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A novel efficient enzyme-immobilization reaction on NH2 polymers by means of L-ascorbic acid.

A new enzyme-immobilization reaction by means of L-ascorbic acid (ASA) is described using NH(2) polymers based on cellulose or poly(vinyl alcohol) with the example of oxidoreductase enzymes. In this way, enzyme proteins such as glucose oxidase (GOD), glutamate oxidase, lactate oxidase, urate oxidase and peroxidase can be covalently fixed with a high surface loading to ultrathin and transparent NH(2)-polymer films if their surfaces are previously treated with an ASA solution, in, for example, N,N-dimethyl acetamide, DMSO or methanol. ASA then obviously reacts like a diketo compound with amino groups of the NH(2)-polymer film and enzyme protein, forming dehydroascorbic acid derivatives with neighbouring Schiff's-base structures. In a subsequent fragmentation reaction, the latter presumably form stable oxalic acid diamide derivatives as coupling structures between enzyme protein and NH(2)-polymer film, as suggested by results from investigations of the ASA reaction with n-butylamine. The immobilized enzymes can be stored at 4 degrees C in bidistilled water for at least 1 month without becoming detached from the NH(2)-polymer film and without diminished enzyme activity. The apparent K(m) values of the immobilized enzymes are in part clearly smaller than those of the dissolved enzymes or those found in other immobilization processes such as the diazo coupling or the bifunctional glutardialdehyde reaction. For example, the K(m) value of the immobilized GOD with different NH(2) polymers as the matrix structure is smaller by a factor of approx. 20 than that of the dissolved enzyme.

Acetamides↗

Crystal structure of the protein drug urate oxidase-inhibitor complex at 2.05 A resolution.

The gene coding for urate oxidase, an enzyme that catalyzes the oxidation of uric acid to allantoin, is inactivated in humans. Consequently, urate oxidase is used as a protein drug to overcome severe disorders induced by uric acid accumulation. The structure of the active homotetrameric enzyme reveals the existence of a small architectural domain that we call T-fold (for tunnelling-fold) domain. It assembles to form a perfect unusual dimeric alpha 8 beta 16 barrel. Urate oxidase may be the archetype of an expanding new family of tunnel-shaped proteins that now has three members; tetrahydropterin synthase, GTP cyclohydrolase I and urate oxidase. The structure of the active site of urate oxidase around the 8-azaxanthine inhibitor reveals an original mechanism of oxidation that does not require any ions or prosthetic groups.

Aspergillus flavus↗

Determination of the cross-points of rat liver peroxisomes, peroxisomal core and the core components by cross-partition.

The cross-points of rat liver peroxisomes, peroxisomal core and the core components were determined by means of cross-partition in two phase systems. The partitions were carried out in the systems containing 6% (w/w) Dextran T 500 and 6% (w/w) polyethyleneglycol 4000 in sodium salts. The same cross-point, pH 5.6, was obtained in peroxisomal marker enzymes in light mitochondrial fraction of liver homogenate, such as catalase, D-amino acid oxidase and urate oxidase. The cross-point as determined by cross-partition of purified peroxisomal core was 6.7. The cross-points of urate oxidase and framework protein fractions obtained by alkali treatment on the purified core were 7.8 and 4.2, respectively, and the ratio of the proteins of urate oxidase to framework protein was 2 : 1. The theoretical value of cross-point of the core calculated from from the relationship between the cross-point and protein ratio of each component of the core coincided with the experimental value obtained by this method.

Animals↗

Biogenesis and cytochemistry of unspecialized peroxisomes in root cortical cells of Yucca torreyi L.

Microbodies containing bipyramidal crystalline nucleoid inclusions occur within every cortical cell in roots of Yucca torreyi. Reaction product deposition attributable to catalase, glycolate oxidase, and urate oxidase activities are cytochemically localized to Yucca root microbodies and classifies them as unspecialized peroxisomes on the basis of their enzyme complement and tissue origin. Crystalline nucleoids do not stain for glycolate or urate oxidase activities, appearing as negatively-stained inclusions, but are apparently reactive for catalase activity. Development of unspecialized peroxisomes in Yucca roots is consistent with all evidence for glyoxysome and leaf-type peroxisome biogenesis from ER. Dilated ends of ER cisternae accumulate cytochemically detectable glycolate oxidase activity. After considerable dilation, paracrystalline precursors to nucleoids form within the bulge, and the inclusion enlarges to comprise the majority of peroxisomal volume. Peroxisomes that are not attached to ER are observed with high voltage electron microscopy and in serial thin sections, implying that eventually the budding peroxisomes are vesiculated. The functions of these unspecialized peroxisomes are suggested based upon cytochemical detection of their partial enzyme complement and their spatial and developmental timing relationships within developing Yucca root cortical parenchyma cells.

Alcohol Oxidoreductases↗

Peroxisomal enzymes in normal and tumoral human breast.

The presence of peroxisomes and their enzymatic content were investigated and compared in healthy and neoplastic human breast epithelial cells using cytochemical studies at the ultrastructural level as well as Western blot and biochemical analyses. Ultrastructural cytochemistry revealed the presence of these organelles in both normal and neoplastic breast tissues. Their mean diameter was 0.27 +/- 0.11 micron. No significant difference was noted between numbers of peroxisomes in normal and neoplastic breast epithelia. Catalase, D-amino acid oxidase, and urate oxidase were found to be expressed in mammary carcinoma and in surrounding non-malignant tissue when the postnuclear supernatant fractions prepared from homogenates were assessed by Western blot techniques. Their specific activities and that of fatty acyl CoA oxidase as determined spectrophotometrically were found to be diminished in the tumour when compared with the control tissue. On the other hand, no significant difference was found in the specific activity of the L-alpha-hydroxy acid oxidase of normal and neoplastic human breast tissues. Investigations of the relationship between peroxisomal enzymes and tumour grade revealed that catalase, urate oxidase, and fatty acyl CoA oxidase activities in breast neoplastic tissues belonging to grade III were significantly lower than in the adjacent normal tissues.

Adult↗

Elitek-rasburicase: an effective means to prevent and treat hyperuricemia associated with tumor lysis syndrome, a Meeting Report, Dallas, Texas, January 2002.

Renal precipitation of uric acid associated with tumor lysis syndrome (TLS) is a major complication in the management of leukemia, lymphoma, and other drug-sensitive cancers. Management of hyperuricema has historically consisted of administration of allopurinol, hydration, alkalinization to maintain pH between 7.0 and 7.3, and in some cases diuresis. Allopurinol, a xanthine analogue, blocks xanthine oxidase and formation of uric acid. Urate oxidase converts uric acid to allantoin, which is 5-10 times more soluble than uric acid. Homo sapiens cannot express urate oxidase because of a nonsense mutation. Urate oxidase was initially purified from Aspergillus flavus fungus. Treatment with this nonrecombinant product had been effective in preventing renal precipitation of uric acid in cancer patients, but was associated with a relatively high frequency of allergic reactions. This enzyme was recently cloned from A. flavus and is now manufactured as a recombinant protein. Clinical trials have shown this drug to be more effective than allopurinol for prevention and treatment of hyperuricemia in leukemia and lymphoma patients. This drug has been approved in Europe as well as the US and several clinical trials are in progress to further determine its clinical utility in other patient subsets. The purpose of this meeting was to discuss usefulness of recombinant urate oxidase, also known as rasburicase, Fasturtec, and Elitek, for the management of TLS in certain cancer patients.

Adolescent↗

Ultrastructural cytology of Basidiobolus haptosporus: morphology and electron cytochemistry of microbodies.

Vegetative and reproductive cells of Basidiobolus haptosporus possess naturally occurring organelles identified as microbodies. Cells of four other species of the genus contained morphologically indistinguishable organelles. Microbodies were invariably present in cells of the fungi grown on routine mycological media. The constitutive microbody was characterized by a single, intensely electron-opaque crystalloid body which rapidly enlarged to fill the organellar compartment. The microbody then underwent degeneration by an autolytic-like process. Growth of the fungi on xanthine and its catabolites as sole nitrogen sources (but not urea) greatly enhanced the production of new microbodies in which protein was initially accumulated as paracrystalline arrays. These inclusions then underwent reorganization and compaction to form crystalloid bodies. Key enzymes of the purine degradation pathway are believed to be core proteins of the crystalloid. D-amino acid oxidase, alpha-hydroxy acid oxidase, xanthine oxidase and urate oxidase (but not catalase) were detected cytochemically in mature microbodies. Significant levels of phosphorus and molybdenum were present in the microbody crystalloid by X-ray dispersive microanalysis; iron and copper were not detected. The ability of Basidiobolus species to assimilate xanthine and its catabolites might explain their ecological association with the gut and cloacal contents of various amphibia, reptiles and fish.

Alcohol Oxidoreductases↗

Molecular evolution of the urate oxidase-encoding gene in hominoid primates: nonsense mutations.

Nucleotide sequences of portions of second and fifth exons of urate oxidase encoding gene (UOX) of chimpanzee, gorilla, orangutan, rhesus monkey and squirrel monkey obtained following amplification by polymerase chain reaction have been compared with corresponding sequences of human, baboon and rat UOX. Two or more nonsense mutations are found in the coding regions of this UOX gene thus far analyzed in human, chimpanzee, gorilla and orangutan, but not in the baboon, rhesus monkey and squirrel monkey. Of these nonsense mutations, the stop codon at amino acid position 33 is constant in the human and the three great apes suggesting that this may be the original mutation responsible for the inactivation of the UOX gene during hominoid evolution.

Amino Acid Sequence↗

Effects of long-term vitamin E deficiency and restoration on rat hepatic peroxisomes.

Effects of vitamin E deficiency and its restoration on biochemical characteristics of hepatic peroxisomes were studied. Rats were maintained on the vitamin E-deficient diet for 25 weeks and then on a diet supplemented with vitamin E for 5 weeks. Blood hemolysis by hydrogen peroxide and lipid peroxidation in the liver increased markedly in vitamin E-deficient rats. The former returned to the control level after the resupplying of vitamin E, but the latter did not. Of liver peroxisomal enzymes, the activities of catalase, D-amino-acid oxidase and urate oxidase decreased in vitamin E-deficient rats. On the other hand, activities of fatty acyl-CoA oxidase and carnitine acetyltransferase increased significantly in vitamin E-deficient rats. All activities of these peroxisomal enzymes were restored to the control levels in vitamin E-supplemented rats. The activities of the mitochondrial, lysosomal and microsomal enzymes tested showed no apparent change except that the change of mitochondrial palmitoyltransferase was shown to be similar to that of peroxisomal fatty acid oxidation. These results were also supported by cell fractionation techniques. Following the methods of aqueous polymer two-phase systems, the characteristics of peroxisomal surface membranes altered in respect of their hydrophobicity, but not in respect of the surface charge of peroxisomal membranes. These results indicate that peroxisomal functions, especially those of the fatty acid oxidation system, change their activities more sensitively than other intracellular organelles in response to the condition of vitamin E deficiency.

Animals↗

Determination of inorganic phosphate by flow injection method with immobilized enzymes and chemiluminescence detection.

A flow injection method with chemiluminescence detection has been developed for the enzymatic determination of inorganic phosphate. Purine nucleoside phosphorylase, xanthine oxidase, and urate oxidase were immobilized on controlled-pore glass beads. Hydrogen peroxide released by the enzymatic reactions of phosphate and inosine in carrier buffer was detected by the luminol-microperoxidase system in a flow cell. The calibration graph was linear over the range of 5 to 250 pmol, and reproducibility was 1.75% at 10 pmol. The detection limit was 500 fmol of phosphate in 50 microliters of sample injected. The phosphate content in deoxyribonucleic acid was measured by this method.

Animals↗

Evolution of urate-degrading enzymes in animal peroxisomes.

The end product of purine metabolism varies from species to species. The degradation of purines to urate is common to all animal species, but the degradation of urate is much less complete in higher animals. The comparison of subcellular distribution, intraperoxisomal localization forms, molecular structures, and some other properties of urate-degrading enzymes (urate oxidase, allantoinase, and allantoicase) among animals is described. Liver urate oxidase (uricase) is located in the peroxisomes in all animals with urate oxidase. On the basis of the comparison of intraperoxisomal localization forms, mol wt, and solubility of liver urate oxidase among animals, it is suggested that amphibian urate oxidase is a transition form in the evolution of aquatic animals to land animals. Allantoinase and allantoicase are different proteins in fish liver, but the two enzymes form a complex in amphibian liver. The subcellular localization of allantoinase and allantoicase varies among fishes. Hepatic allantoinase is located both in the peroxisomes and in the cytosol in saltwater fishes, and only in the cytosol in freshwater fishes. Hepatic allantoicase is located on the outer surface of the peroxisomal membrane in the mackerel group and in the peroxisomal matrix in the sardine group. Amphibian hepatic allantoinase-allantoicase complex is probably located in the mitochondria. On the basis of previous data, changes of allantoinase and allantoicase in molecular structure and intracellular localization during animal evolution may be as follows: Fish liver allantoinase is a single peptide with a mol wt of 54,000, and is located both in the peroxisomes and in the cytosol, or only in the cytosol. Fish liver allantoicase consists of two identical subunits with a mol wt of 48,000, and is located in the peroxisomal matrix or on the outer surface of the peroxisomal membrane. The evolution of fishes to amphibia resulted in the dissociation of allantoicase into subunits, and in the association of allantoinase with the subunit of allantoicase. This amphibian enzyme was lost by further evolution.

Amidohydrolases↗

Effects of hypolipidaemics cetaben and clofibrate on mitochondrial and peroxisomal enzymes of rat liver.

Clofibrate or cetaben was administered to male rats for 10 days. Peroxisomal and mitochondrial enzymes were assayed in liver subcellular fractions. Clofibrate affected the specific activities of both mitochondrial enzymes (glycerol-3-phosphate dehydrogenase and nicotinamide-linked isocitrate dehydrogenase) and peroxisomal enzymes (fatty acyl-CoA oxidase, glycerone phosphate acyltransferase, urate oxidase, and D-amino-acid oxidase). In contrast, cetaben raised only the peroxisomal enzymes, acyl-CoA oxidase, glycerone-phosphate acyltransferase, D-amino-acid oxidase, catalase, and urate oxidase. Thus, the hypolipidaemic activity of these drugs may be exclusively related to stimulated peroxisomal functioning, while mitochondria play only a minor role.

4-Aminobenzoic Acid↗

European experience in the treatment of hyperuricemia.

The nonrecombinant form of urate oxidase has been routinely used in France since 1975 as standard practice in the initial management of non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL), and for prevention of tumor lysis syndrome (TLS). A retrospective study was performed to evaluate the frequency of metabolic complications and dialysis in 410 patients with B-cell stage III and IV NHL and L-3 ALL treated in France according to the LMB89 protocol, and to compare these results to those of other series of patients treated without urate oxidase. Of the 57 patients treated at Institut Gustave-Roussy, only five had metabolic complications occurring in the first cycle of chemotherapy. Two patients (3.5%) underwent dialysis: one because of oliguria, the second for preventive reasons. In all the other cases, metabolic problems were successfully resolved or prevented, using nonrecombinant urate oxidase (Uricozyme, Sanofi-Sythélabo, Inc, Paris, France) in combination with hyperhydration. Nonrecombinant urate oxidase is generally well tolerated. However, allergic reactions may occur, with rates varying from 0% to 4.5%. In addition, the extraction technology used to produce the product is limited by a low yield. A recombinant form of urate oxidase (rasburicase) was therefore developed. European clinical development results indicate that this agent produces a sharp and consistent decrease in uric acid levels in patients undergoing cytoreductive therapy. Additionally, there is a very low incidence of anaphylaxis. Studies have demonstrated the efficacy of urate oxidase in lowering uric acid levels, preventing hyperuricemia after the initiation of cytoreductive therapy, and preserving renal function in patients with B-cell advanced stage NHL and ALL.

Adolescent↗

Effect of elevated serum uric acid on cisplatin-induced acute renal failure.

Marked hyperuricemia is known to cause acute renal failure via intrarenal crystal deposition. However, recent studies suggest mild hyperuricemia may have vasoactive and proinflammatory effects independent of crystal formation. We therefore tested the hypothesis that mild hyperuricemia might exacerbate renal injury and dysfunction in a model of cisplatin-induced acute renal failure in the rat. Cisplatin was administered to normouricemic and hyperuricemic rats (the latter generated by administering the urate oxidase inhibitor, oxonic acid). Recombinant urate oxidase (rasburicase) was administered in a third group to assess the effect of lowering uric acid on outcomes. Other control groups include normal rats and hyperuricemic rats without cisplatin-induced injury. Cisplatin induced injury of the pars recta (S3) segment of the proximal tubule in association with a mild monocyte infiltration. Hyperuricemic rats showed significantly greater tubular injury and proliferation with significantly greater macrophage infiltration and increased expression of monocyte chemoattractant protein-1. However, renal function was not different between normouricemic and hyperuricemic rats with cisplatin injury. Treatment with rasburicase reversed the inflammatory changes and lessened tubular injury with an improvement in renal function (relative to the hyperuricemic group). No intrarenal crystals were observed in any groups. These data provide the first experimental evidence that uric acid, at concentrations that do not cause intrarenal crystal formation, may exacerbate renal injury in a model of acute renal failure. The mechanism may relate to a proinflammatory pathway involving chemokine expression with leukocyte infiltration.

Acute Kidney Injury↗

In vitro association with peroxisomes and conformational change of peroxisomal serine:pyruvate/alanine:glyoxylate aminotransferase in rat and human livers.

To understand the targeting mechanisms of peroxisomal serine:pyruvate aminotransferase, in vitro import experiments were carried out using this 43 kDa peroxisomal enzyme, which was synthesized in a coupled transcription/translation system. Being different from other peroxisomal enzymes, such as acyl-CoA oxidase and urate oxidase used in previous in vitro import experiment, the soluble form of peroxisomal serine:pyruvate aminotransferase was fairly resistant to proteinase K digestion. However, the enzyme recovered in the peroxisomal fraction was proteinase K sensitive. This indicates that the association of peroxisomal serine:pyruvate aminotransferase with the peroxisomal membrane causes a marked conformational change in the structure of this protein.

Alanine Transaminase↗

Regulation of purine nucleotide metabolism in hypoxic liver and intestine of rats: radical scavenging effects of allopurinol and oxypurinol.

The relationship between nucleotide catabolism and generation of activated oxygen species was investigated in liver, hepatocytes and small intestine of rats. In severe hypoxia nucleotide degradation via xanthine oxidase and urate oxidase requires about half of the oxygen consumed. Data on the changes of nucleobase compounds in rat hepatocytes and small intestine during ischemia and reoxygenation and the effects of allopurinol and oxypurinol thereon are presented. From EPR measurements it is concluded that OH. radicals induce reactions of allopurinol yielding long-living products which are able to react with DMPO-OH with loss of its radical properties.

Allopurinol↗

Analyses in transfected cells and in vitro of a putative peroxisomal targeting signal of rat liver serine:pyruvate aminotransferase.

Serine:pyruvate aminotransferase (SPT; EC 2.6.1.51) of rat liver is a unique enzyme in that it is located in both mitochondria and peroxisomes. To analyze a peroxisomal targeting signal (PTS) of SPT, we constructed in this study various peroxisomal SPT clones having mutations at the C-terminal 20-amino acid region in which a putative PTS is located, and we examined subcellular localization of mutated products expressed in transfected COS-1 cells. When the mutant SPTs were unstable in transfected COS-1 cells, their translocation into peroxisomes was examined using an in vitro peroxisomal import system. Deletion of the C-terminal tripeptide, NKL, and amino acid substitution of K2 (the second lysine from the C-terminus), K4, or E15 abolished or impaired the peroxisomal import of the translated product, resulting in cytosolic accumulation in the cell. In the cases of mutation of R18G, D19A, or K2Q and the conversion to proline of L9, L13, V17, or A20, no products were detected in transfected cells. However, the results of an in vitro peroxisomal import experiment showed that the mutation of L9P, L13P, V17P, and A20P caused loss of the PTS function. When serine was introduced instead of N3 to generate a typical PTS1, the SKL motif, at the C-terminus, all of the proteins having mutations at P5, E11, R12, or E15 showed extensive localization in peroxisomes. These results suggest that the putative C-terminal PTS of SPT is not equivalent to the typical PTS1 shown in acyl-CoA oxidase and urate oxidase, because the PTS of SPT is not restricted to the C-terminal tripeptide. The results also suggest that the alpha-helical structure of the C-terminal region of SPT is important for the stable conformation of the enzyme and the peroxisomal targeting function of its PTS.

Animals↗

Hydrogen peroxide generation in peroxisome proliferator-induced oncogenesis.

Peroxisome proliferators are a structurally diverse group of non-genotoxic chemicals that induce predictable pleiotropic responses including the development of liver tumors in rats and mice. These chemicals interact variably with peroxisome proliferator-activated receptors (PPARs), which are members of the nuclear receptor superfamily. Evidence derived from mice with PPARalpha gene disruption indicates that of the three PPAR isoforms (alpha, beta/delta and gamma), the isoform PPARalpha is essential for the pleiotropic responses induced by peroxisome proliferators. Peroxisome proliferator-induced activation of PPARalpha leads to profound transcriptional activation of genes encoding for the classical peroxisomal beta-oxidation system and cytochrome P450 CYP 4A isoforms, CYP4A1 and CYP4A3, among others. Livers with peroxisome proliferation manifest substantial increases in the expression of H(2)O(2)-generating peroxisomal fatty acyl-CoA oxidase, the first enzyme of the classical peroxisomal fatty acid beta-oxidation system, and of microsomal cytochrome P450 4A1 and 4A3 genes. Disproportionate increases in H(2)O(2)-generating enzymes and H(2)O(2)-degrading enzyme catalase and reductions in glutathione peroxidase activity by peroxisome proliferators, lead to increased oxidative stress in liver cells. Sustained oxidative stress resulting from chronic increases in H(2)O(2)-generating enzymes manifests as massive accumulation of lipofuscin in hepatocytes, and increased levels of 8-hydroxydeoxyguanosine adducts in liver DNA; this supports the hypothesis that oxidative stress plays a critical role in the development of liver tumors induced by these non-genotoxic chemical carcinogens. Evidence also indicates that cells stably overexpressing H(2)O(2)-generating fatty acyl-CoA oxidase or urate oxidase, when exposed to appropriate substrate(s), reveal features of neoplastic conversion including growth in soft agar and formation of tumors in nude mice. Mice with disrupted fatty acyl-CoA oxidase gene (AOX(-/-) mice), which encodes the first enzyme of the PPARalpha regulated peroxisomal beta-oxidation system, exhibit profound spontaneous peroxisome proliferation, including development of liver tumors, indicative of sustained activation of PPARalpha by the unmetabolized substrates of acyl-CoA oxidase. With the exception of fatty acyl-CoA oxidase, all PPARalpha responsive genes including CYP4A1 and CYP4A3 are up-regulated in the livers of these AOX(-/-) mice. Thus, the substrates of acyl-CoA oxidase serve as endogenous ligands for this receptor leading to a receptor-enzyme cross-talk, because acyl-CoA oxidase gene is transcriptionally regulated by PPARalpha. Peroxisome proliferators induce only a transient increase in liver cell proliferation and this may serve as an additional contributory factor, rather than play a primary role in liver tumor development. Thus, sustained activation of PPARalpha by either synthetic or natural ligands leads to reproducible pleiotropic responses culminating in the development of liver tumors. This phenomenon of peroxisome proliferation provides fascinating challenges in exploring the molecular mechanisms of cell specific transcription, and in identifying the PPARalpha responsive target genes, as well as events involved in their regulation. Genetically altered animals and cell lines should enable investigations on the role of H(2)O(2)-producing enzymes in neoplastic conversion.

Animals↗