w), are necessary to hydrate two of the four polar moieties in poly(DTH succinate): the pendent chain ester carbonyls and the amide carbonyls in the polymer backbone. Water appeared to be more tightly bound to the amide carbonyl group and more loosely bound to the ester carbonyl group in the pendent chain. Even at a high state of hydration (1.2% w/w), TDSC indicated that no water was associated with the phenyl ester bond in the polymer backbone. This finding may explain the unexpectedly high stability of this polymer toward hydrolysis under physiological conditions. Polymer packing was also affected by hydration. In an intermediate hydration state (water content: 0.5% w/w) polymer packing was less dense than in the wet state (water content: 1.2% w/w). This study represents the first application of the TDSC technique to the study of hydration in a degradable biomedical polymer. The results obtained indicate that the TDSC technique may be useful to assist in the understanding of the mechanisms of hydration and subsequent hydrolytic degradation in degradable biomaterials.

Biocompatible Materials↗
PubMed2001

Recombinant Escherichia coli engineered for production of L-lactic acid from hexose and pentose sugars.

Recombinant Escherichia coli have been constructed for the conversion of glucose as well as pentose sugars into L-lactic acid. The strains carry the lactate dehydrogenase gene from Streptococcus bovis on a low copy number plasmid for production of L-lactate. Three E. coli strains were transformed with the plasmid for producing L-lactic acid. Strains FBR9 and FBR11 were serially transferred 10 times in anaerobic cultures in sugar-limited medium containing glucose or xylose without selective antibiotic. An average of 96% of both FBR9 and FBR11 cells maintained pVALDH1 in anaerobic cultures. The fermentation performances of FBR9, FBR10, and FBR11 were compared in pH-controlled batch fermentations with medium containing 10% w/v glucose. Fermentation results were superior for FBR11, an E. coli B strain, compared to those observed for FBR9 or FBR10. FBR11 exhausted the glucose within 30 h, and the maximum lactic acid concentration (7.32% w/v) was 93% of the theoretical maximum. The other side-products detected were cell mass and succinic acid (0.5 g/l).

Culture Media↗
PubMed2005

Crystallization and preliminary X-ray crystallographic analysis of 2-methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) oxygenase from Pseudomonas sp. MA-1.

2-Methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) oxygenase (MHPCO) catalyzes the conversion of an aromatic substrate, MHPC, to an aliphatic compound, alpha-(N-acetylaminomethylene)-succinic acid, and is involved in the degradation of vitamin B6 by the soil bacterium Pseudomonas sp. MA-1. Using only FAD as a cofactor, MHPCO is unique in catalyzing hydroxylation and subsequent aromatic ring cleavage without requiring a metal-ion cofactor. Here, the crystallization of MHPCO is reported together with preliminary X-ray crystallographic data. An MHPCO crystal obtained by hanging-drop vapour diffusion diffracted X-rays to 2.25 A resolution and belonged to the triclinic space group P1, with four molecules per asymmetric unit.

Bacterial Proteins↗
PubMed1985

Chemotaxis to aromatic and hydroaromatic acids: comparison of Bradyrhizobium japonicum and Rhizobium trifolii.

Rhizobia are bacteria well known for their ability to fix nitrogen in symbiosis with leguminous plants. Members of diverse rhizobial species grow at the expense of hydroaromatic and aromatic compounds commonly found in plant cells and plant litter. Using a quantitative capillary assay to measure chemotaxis, we tested the ability of hydroaromatic acids, selected aromatic acids, and their metabolites to serve as chemoattractants for two distantly related rhizobial species, Bradyrhizobium japonicum and Rhizobium trifolii. Slow-growing B. japonicum I-110 demonstrated positive chemotaxis to shikimate, quinate, protocatechuate, and vanillate; threshold concentrations for the compounds were as low as 10(-6) M. The dicarboxylic acids succinate and beta-ketoadipate, metabolites in the catabolism of many aromatic compounds, were positive chemoattractants with low threshold concentrations as well. Taxis to beta-ketoadipate occurred constitutively and, of the tested compounds, beta-ketoadipate gave the strongest peak response. Taxis to shikimate or quinate was induced by growth on either substrate but not by growth on protocatechuate or succinate. In contrast, fast-growing R. trifolii 2066 was only weakly attracted to quinate and other aromatic and dicarboxylic acids that were strong attractants for B. japonicum. The R. trifolii strain exhibited positive chemotaxis to shikimate, but the threshold concentration of shikimate required to elicit a response (10(-4) M) was 2 orders of magnitude higher than that for the B. japonicum strain.

Carboxylic Acids↗
PubMed1998

Development of controlled-release SK&F 82526-J buffer bead formulations with tartaric acid as the buffer.

The purpose of this research was to design and develop a novel controlled-release bead formulation for oral administration with buffer crystals as a carrier for loading of fenoldopam mesylate, an intravenous antihypertensive agent, which provides an in vitro release rate of 30-50 mg/hr for 6-8 hr. Buffer crystals were coated in a fluid-bed granulator with a blend of gastrointestinal (GI) insoluble/enteric Eudragit polymers (such as RSPM/S100 polymer blend), drug was layered on these polymer-subcoated buffer beads by a slurry coating process, and the drug-layered beads were subsequently overcoated using a blend of GI insoluble/enteric polymers. The release of fenoldopam and tartaric acid was monitored by a two-stage dissolution procedure using USP Apparatus 2 (paddles at 50 rpm) and HPLC methodologies. The overcoating of drug-layered tartaric acid crystals with Eudragit polymers with different permeabilities significantly affected the release of fenoldopam. However, even the least permeable polymer, Eudragit RS, could not sustain the release of tartaric acid beyond 2 hr, suggesting the need to subcoat freely water-soluble tartaric acid crystals prior to drug layering. By varying the type/ratios of the GI insoluble/enteric polymers for subcoat and overcoat, capsule formulations were developed, which released fenoldopam and tartaric acid at different rates. The use of Eudragit polymer blends at the optimized ratios for both subcoat and overcoat resulted in a significant retardation in the release of tartaric acid; still, the tartaric acid release was faster than that of fenoldopam, suggesting the need to use a less water-soluble fumaric or succinic acid crystals as the buffer. However, the technology described using tartaric acid crystals as the buffer will be highly useful for weakly basic drug substances with less stringent pH-dependent solubility profiles.

Antihypertensive Agents↗
PubMed1979

Identification and quantitation of urinary dicarboxylic acids as their dicyclohexyl esters in disease states by gas chromatography mass spectrometry.

Clinical studies were conducted by gas chromatography mass spectrometry selected ion monitoring of urinary dicarboxylic acids as dicyclohexyl esters. The dicyclohexyl esters of the dicarboxylic acids give characteristic electron impact mass spectra suitable for selected ion monitoring. The mass spectra exhibit a prominent acid + 1H ion and an (acid + 1H)-H2O ion for use as quantitating and confirming ions. The cyclohexyl esters are stable for days at room temperature and have excellent chromatographic properties. Dicarboxylic acid quantitation is performed within one hour using only 50 microliter of unpurified urine. A rapid method specifically for methylmalonic acid quantitation is described which has assisted physicians in the diagnosis of pernicious anemia and methylmalonic aciduria. This procedure is applicable for screening urinary organic acids for detection of inborn errors of metabolism. The detection of a child with elevated medium length dicarboxylic acids in the terminal urine specimen is reported. This condition, previously described as an inborn error, is attributed to a terminal event. Finally, an increase in urinary succinic acid paralleling putrescine levels is described during a response to cancer chemotherapy.

Dicarboxylic Acids↗
PubMed2003

The value of quantitative 99M technetium dimercaptosuccinic acid renal scintigraphy for predicting postoperative renal insufficiency in patients undergoing nephrectomy.

PURPOSE: Radical nephrectomy is a routine urological practice. However, little is known about the use of dimercapto-succinic acid (DMSA) scan to evaluate compensatory changes after surgery and its ability to identify patient at risk for postoperative chronic renal failure or insufficiency. We predicted remaining kidney function using DMSA scan and serum creatinine. MATERIALS AND METHODS: A total of 42 patients were enrolled in the study. All underwent DMSA scan before surgery and in 38 DMSA scan was done after unilateral nephrectomy. Serum creatinine was determined before and 1 year after surgery. The Student t test was used to determine statistical significance. Spearman rank core analysis was used to evaluate the association of calculated creatinine clearance time after surgery and renal absolute uptake before surgery. We performed 1-way ANOVA comparison of the means to determine the influence of age distribution on kidney hypertrophy and the increase in kidney uptake. RESULTS: Average patient age was 61.5 years. Baseline mean creatinine clearance time was 71.5 ml. per minute, which decreased to 58.6 ml. per minute after nephrectomy (p <0.0001). Before surgery DMSA scan of the remaining kidney demonstrated an absolute uptake of 4.2% higher than that in the resected kidney (13.5% versus 9.35%, p = 0.0008). After nephrectomy the remaining kidney had an average increase of 3.9% of mean absolute uptake (17.7% versus 13.8%, p = 0.0001). Spearman rank core analysis demonstrated an association of higher preoperative absolute uptake in the remaining kidney with postoperatively high creatinine clearance time (r = 0.458, p = 0.003). Furthermore, 75% of patients with postoperative creatinine clearance time less than 40 ml. per minute presented with a preoperative absolute uptake of lower than 11% in the remaining kidney. In contrast, 75% of those with a postoperative creatinine clearance time of higher than 40 ml. per minute had a preoperative absolute uptake of higher than 11%. CONCLUSIONS: A preoperative absolute uptake of lower than 11% in the remaining kidney was a significant risk factor for postoperative chronic renal insufficiency.

Adult↗
PubMed2000

Antioxidant compounds interfere with the 3.

Antioxidants are often added to culture media as cytoprotective agents. We examined the effects of antioxidants on the results and interpretation of the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay for cell viability. Without cells, the thiol-containing antioxidant compounds beta-mercaptoethanol, dithiothreitol, pyrrolidine-dithiocarbamate, and N-acetyl-L-cysteine (acetylcysteine) reduced MTT tetrazolium salts to a blue formazan product in a dose-dependent manner. Addition of the compounds L-ascorbic acid and (+)-alpha-tocopherol acid succinate had different effects. In contrast, addition of the antioxidants N-acetyl-5-methoxytryptamine and (-)-2-oxo-4-thiazolidine carboxylic acid, which do not contain reactive thiol groups, did not result in the development of blue formazan product. These results showed that antioxidants, and potentially other chemotherapeutic compounds that contain free thiol groups or other reducing equivalents, readily reduce MTT to produce the blue formazan, irrespective of the viability of the cells present. This undescribed reaction can, therefore, significantly influence the results and interpretation of cell-viability experiments.

Acetylcysteine↗
PubMed1993

Metabolism of the insulin secretagogue methyl succinate by pancreatic islets.

Previous work demonstrated that methyl esters of succinate are potent insulin secretagogues in pancreatic islets, while unesterified succinate is not. This can be explained by studies reported here, which show that 14C-labeled dimethyl succinate is metabolized to 14CO2 by pancreatic islets, but that 14C-labeled succinic acid is not metabolized. Islets maintained at 1 mM glucose in tissue culture medium for 1 day lose the ability to release insulin in response to glucose and glucose metabolism is decreased 50-80%. The metabolism of dimethyl [1,4-14C]succinate and dimethyl [2,3-14C]succinate is decreased 50-60% in these incapacitated islets relative to islets maintained at 20 mM glucose. From the ratio of 14CO2 formed from dimethyl [1,4-14C]succinate, relative to that from dimethyl [2,3-14C]succinate, "acetate" ratios of 4.9-6.2 were calculated and from the ratio of 14CO2 formed from [2-14C]glucose, relative to that from [6-14C]glucose, "pyruvate ratios" of 1.6-1.7 were calculated. According to the 14CO2 ratios method, these ratios indicate that 53-66% of pyruvate derived from glucose enters the citric acid cycle via carboxylation and 34-47% enters via decarboxylation. Malic enzyme, which carboxylates pyruvate in the cytosol, was normal in islets maintained at 1 mM glucose. Previous work indicated that inhibition of glucose metabolism in islets maintained at low glucose is due to decreased net synthesis of the mitochondrial enzymes pyruvate dehydrogenase and pyruvate carboxylase [J. Biol. Chem. (1991) 266, 22392-22397], which decarboxylate and carboxylate pyruvate, respectively. Acetate (1 mM) but not pyruvate, when added to islets maintained at low glucose, increased dimethyl succinate metabolism to almost that of islets maintained at high glucose. This is consistent with a low amount of pyruvate dehydrogenase being unable to supply acetyl-CoA for condensation with oxalacetate (derived from succinate) and that the rate of the citric acid cycle could be enhanced by adding acetate which can bypass the reaction catalyzed by pyruvate dehydrogenase.

Animals↗
PubMed2005

The 188Re(III)-EDTA complex--a multipurpose starting material for the preparation of relevant 188Re complexes under mild conditions.

An easy and gentle method for the preparation of 188Re(V) complexes with bidentate and tetradentate ligands is described starting from the precursor complex 188Re(III)-EDTA. That complex is prepared at room temperature in acidic solution and reacts by a combined re-oxidation/ligand exchange reaction with appropriate ligands like DMSA or ECD (DMSA = dimercapto succinic acid, ECD = L,L-ethylene dicysteine diethyl ester) or en, tau, and cyclam (en = ethylene diamine, tau = 1,4,8,11-tetraazaundecane, cyclam = 1,4,8,11-tetraazacyclo-tetradecane) to the 188Re(V)-oxo- and dioxocomplexes, respectively. The chelates were unambiguously identified by chromatographic comparison with spectroscopically characterised samples or known 99mTc-kit reconstitutions. The reaction succeeds under mild conditions (room temperature, short time, neutral or weak basic solutions) with high yields and has potential for labelling of sensitive biomolecules with 188Re.

Journal Article↗
PubMed1988

Two randomized controlled trials of virucidal nasal tissues in the prevention of natural upper respiratory infections.

Two six-month randomized, controlled double-blind trials of the efficacy of virucidal nasal tissues in the prevention of natural colds were conducted in Charlottesville, Virginia, between 1983 and 1986. Tissues impregnated with malic and citric acids and sodium lauryl sulfate were used in both trials. Placebo tissues contained saccharin in the first trial and a mixture including succinic acid in the second. A total of 186 families were evaluable after completion of trial I, and 98 families were evaluable in trial II. The antiviral tissues were associated with 14 and 5% relative reductions in the overall rate of colds in the first and second trials, respectively. In the first study, this appeared to be due to an appropriate fall in secondary illnesses with a relative reduction in the ratio of secondary to primary illnesses of 32%. In trial II, however, the small and statistically insignificant reduction was primarily due to a drop in the rate of primary illness (which cannot be attributed to tissue efficacy), and the ratio of secondary to primary illness was actually 5% higher in the group with active tissues than in the placebo group. We conclude that when rigorously used in a study protocol, virucidal tissues may offer a modest reduction of secondary colds in the home, but for reasons currently unknown, do not have a major effect on the overall rate of colds.

Antiviral Agents↗
PubMedDate not supplied

[Effect of hypokinesia on the intensity of gluconeogenesis in the rat kidney cortex].

The rate of gluconeogenesis was measured in the cortical layer of kidneys of 95 white rats on hypokinesia days 1, 3, 7, 15, 30 and 60. At early stages of hypokinesia the rate of glucose formation from aspartic, glutamic, pyruvic, alpha-ketoglutaric acids and glycerol increased, specifically on hypokinesia day 3. The rate of glucose formation from the amino acids on hypokinesia day 30 was identical to that in the controls. The rate of glucose formation from alpha-ketoglutaric and succinic acids increased and that from pyruvic acid significantly decreased. On hypokinesia day 30 the rate of glucose formation from every substrate used, except for pyruvic acid, increased. The glucose concentration in serum was higher on hypokinesia days 1-7 and lower on hypokinesia days 15-60. The changes in the rate of glucose formation in the kidneys make inexplicable stable hypoglycemia seen at later stages of hypokinesia.

Animals↗
PubMed2002

An NMR and quantum-mechanical investigation of tetrahydrofuran solvent effects on the conformational equilibria of 1,4-butanedioic acid and its salts.

Vicinal proton-proton NMR couplings have been used to compare the influences of water and tetrahydrofuran (THF) as solvents on the conformational equilibria of 1,4-butanedioic (succinic) acid and its mono- and dianionic salts. An earlier NMR investigation (Lit, E. S.; Mallon, F. K.; Tsai, H. Y.; Roberts, J. D. J. Am Chem. Soc. 1993, 115, 9563-9567) showed that, in water, the conformational preferences for the gauche conformations for butanedioic acid and its monoanion and dianion were, respectively, approximately 84%, 66%, and 43%, essentially independent of the nature of the cation or concentration. We now report the corresponding gauche percentages calculated in the same way for 0.05 M solutions in THF to be 66%, 90-100%, and 46-64%. Substantial evidence was adduced for the rotational angle between the substituents in the monoanion being approximately 70 degrees. The positions of conformational equilibria of the salts in THF, particularly of the dianion, were found to be rather insensitive to concentration and temperature, but more sensitive to the amount of water present. Ab initio quantum-mechanical calculations for 1,4-butanedioate dianion indicate that, as expected for the gas phase, the trans conformation of the dianion should be heavily favored over the gauche, but, in both THF and water, the gauche conformation is calculated to predominate with rotational angles substantially less than 60 degrees. This conclusion is, in fact, generally consistent with the experimental vicinal proton couplings, which are wholly inconsistent with the trans conformation.

Journal Article↗