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PubMed1997

Fermentation of biomass-derived glucuronic acid by pet expressing recombinants of E. coli B.

The economics of large-scale production of fuel ethanol from biomass and wastes requires the efficient utilization of all the sugars derived from the hydrolysis of the heteropolymeric hemicellulose component of lignocellulosic feedstocks. Glucuronic and 4-O-methyl-glucuronic acids are major side chains in xylans of the grasses and hardwoods that have been targeted as potential feedstocks for the production of cellulosic ethanol. The amount of these acids is similar to that of arabinose, which is now being viewed as another potential substrate in the production of biomass-derived ethanol. This study compared the end-product distribution associated with the fermentation of D-glucose (Glc) and D-glucuronic acid (GlcUA) (as sole carbon and energy sources) by Escherichia coli B (ATCC 11303) and two different ethanologenic recombinants--a strain in which pet expression was via a multicopy plasmid (pLOI297) and a chromosomally integrated construct, strain KO11. pH-stat batch fermentations were conducted using a modified LB medium with 2% (w/v) Glc or GlcUA with the set-point for pH control at either 6.3 or 7.0. The nontransformed host culture produced only lactic acid from glucose, but fermentation of GlcUA yielded a mixture of ethanol, acetic, and lactic acids, with acetic acid being the predominant end-product. The ethanol yield associated with GlcUA fermentation by both recombinants was similar, but acetic acid was a significant by-product. Increasing the pH from 6.3 to 7.0 increased the rate of glucuronate fermentation, but it also decreased the ethanol mass yield from 0.22 to 0.19 g/g primarily because of an increase in acetic acid production. In all fermentations there was good closure of the carbon mass balance, the exception being the recombinant bearing plasmid pLOI297 that produced an unidentified product from GlcUA. The metabolism of GlcUA by this metabolically engineered construct remains unresolved. The results offered insights into metabolic fluxes and the regulation of pyruvate catabolism in the wild-type and engineered strains. End-product distribution for metabolism of glucuronic acid by the nontransformed, wild-type E. coli B and recombinant strain KO11 suggests that the enzyme pyruvate-formate lyase is not solely responsible for the production of acetylCoA from pyruvate and that derepressed pyruvate dehydrogenase may play a significant role in the metabolism of GlcUA.

Acetyltransferases↗
PubMed1999

Effect of nonenzymatic glycation of albumin and superoxide dismutase by glucuronic acid and suprofen acyl glucuronide on their functions in vitro.

Acyl glucuronides bind irreversibly to plasma proteins, and one mechanism proposed for this covalent binding is similar to that for glycation of protein by reducing sugars. Because glycation of protein by glucose and other reducing sugars can alter protein function, this lead to the hypothesis that the glycation of proteins by acyl glucuronides may cause similar effects. When human serum albumin (HSA) was incubated with 0.5 M glucose for 5 days, the unbound fractions of diazepam and warfarin were increased by 41 and 35%, respectively, less than that caused by glucuronic acid which increased the unbound fractions by 90% for diazepam and 420% for warfarin. When HSA was incubated with suprofen glucuronide (SG) at a much lower concentration of 0.005 M for only 24 h, the effects on the unbound fractions of diazepam and warfarin to HSA were altered dramatically with increases of 340 and 230%, respectively. After incubation of superoxide dismutase (SOD) with 0.5 or 1 M reducing sugars for 14 days, the enzyme activity decreased to 82 and 61% of initial levels at day 14, respectively, whereas glucuronic acid almost completely inactivated the enzyme activity over the same period. Even at a very low concentration (0.005 M) of SG, SOD activity was reduced significantly to 11% of initial levels by day 14, which was comparable to the effect by 0.5 and 1.0 M concentrations of glucuronic acid. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and matrix associated laser desorption/ionization time of flight mass spectrometry indicated that several equivalents of reducing sugars or SG became attached to albumin after incubation. These results suggest that acyl glucuronides may affect the function of proteins by the formation of glycated protein in vivo and may be associated with the toxicity of xenobiotics metabolized to labile acyl glucuronides.

Animals↗
PubMed1978

Responses of the D-glucuronic acid pathway in rat tissues to treatment with tetrachlorodibenzodioxin.

1. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was administered to rats to study its effects on the enzyme activities of the D-glucuronic acid pathway in the liver, small intestine and kidney. 2. The UDP-glucuronosyl transferase activity of male albino rats given TCDD (80 mug/kg, one dose, i.p.) 6 days before killing was significantly increased in all tissues examined, and UDP-glucuronic acid pyrophosphatase activity was markedly decreased in the liver. D-Glucuronolactone and L-gulonate dehydrogenase activities in the liver and small intestine were slightly decreased after TCDD treatment. 3. The activities of UDP-glucose dehydrogenase and beta-glucuronidase were unchanged. 4. The 24 h urinary excretion of L-ascorbic acid was enhanced 8-fold, although no difference was detected in the excretion of D-glucaric acid between the control and experimental animals. 5. These results suggest an increased capacity for glucuronide conjugation after treatment with TCDD. 6. The lack of increase in the urinary excretion of D-glucaric acid further challenges its use as a reliable indicator of enhanced drug metabolism.

Animals↗
PubMed1983

A soybean lectin having 4-O-methyl-D-glucuronic acid specificity.

Evidence is presented for the presence of a new lectin activity in soybean seeds [Glycine max (L.) Merrill] that has specificity towards the 4-O-methyl-D-glucurono-L-rhamnan exopolysaccharide produced by certain strains of Rhizobium japonicum. Bacterial agglutination and precipitin reactions revealed the lectin activity in phosphate-buffered saline extracts of seeds of all cultivars tested, including the "lectinless" varieties. Reaction of such extracts with carbohydrate haptens demonstrated that the specificity of the binding was towards 4-O-methyl-D-glucuronic acid, D-glucuronic acid and their methyl glycosides.

Binding Sites, Antibody↗
PubMed1982

The formation of beta-glucuronidase resistant glucuronides by the intramolecular rearrangement of glucuronic acid conjugates at mild alkaline pH.

It is well known to carbohydrate chemists that substituted sugars may undergo facile rearrangement involving the migration of the aglycone from --OH to adjacent --OH. Despite the importance of glycoside conjugates, notably involving glucuronic acid, in the metabolism of xenobiotics, drug metabolism workers have neglected this phenomenon. The potential rearrangement of glucuronides from the biosynthetic C-1 isomers to other positional and stereo-isomers is important, since only 1-O-substituted beta-D-glucosiduronates are substrates for beta-glucuronidase, which is commonly used to identify such conjugates. The intramolecular rearrangement of clofibryl glucuronide has been studied over the pH range 5.2-8.6, by enzymic hydrolysis with beta-glucuronidase, and by HPLC. The amount of clofibric acid released from the conjugate by beta-glucuronidase falls with increasing pH of preincubation above pH 7.4, and this is accompanied by the appearance of three new peaks, each containing both clofibric and glucuronic acids, in the HPLC traces of the incubation mixtures. Similar experiments with three other glucuronides, those of p-nitrophenol, phenolphthalein and 7-hydroxycoumarin, did not show any conversion to beta-glucuronidase resistant forms. The phenomenon of intramolecular rearrangement of ester glucuronides must be considered whenever beta-glucuronidase is used in the analysis of conjugates of carboxylic acids.

Chromatography, High Pressure Liquid↗
PubMed1977

Isolation of uridine 5'-pyrophosphate glucuronic Acid pyrophosphorylase and its assay using p-pyrophosphate.

A procedure was devised to detect and assay uridine 5'-pyrophosphate (UDP)-glucuronic acid pyrophosphorylase in plant extracts. Substrates are UDP-glucuronic acid and (32)P-pyrophosphate, and the (32)P-uridine 5'-triphosphate produced is selectively adsorbed to charcoal. The charcoal adsorption procedure is a modification of that used to determine (32)P-adenosine 5'-triphosphate produced by adenosine 5'-pyrophosphate glucose pyrophosphorylase, and the modification greatly improves the retention of uridine 5'-triphosphate.

Journal Article↗
PubMed1988

Antibodies to sulfated glucuronic acid containing glycosphingolipids in neuropathy associated with anti-MAG antibodies and in normal subjects.

Serum of patients with neuropathy and IgM monoclonal antibodies (M-proteins) that bind to the myelin-associated glycoprotein (MAG) were tested for binding to the major cross-reactive sulfated glucuronic acid containing glycosphingolipid, sulfated glucuronic acid paragloboside (SGPG). IgM binding to the glycolipid was detectable at serum dilutions of 1:10,000 and reactivity was greatest at 4 degrees C. Low titers of IgM binding to the glycolipid were also detected in sera from normal subjects and from patients with neurologic or rheumatologic diseases without serum M-proteins. Binding activity was present in 25% of the sera tested, and titers ranged between 1:25 and 1:400. One patient with peripheral neuropathy, however, had a measurable titer of 1:12,800 in the absence of monoclonal gammopathy. The study indicates that cold reacting anti-SGPG IgM antibodies are frequent constituents of the normal human antibody repertoire, and that monoclonal or polyclonal expansion of B cells that secrete these antibodies, is associated with peripheral neuropathy.

Antibodies, Monoclonal↗
PubMed1997

Photoaffinity labeling studies of the human recombinant UDP-glucuronosyltransferase, UGT1*6, with 5-azido-UDP-glucuronic acid.

Recombinant human liver UDP-glucuronosyltransferase (UGT), UGT1*6, which catalyzes the glucuronidation of small phenols, previously expressed in a V79 cell line (1) was photolabeled with [beta-32P]5N3UDP-glucuronic acid ([beta-32P]5N3UDP-GlcUA). Two polypeptides with an approximate molecular weight of 54 kDa were extensively photolabeled in the recombinant cell line while the nontransfected cell line showed no photoincorporation in this area. The identity of the two polypeptides as UGTs, which correspond to two different glycosylation forms of the same enzyme, was confirmed by Western blot using a polyclonal monospecific antibody directed against the 120 amino acids of the N-terminal end of UGT1*6. Preincubation with UDP-glucuronic acid (UDP-GlcUA) inhibited the photoincorporation of the probe into the polypeptides indicating competition of both the photoprobe and the nucleotide-sugar for the same binding site. It was further shown that photoincorporation of [beta-32P]5N3UDP-GlcUA into the UDP-GlcUA-binding site was saturable. The lack of photoincorporation of a related photoprobe, [beta-32P]5N3UDP-glucose ([beta-32P]5N3UDP-Glc), into UGT1*6 demonstrated specificity of this enzyme for UDP-GlcUA. In enzymatic assays, unlabeled 5N3UDP-GlcUA was shown to be an effective cosubstrate of the glucuronidation of 4-nitrophenol catalyzed by UGT1*6. The studies were further extended by demonstrating that photolabeling of UGT1*6 was inhibited by several active site-directed inhibitors. Finally, photoaffinity labelling was used in the purification of the labeled UGT1*6 using preparative gel electrophoresis. In conclusion, we have demonstrated that photoaffinity labeling with [beta-32P]5N3UDP-GlcUA is an effective tool for the characterization of enzymes such as recombinant UGTs that use UDP-GlcUA.

Affinity Labels↗
PubMed1977

Isolation of the glucuronic acid conjugate of n-hydroxy-4-aminobiphenyl from dog urine and its mutagenic activity.

The glucuronic acid conjugate of N-hydroxy-4-aminobiphenyl (NOH-4-ABP) has been isolated in relatively pure form from the urine of dogs given 4-aminobiphenyl, utilizing molecular size, ion exchange, adsorption, and partition chromatography. This conjugate is an active mutagen in Salmonella typhimurium strains TA1538 and TA98 but not in TA1535 or TA1537. NOH-4-ABP and 4-nitrosobiphenyl are also highly active in TA1538 and TA98 and inactive in TA1535 and TA1537. These observations support the concept that this conjugate is the water-soluble carrier that delivers the active metabolite to the bladder. A substance of identical chromatographic and spectral properties to the conjugate isolated from dog urine has been synthesized in low yield by the direct condensation of NOH-4-ABP with glucuronic acid. This substance yields NOH-4-ABP on dilute acid hydrolysis. Sodium (N-4-biphenylhydroxylamino-beta-D-glucopyranosid) uronate, the N-O-C isomer, was also synthesized. It was found to have differing chromatographic and chemical properties to the natural conjugate. This evidence suggests that the urinary conjugate is the compound in which conjugation has occurred with the nitrogen atom of the hydroxylamine group rather than the oxygen atom.

Aminobiphenyl Compounds↗
PubMed1972

Uridine diphosphate glucuronic acid production and utilization in various tissues actively synthesizing glycosaminoglycans.

1. UDP-glucose dehydrogenase has been partially purified from sheep nasal septum cartilage, neonatal rat skin and bovine corneal epithelium. 2. The pH profile, K(m) values for NAD(+) and UDP-glucose, activation energy and molecular weight have been determined for the enzyme from several of the tissues. 3. The sugar nucleotide concentrations in each of the tissues have been related to the spectrum of glycosaminoglycans produced by each tissue. 4. The presence of an allosteric UDP-xylose-binding site distinct from the active site(s) in sheep nasal septum UDP-glucose dehydrogenase has been demonstrated. 5. An active UDP-glucuronic acid nucleotidase has been demonstrated in sheep nasal cartilage. 6. Tissue-space experiments have shown the cell water content of sheep nasal septum cartilage to be 14% of the wet weight. 7. Glucuronic acid 1-phosphate does not occur in measurable amounts in sheep nasal septum cartilage and no UDP-glucuronic acid pyrophosphorylase activity could be detected in this tissue. 8. The inhibition by UDP-xylose with respect to both substrates, UDP-glucose and NAD(+), has been examined, and shown to be allosteric.

Alcohol Oxidoreductases↗
PubMed2001

Cloning, Golgi localization, and enzyme activity of the full-length heparin/heparan sulfate-glucuronic acid C5-epimerase.

While studying the cellular localization and activity of enzymes involved in heparan sulfate biosynthesis, we discovered that the published sequence for the glucuronic acid C5-epimerase responsible for the interconversion of d-glucuronic acid and l-iduronic acid residues encodes a truncated protein. Genome analysis and 5'-rapid amplification of cDNA ends was used to clone the full-length cDNA from a mouse mastocytoma cell line. The extended cDNA encodes for an additional 174 amino acids at the amino terminus of the protein. The murine sequence is 95% identical to the human epimerase identified from genomic sequences and fits with the general size and structure of the gene from Drosophila melanogaster and Caenorhabditis elegans. Full-length epimerase is predicted to have a type II transmembrane topology with a 17-amino acid transmembrane domain and an 11-amino acid cytoplasmic tail. An assay with increased sensitivity was devised that detects enzyme activity in extracts prepared from cultured cells and in recombinant proteins. Unlike other enzymes involved in glycosaminoglycan biosynthesis, the addition of a c-myc tag or green fluorescent protein to the highly conserved COOH-terminal portion of the protein inhibits its activity. The amino-terminally truncated epimerase does not localize to any cellular compartment, whereas the full-length enzyme is in the Golgi, where heparan sulfate synthesis is thought to occur.

Amino Acid Sequence↗
PubMed2003

Cloning and expression of a UDP-glucuronic acid decarboxylase gene in rice.

A cDNA fragment was cloned from rice immature seeds by the RT-PCR method. The deduced amino acid sequence of the cDNA showed a high degree of identity with UDP-d-glucuronic acid decarboxylase (UXS) from other plants and was most similar to the soluble UXS from Arabidopsis. The recombinant protein, expressed in an Escherichia coli system, catalysed the conversion of UDP-d-glucuronic acid to UDP-d-xylose, confirming that the gene encoded UXS. The uxs gene was expressed in mature, harvested rice seeds as well as in immature seeds 14 d post-anthesis, suggesting that the uxs gene is necessary at the beginning of the germination period. This is the first report of the cloning of the uxs gene from monocots.

Amino Acid Sequence↗
PubMed1984

Ascorbic acid in thyroidectomized rats. II) Ascorbic acid status of the storage tissues and hepatic biosynthesis of glucuronic acid.

Depletion of ascorbic acid from adrenals, brain and epididymis along with loss in weight were noticed in the state of thyroidectomy. This decrease appears to be due to an effect of thyroidectomy on the membrane integrity since the membrane bound sialic acid was found to be significantly lowered in these tissues as a consequence of the elevated activity of sialidase. Thyroidectomy was also found to cause an adverse effect on the activities of hepatic UDP-glucuronyl transferase and beta-glucuronidase with no alteration in UDP-glucose dehydrogenase.

Adrenal Glands↗
PubMed1998

Interaction of periodate-oxidized UDP-glucuronic acid with recombinant human liver UDP-glucuronosyltransferase 1A6.

Sodium periodate reacts with UDP-glucuronic acid (UDP-GlcUA) to generate a reactive derivative [periodate-oxidized UDP-GlcUA (o-UDP-GlcUA)]. The ability of this analog of UDP-GlcUA to inactivate and label the human recombinant UDP-glucuronosyltransferase (UGT) UGT1A6 via the UDP-GlcUA binding site was investigated. At an o-UDP-GlcUA concentration of 20 mM, the enzymatic activity of UGT1A6 was totally inactivated after 30 min of incubation at pH 7.4. Inhibition was irreversible, time-dependent, and concentration-dependent and exhibited pseudo-first order kinetics (kinact = 4.0 M-1.min-1). Cosubstrate protection with UDP-GlcUA was biphasic, with no protection in the first phase and almost total protection in the second phase, suggesting that at least 65% of the cross-linking occurs at the cosubstrate binding site. Partial inactivation by o-UDP-GlcUA led to a decrease in Vmax, suggesting that o-UDP-GlcUA can act as an active site-directed inhibitor. Furthermore, proteins, including the UGTs, from membrane fractions of a recombinant V79 cell line expressing the UGT1A6 enzyme and from rat liver microsomes were cross-linked by in situ periodate oxidation of [beta-32P]UDP-GlcUA. The present results suggest that periodate-oxidized UDP-GlcUA, which inactivates UGT1A6 by the possible formation of a Schiff base adduct with active site lysyl residues, can be used as a new affinity label for the UDP-GlcUA binding site.

Animals↗