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PubMed1979

Effect of Triton WR-1339 on the rates of synthesis and degradation of hepatic catalase of rat.

The effect of Triton WR-1339 on the rates of synthesis and degradation of hepatic catalase was examined. Triton WR-1339 was injected intraperitoneally into rats at a dose of 200 mg per 100 g body weight. Catalase activity decreased to about 35% of that of the control at 42-48 h after the injection and recovered to the normal level at 96 h. Other peroxisomal enzymes, D-amino acid oxidase and urate oxidase, showed similar patterns of the activities to those of catalase. During the first 48 h after the injection of Triton WR-1339, the rate of catalase synthesis (ks) fell to below a detectable value, while that of the degradation (kd) did not show any significant change. On the other hand, during the period 48-96 h after the injection, the rate of the synthesis (ks) returned to the normal level though that of the degradation (kd) decreased to about 50% of the control.

Amitrole↗
PubMed1987

Effects of some hypolipidemic agents on biochemical values and hepatic peroxisomal enzymes in rats: comparison of probucol, CGA, KCD-232, MLM-160, AL-369 and clinofibrate with clofibrate.

The effect of some hypolipidemic agents, which are commercially available and those being developed, on certain biochemical values and on hepatic peroxisomal enzyme activities of rats were examined. Clofibrate (0.25% (w/w) in the diet), p-chlorophenoxy-isobutyryl-glycinamide (CGA) (0.25%), clinofibrate (0.1%), KCD-232 (0.1%) and MLM-160 (0.1%) increased the activities of peroxisomal fatty acyl-CoA oxidizing system, carnitine acetyltransferase, and mitochondrial carnitine palmitoyltransferase. Of peroxisomal enzymes, catalase activity was increased by the above agents, whereas the activities of D-amino acid oxidase and urate oxidase were decreased by clofibrate and CGA, and but were increased by KCD-232 and MLM-160 which are structurally unrelated to clofibrate. No influence on these enzyme activities by AL-369 and probucol treatments were observed. Hepatomegaly was induced by clofibrate, CGA, KCD-232 and MLM-160. Concerning serum lipid levels, clofibrate, CGA, clinofibrate, KCD-232 and MLM-160 decreased both cholesterol and triglyceride levels, whereas probucol decreased only cholesterol level. AL-369 had no influence on serum lipid levels under this condition using normolipemic rat. From these results, it was concluded that differing clofibrate and CGA, clinofibrate, MLM-160 and KCD-232 might not induce peroxisome proliferation in hepatic cells, although these have an influence on the enzyme composition of hepatic peroxisomes.

Animals↗
PubMed1976

Stereospecificity of conversion of uric acid into allantoic acid by enzymes of Canadida utilis.

1. Allantoinase [EC 3.5.2.5] was isolated from cells of Candida utilis and unpurified by chromatography on columns of DEAE-cellulose and Sephadex G-200 after treatment with urea to remove urate oxidase [EC 1.7.3.3.]. 2. The purified allantoinase catalyzed the hydrolysis of allantoin into allantoic acid. However, only half of the allantoin produced from uric acid by urate oxidase was converted. The rest of the allantoin was unchanged, and showed a negative optical rotation. 3. On the other hand, the combined action of crude urate oxidase and allantoinase resulted in nearly complete conversion of uric acid into allantoic acid. Furthermore, the unpurified allantoinase preparation hydrolyzed racemic allantoin to allantoic acid completely. 4. These results indicate that the urate oxidase produces racemic allantoin from uric acid and that the allantoinase attacks only allantoin of positive optical rotation. The results also suggest that allantoin racemase is present in the yeast cells.

Amidohydrolases↗
PubMed1992

Transformation of Aspergillus flavus: construction of urate oxidase-deficient mutants by gene disruption.

A transformation procedure based on the complementation of a genetic defect was developed using a nitrate reductase-deficient mutant of Aspergillus flavus. The initial transformation efficiency was improved 40-fold by combining factors in a planned experimental program. Although low, this transformation rate was sufficient to obtain transformants in which the urate oxidase-encoding gene (uaZ) was disrupted in a gene replacement experiment. These new uaZ- strains were unable to utilize uric acid as the unique nitrogen source and could be reversed directly to the wild-type phenotype in second order transformation experiments using a urate oxidase-expressing vector.

Aspergillus flavus↗
PubMed1981

A study of some mitochondrial and peroxisomal enzymes in human colonic adenocarcinoma.

Three mitochondrial enzymes, cytochrome oxidase, succinate dehydrogenase, and monoamine oxidase, and two peroxisomal enzymes, catalase and urate oxidase, were measured spectrophotometrically in the postnuclear supernatant prepared from homogenates of normal mucosa and carcinoma of the human colon. The specific activities, in both normal mucosa and carcinoma, varied from patient to patient. However, the difference in these activities between normal mucosa and carcinoma was consistent when patients were compared. The activities of cytochrome oxidase, succinate dehydrogenase, monoamine oxidase, and catalase were greater in normal mucosa than in carcinoma. In contrast, urate oxidase activity increased in carcinoma as compared with normal mucosa. Furthermore, cytochrome oxidase and succinate dehydrogenase decreased proportionally in carcinoma, supporting the concept that the mitochondrial respiration in normal tissue and carcinoma is quantitatively but no qualitatively changed. However, the decrease in monoamine oxidase activity in carcinoma was greater than that observed with other mitochondrial enzyme activities and was irregular. This suggests that a qualitative mitochondrial change may occur in carcinoma. In particular, the ratio between outer membrane enzyme activity and respiratory enzyme activity may be altered.

Adenocarcinoma↗
PubMed2002

Uricase formulated with polyethylene glycol (uricase-PEG 20): biochemical rationale and preclinical studies.

OBJECTIVE: Humans have a non-sense codon inserted into the 5 prime end of the open reading frame of urate oxidase, and thus express an enzymatically inactive fragment of this enzyme; and consequently are unable to metabolize uric acid into allantoin and are prone to develop hyperuricemia and gout. Various urate oxidases (uricase) from mammals and microorganisms have been administered to humans with hyperuricemia and gout. Although successful in lowering plasma uric acid, these therapies have had limited application due to undesirable biochemical properties of the enzymes used, the short circulating half-life, and inherent antigenicity of these preparations. METHODS: We compared urate oxidase from a variety of sources for specific enzyme activity, pH optimum, affinity, and retention of enzyme activity under physiological conditions. A variety of polyethylene glycols (PEG) were tested to formulate uricase. RESULTS: Urate oxidase from Candida utilis had more favorable enzymatic properties and PEG of 20,000 MW (termed uricase-PEG 20) had greatly reduced antigenicity and increased circulating half-life as compared to those previously described. CONCLUSION: It is anticipated that uricase-PEG 20 may have utility as a treatment for hyperuricemia and gout.

Animals↗
PubMed2006

NMR metabolic profiling of Aspergillus nidulans to monitor drug and protein activity.

We describe a general protocol for using comparative NMR metabolomics data to infer in vivo efficacy, specificity and toxicity of chemical leads within a drug discovery program. The methodology is demonstrated using Aspergillus nidulans to monitor the activity of urate oxidase and orotidine-5'-phosphate decarboxylase and the impact of 8-azaxanthine, an inhibitor of urate oxidase. 8-azaxanthine is shown to inhibit A. nidulans hyphal growth by in vivo inactivation of urate oxidase.

Animals↗
PubMed1998

Advances in the management of malignancy-associated hyperuricaemia.

Acute tumour lysis syndrome (ATLS) is a metabolic derangement (hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia) associated with lymphoproliferative malignancies. The nature and severity of the metabolic alterations are variable. Major complications are oliguric acute renal failure and delays in initiating chemotherapy. Current management of ATLS includes hydration, alkalinization, diuretics, when indicated, and the reduction of uric acid levels using allopurinol or urate oxidase. Allopurinol inhibits xanthine oxidase, an enzyme that catalyses the conversion of hypoxanthine and xanthine to uric acid. Urate oxidase (Uricozyme), a naturally occurring proteolytic enzyme in many mammals, degrades uric acid to allantoins, which are ten times more soluble than uric acid and easily eliminated by the kidneys. Recently, Sanofi Research isolated a recombinant urate oxidase (SR29142) as a cDNA clone from Aspergillus flavus, expressed in the yeast strain Saccharomyces cerevisiae. Preclinical studies have documented its biological effects as a urolytic enzyme. Twenty-eight healthy male volunteers received SR29142, and a rapid decline of uric acid below measurable levels was seen within 4 h in all patients receiving a dose of more than 0.10 mg kg(-1). Currently, SR29142 is undergoing clinical studies in both Europe and the USA in patients with acute leukaemias or B-cell non-Hodgkin's lymphoma to demonstrate its efficacy and safety in this population of patients at highest risk of developing ATLS or its life-threatening sequelae.

Allopurinol↗
PubMed2004

Management of hyperuricemia with rasburicase review.

Tumor lysis syndrome (TLS) is a serious complication in patients with hematological malignancies. Massive lysis of tumor cells can lead to hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcaemia. These metabolic disturbances may result in renal failure, because of precipitation of uric acid crystals and calcium phosphate salts in the kidney. The standard prophylaxis or treatment of hyperuricemia consists of decreasing uric acid production with allopurinol and facilitating its excretion by urinary alkalinization and hyperhydration. By inhibiting the enzyme xanthine oxidase, allopurinol blocks the conversion of hypoxanthine and xanthine into uric acid. An alternative treatment is urate oxidase which oxidates uric acid into allantoin. Allantoin is 5-10 times more soluble than uric acid and is therefore excreted easily. In several clinical trials rasburicase, the recombinant form of urate oxidase, has shown to be very effective in preventing and treating hyperuricemia. Rasburicase, in contrast with the non-recombinant form of urate oxidase uricozyme, is associated with a low incidence of hypersensitivity reactions. In addition to the demonstrated clinical benefit, rasburicase also proved to be a cost-effective option in the management of hyperuricemia.

Allopurinol↗
PubMed1996

Dietary docosahexaenoic acid has little effect on peroxisomes in healthy mice.

NMRI mice were fed diets supplemented with 0.05, 0.2, or 2% (w/w) docosahexaenoic acid (DHA), a polyunsaturated fatty acid present in fish oil, for 3 d, 3 wk, or 3 mon. The doses of DHA were chosen to supply the mice with concentrations of DHA which approximate those that have been reported to be beneficial to patients with peroxisomal disease. Diets containing 0.05 or 0.2% DHA did not change hepatic, myocardial, and renal catalase (EC 1.11.1.6) activity except for a slight but significant increase (to 120%) in myocardial catalase activity in mice treated with the 0.05% DHA diet for 3 mon. A diet with 2% DHA induced myocardial catalase activity to 150% after both 3 d and 3 wk of administration. In the liver of mice fed this diet for 3 wk, hepatic catalase activity was increased to 140% while no induction of palmitoyl-CoA oxidase (EC 1.3.99.3), urate oxidase (EC 1.7.3.3), and L-alpha-hydroxyisovalerate oxidase (EC 1.1.3.a) was observed. With the light microscope, no changes in peroxisomal morphology were visually evaluated in catalase stained sections of liver, myocardium, and kidney of mice fed either diet. Our results show that in healthy mice a low dietary DHA dose (< 0.2%; this corresponds to a dose prescribed to peroxisomal patients) has no effect on several hepatic peroxisomal H2O2-producing enzymes, including the rate-limiting enzyme of the peroxisomal fatty acid beta-oxidation. This may indicate that such a DHA dose will not add a strong load on the often disturbed fatty acid metabolism in the liver of patients with peroxisomal disorders.

Acyl-CoA Oxidase↗
PubMed2006

Completing the uric acid degradation pathway through phylogenetic comparison of whole genomes.

Mammals that degrade uric acid are not affected by gout or urate kidney stones. It is not fully understood how they convert uric acid into the much more soluble allantoin. Until recently, it had long been thought that urate oxidase was the only enzyme responsible for this conversion. However, detailed studies of the mechanism and regiochemistry of urate oxidation have called this assumption into question, suggesting the existence of other distinct enzymatic activities. Through phylogenetic genome comparison, we identify here two genes that share with urate oxidase a common history of loss or gain events. We show that the two proteins encoded by mouse genes catalyze two consecutive steps following urate oxidation to 5-hydroxyisourate (HIU): hydrolysis of HIU to give 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) and decarboxylation of OHCU to give S-(+)-allantoin. Urate oxidation produces racemic allantoin on a time scale of hours, whereas the full enzymatic complement produces dextrorotatory allantoin on a time scale of seconds. The use of these enzymes in association with urate oxidase could improve the therapy of hyperuricemia.

Allantoin↗
PubMed1971

Studies on the physiology of Bacillus fastidiosus.

Bacillus fastidiosus was grown in a minimal medium that contained uric acid or allantoin, aerated by vigorous stirring. A constant, optimum pH of 7.4 was maintained by controlled addition of sulfuric acid. Washed cells converted both urate and allantoin into carbon dioxide and ammonia, simultaneously assimilating part of the available carbon and nitrogen. Urate oxidase (formerly called uricase) was present in extracts from urate-grown but not allantoin-grown cells. The formation of urate oxidase was apparently induced by urate. Urea was detected as an intermediate in some but not all of these experiments. However, the high urease activity observed in cell-free extracts may have prevented accumulation of urea in many of the experiments. The presence of glyoxylate carboligase and tartronic semialdehyde reductase activities indicates that the glycerate pathway may be involved in urate and allantoin catabolism in this organism.

Alcohol Oxidoreductases↗
PubMed1994

Amphibian allantoinase. Molecular cloning, tissue distribution, and functional expression.

The chain of enzymes necessary to convert uric acid to its metabolic products urea and glyoxylic acid in vertebrates is truncated through the successive loss of allantoicase, allantoinase, and urate oxidase during phylogenetic evolution. Previous studies have assigned the localization of both urate oxidase and allantinase to the peroxisome in the amphibian liver. This study reports the cloning of a cDNA encoding bullfrog (Rana catesbeiana) allantoinase, an enzyme that converts allantoin to allantoic acid. The cDNA is 2112 base pairs in length containing a 1449-base pair open reading frame which corresponds to a 483-residue protein (53,296 Da). Structural analysis of the deduced protein suggested two potential transmembrane segments and the presence of a putative mitochondrial localization sequence in the amino terminus. Immunocytochemical analysis revealed that allantoinase is localized to mitochondria and not to peroxisomes. On Northern blotting, a single mRNA species was detected in the liver and kidney of frog but not in other tissues; this distribution was confirmed by immunoblotting. The hepatic- and renal-specific expression of allantoinase coincides with the distribution of urate oxidase in these tissues in the frog. The allantoinase expressed in Saccharomyces cerevisiae and in Spodoptera frugiperda (Sf9) insect cells exhibits catalytic activity and is antigenically identical to the native frog enzyme.

Amidohydrolases↗
PubMed2002

Prevention and treatment of hyperuricemia in hematological malignancies.

The standard prophylactic and treatment regimen for hyperuricemia in patients with hematological malignancies previously included vigorous hydration, urinary alkalinization, and a xanthine oxidase inhibitor, allopurinol, which blocks the conversion of hypoxanthine and xanthine to uric acid. However, xanthine is less soluble than uric acid, and preexisting uric acid is not affected by allopurinol. The enzyme urate oxidase, not present in mammals, converts uric acid to allantoin, which is 5-10 times more soluble than uric acid. A new recombinant form of urate oxidase, rasburicase, has recently been developed. In a phase I/II study of rasburicase in children and young adults with hematological malignancies, rasburicase was demonstrated to be well tolerated at 0.2 mg/kg/day intravenously, had a mean T1/2 of 21.2 +/- 12.0 hours, and induced a median decrease in uric acid from 9.7 mg/dL to 1.0 mg/dL (P < 0.001). We recently demonstrated, in a randomized prospective trial comparing rasburicase versus allopurinol in children with hematological malignancies at high risk of tumor lysis syndrome, that rasburicase significantly lowered the mean uric acid area under the curve 0 to 96 hours (128 +/- 70 mg/dL/hour vs. 329 +/- 129 mg/dL/hour; P < 0.001) and 4 hours post uric acid by 86% versus 12% (P < 0.001). Furthermore, in the hyperuricemic group, the baseline creatinine level decreased from 144% to 102% by 96 hours following rasburicase compared to an increase from 132% to 147% following allopurinol. Although the difference in effect on creatinine levels is not significant, the study was not designed or powered to question this effect. Lastly, in 510 patients with hematological malignancies at risk for tumor lysis syndrome who received rasburicase, only 2 (0.4%) have developed new renal complications requiring hemodialysis. In summary, in the prevention and treatment of hyperuricemia, patients with hematological malignancies at risk of tumor lysis syndrome appear to benefit significantly from the use of a recombinant urate oxidase (rasburicase).

Allopurinol↗
PubMed1975

Studies on peroxisomes. V. Effect of ethyl p-chlorophenoxyisobutyrate on the centrifugal behavior of rat liver peroxisomes.

After Wistar male rats had been fed on a diet containing 0.25% of ethyl p-chlorophenoxyisobutyrate (CPIB) for 28 days, changes in the enzyme activities and centrifugal behavior of rat liver peroxisomes were investigated. (1) Compared with control rats fed on the basal diet, the catalase [EC 1.11.1.6] activity of rat livers after the administration of CPIB increased about 2.5-fold, while urate oxidase [EC 1.7.3.3] activity did not change significantly. Though D-amino acid oxidase [EC 1.4.3.3] activity markedly decreased to approximately one-sixth of the control, the activity of L-alpha-hydroxy acid oxidase [EC 1.1.3.15], a flavin enzyme like D-amino acid oxidase, was not affected significnatly after the administration of CPIB. (2) When the hepatic cells of CPIB-treated rats were fractionated by differential centrifugation, most of the increase of catalase activity appeared in the supernatant fraction. A decrease in the hepatic D-amino acid oxidase activity of CPIB-treated rats was observed in all the fractions. As for the subcellular distribution of the particle-bound enzymes, the specific activities of both catalase and urate oxidase of CPIB-treated rat livers were higher in the light mitochondrial fraction than in other fractions. (3) Sedimentation patterns in a sucrose density gradient did not show any difference between normal peroxisomers, and CPIB-treated ones. (4) In the case of CPIB-treated rats, studies of their sedimentation patterns by Ficoll density gradient centrifugation showed two main particulate peaks containing both catalase and urate oxidase, although only a single peak was observed in the case of control rats.

Alcohol Oxidoreductases↗
PubMed1978

[Enzymologic study of the structural organization of the matrix or rat liver peroxisomes].

The effect of ionic strength and pH on the release of some enzymes of the matrix of peroxisomes in rat's liver was studied. Catalase, L ALpha-hydroxy acid oxidase, isocitrate dehydrogenase, glycerophosphate dehydrogenase and lactate dehydrogenase were easily released from the particles during their lysis and treatment with 0.16 M KCl, whereas urate oxidase, NADH cytochrome c reductase and D-amino acid oxidase were not solubilized. After the solubilization of peroxisomal membrane by 0.2% Triton X-100, the remaining core contained about 50% amino acid oxidase activity, and had 1.28--1.30 g/cm3 density. These results suggest that D-amino acid oxidase associates with urate oxidase in the peroxisomal core.

Amino Acid Oxidoreductases↗
PubMed1985

Biogenesis and metabolic significance of microbodies in urate-utilizing yeasts.

Growth of Candida famata and Trichosporon cutaneum on uric acid as the sole source of carbon and nitrogen was associated with the development of a number of microbodies in the cells. Cytochemical staining experiments showed that the organelles contained urate oxidase, a key enzyme of uric acid metabolism, and catalase. Transfer of cells, precultured on glucose or glycerol, into uric acid-containing media indicated that these microbodies originated from the organelles, originally present in the inoculum cells, by growth and division. In urate-grown C. famata the microbodies were frequently observed in large clusters; in both organisms they existed in close association with mitochondria and strands of ER. The organelles lacked crystalline inclusions. In freeze-fractured cells their surrounding membranes showed smooth fracture faces. Exposure of urate-grown cells to glucose-excess conditions led to a rapid inactivation of urate oxidase activity but catalase was only slightly inactivated. Glucose-induced enzyme inactivation was not associated with the degradation of the microbodies present in the cells. Similarly, repression of urate oxidase synthesis by ammonium ions also did not lead to the degradation of peroxisomes.

Amidohydrolases↗
PubMed1978

Some characteristics of peroxisomes in the slime mold, Dictyostelium discoideum.

Some characteristics of peroxisomes in the slime mold, Dictyostelium discoideum were studied biochemically. The slime mold contained only two peroxisomal enzymes, urate oxidase and catalase. Both activities were concentrated highest in the light mitochondrial fraction, while the highest activity of acid phosphatase as a marker of lysosomes was found in the heavy mitochondrial fraction. Sucrose density gradient centrifugation showed that the density of peroxisomes was 1.21--1.22 g/ml, and that of lysosomes was approximately 1.21 g/ml. When the light mitochondrial fraction was treated with deoxycholate, major activities of urate oxidase, catalase, and acid phosphatase were solubilized. With development of the slime mold, both activities of urate oxidase and catalse increased at the stationary stage (4--6 h after) to a great extent and also slightly at the aggregation stage (10--12 h), thereafter they decreased gradually. Acid phosphatase remained with moderately high activity till the culmination stage (18--20 h), and then disappeared rapidly. It was found that enhanced activities of peroxisomal enzymes at the stationary stage represented an increase in the particle fraction and supernatant. On the other hand, activities of acid phosphatase at the same stage increased two-fold only in the supernatant, while the activity in the particle fraction was reduced to one-half.

Acid Phosphatase↗