Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Based on the previous report of McCord and co-workers (Crow, J. P., Beckman, J. S., and McCord, J. M. (1995) Biochemistry 34, 3544-3552), the zinc dithiolate active site of alcohol dehydrogenase (ADH) has been studied as a target for cellular oxidants. In the nitrogen monoxide ((*NO)/superoxide (O(2)) system, an equimolar generation of both radicals under peroxynitrite (PN) formation led to rapid inactivation of ADH activity, whereas hydrogen peroxide and ( small middle dot)NO alone reacted too slowly to be of physiological significance. 3-Morpholino sydnonimine inactivated the enzyme with an IC(50) value of 250 nm; the corresponding values for PN, hydrogen peroxide, and (*NO) were 500 nm, 50 microm, and 200 microm. When superoxide was generated at low fluxes by xanthine oxidase, it was quite effective in ADH inactivation (IC(50) (XO) approximately 1 milliunit/ml). All inactivations were accompanied by zinc release and disulfide formation, although no strict correlation was observed. From the two zinc thiolate centers, only the zinc Cys(2)His center released the metal by oxidants. The zinc Cys(4) center was also oxidized, but no second zinc atom could be found with 4-(2-pyridylazo)resorcinol (PAR) as a chelating agent except under denaturing conditions. Surprisingly, the oxidative actions of PN were abolished by a 2-3-fold excess of (*)NO under generation of a nitrosating species, probably dinitrogen trioxide. We conclude that in cellular systems, low fluxes of (*)NO and O(2) generate peroxynitrite at levels effective for zinc thiolate oxidations, facilitated by the nucleophilic nature of the complexed thiolate group. With an excess of (*)NO, the PN actions are blocked, which may explain the antioxidant properties of (*)NO and the mechanism of cellular S-nitrosations.
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PMID:Oxidation and nitrosation in the nitrogen monoxide/superoxide system. 1180 15

The renin-angiotensin system has long been recognized as crucial factor in the regulation of the systemic blood pressure and renal electrolyte homeostasis. Numerous studies have demonstrated the presence of a local renin-angiotensin system in a variety of organs. A recent study of the pancreatic renin-angiotensin system showed that chronic hypoxia significantly increased the mRNA expression for angiotensinogen II receptor subtypes AT1b and AT2. The activation of the renin-angiotensin system may play an important role in cellular pathophysiological processes. Angiotensin II enhances the formation of reactive oxygen species via the activation of xanthine oxidase or NAD(P)H oxidase. The reactive oxygen species can cause oxidative damage in the pancreas and other tissues either directly or indirectly via the formation of other radicals such as reactive nitrogen species. Rhodiola therapy may protect hypoxia-induced pancreatic injury in two ways. It prevents hypoxia-induced biological changes by increasing intracellular oxygen diffusion and efficiency of oxygen utilization. Alternatively, it reduces hypoxia-induced oxidative damage by its antioxidant activities. Additional experimental data are required to fully elucidate the mode of action of this herbal drug.
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PMID:Association of free radicals and the tissue renin-angiotensin system: prospective effects of Rhodiola, a genus of Chinese herb, on hypoxia-induced pancreatic injury. 1186 18

3-Nitrotyrosyl adducts in proteins have been detected in a wide range of diseases. The mechanisms by which reactive nitrogen oxide species may impede protein function through nitration were examined by using a unique model system, which exploits a critical tyrosyl residue in the fluorophoric pocket of recombinant green fluorescent protein (GFP). Exposure of purified GFP suspended in phosphate buffer to synthetic peroxynitrite in either 0.5 or 5 microM steps resulted in progressively increased 3-nitrotyrosyl immunoreactivity concomitant with disappearance of intrinsic fluorescence (IC(50) approximately 20 microM). Fluorescence from an equivalent amount of GFP expressed within intact MCF-7 tumor cells was largely resistant to this bolus treatment (IC(50) > 250 microM). The more physiologically relevant conditions of either peroxynitrite infusion (1 microM/min) or de novo formation by simultaneous, equimolar generation of nitric oxide (NO) and superoxide (e.g., 3-morpholinosydnonimine; NONOates plus xanthine oxidase/hypoxanthine, menadione, or mitomycin C) were examined. Despite robust oxidation of dihydrorhodamine under each of these conditions, fluorescence decrease of both purified and intracellular GFP was not evident regardless of carbon dioxide presence, suggesting that oxidation and nitration are not necessarily coupled. Alternatively, both extra- and intracellular GFP fluorescence was exquisitely sensitive to nitration produced by heme-peroxidase/hydrogen peroxide-catalyzed oxidation of nitrite. Formation of nitrogen dioxide (NO(2)) during the reaction between NO and the nitroxide 2-phenyl-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide indicated that NO(2) can enter cells and alter peptide function through tyrosyl nitration. Taken together, these findings exemplified that heme-peroxidase-catalyzed formation of NO(2) may play a pivotal role in inflammatory and chronic disease settings while calling into question the significance of nitration by peroxynitrite.
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PMID:Direct real-time evaluation of nitration with green fluorescent protein in solution and within human cells reveals the impact of nitrogen dioxide vs. peroxynitrite mechanisms. 1190 13

The authors have previously reported that intratracheal instillation of staphylococcal enterotoxin-B (SEB) induced interstitial pneumonia (IP) in autoimmune-prone mice. SEB-reactive T-cells were critically involved in the development of IP in this model. Concern has arisen about the hazards of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the process of lung injury and fibrosis. Therefore, the involvement of nitric oxide (NO) and superoxide anion (O2-) in the pathogenesis of IP in this autoimmune-prone model has been investigated. Nitrite/nitrate levels were increased in bronchoalveolar lavage (BAL) fluid and serum from SEB-injected mice. The signal of the NO-(N-(dithiocarboxy) sarcosine)2-Fe2+ complex was detected in the SEB-injected lung and whole blood by electron paramagnetic resonance (EPR) spectroscopy. NO production was significantly decreased by aminoguanidine (AG) treatment. Xanthine oxidase (XO) activity in the lung, BAL fluid, and plasma was increased with instillation of SEB, and 4-amino-6-hydroxypyrazolo(3,4-d)-pyrimidine (AHPP) significantly inhibited XO activity. Moreover, both AG and AHPP significantly decreased production of pro-inflammatory cytokines, numbers of infiltrated cells in BAL fluid, and the area of thickened alveolar septa in the SEB-injected lung. In conclusion, the overproduction of nitric oxide and super oxide anion were implicated in the pathogenesis of interstitial pneumonia, and inducible nitric oxide synthase and xanthine oxidase inhibitors had protective effects against interstitial pneumonia in this model.
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PMID:Effects of inducible nitric oxide synthase and xanthine oxidase inhibitors on SEB-induced interstitial pneumonia in mice. 1193 21

Four terpenylnaphthoquinones were found to enhance the rate of superoxide production in the presence of ascorbate as detected from the superoxide dismutase (SOD)-inhibitable initial oxygen consumption rates. Initial rates of oxygen consumption in the presence of ascorbate plus quinone increase with an increase in the half-wave reduction potentials of the quinones. These quinones also enhance the rate of Cyt(III)c reduction by xanthine/xanthine oxidase (X/XO) in both air- and nitrogen-saturated aqueous solutions at pH 7.4. Maximum rates of Cyt(III)c reduction in nitrogen and oxygen-saturated solutions (V(max)), in the presence of X/XO, increase with an increase in the half-wave reduction potentials of the quinones. SOD inhibits Cyt(III)c reduction rates in the presence of these quinones and X/XO in a manner which is also dependent on the quinone half-wave redox potential. The relative antineoplastic activity of two of these quinones follows the order in rates of oxygen consumption or Cyt(III)c reduction. This is consistent with an antineoplastic action of these quinones through the mechanism of redox cycling or possible interference or inhibition of mitochondrial respiration.
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PMID:Reductive activation of terpenylnaphthoquinones. 1204 45

In the intestine, epithelial cells continually produce and secrete low levels of nitric oxide (NO). Salmonella sp. invade epithelium by responding to environmental stimuli. The aims of this study were to determine the effect of reactive nitrogen intermediates (RNIs) on S. dublin and S. typhimurium growth and invasion of T84 epithelial monolayers. Intracellular NO formation was inhibited by 7-nitroindazole (7-NI) or N(G)-monomethyl-L-arginine, monoacetate (L-NMMA); extracellular NO and peroxynitrite were scavenged with ferro-hemoglobin or urate. The effect of authentic peroxynitrite (ONOO-); 3-morpholino-sydnonimine (SIN-1), which releases ONOO- via NO and superoxide; spermine NONOate, which releases only NO; or superoxide generated by xanthine oxidase and pterin on S. dublin and S. typhimurium growth and invasion were examined. Inhibition of NO synthesis and scavenging of extracellular NO or peroxynitrite reduced S. dublin invasion into T84 monolayers and enhanced bacterial growth. Pre-exposure of S. dublin to ONOO- and SIN-1 increased subsequent bacterial invasion into T84 monolayers. Conversely, exposure of bacteria to spermine NONOate or superoxide did not affect S. dublin invasion. In contrast, S. typhimurium invasion was not affected by pre-treatment with NO donors. In conclusion, exposure of S. dublin to ONOO- enhances the ability of the bacteria to invade epithelial cells. These results suggest that luminal ONOO- may have a novel role as an extracellular signal between invasive bacteria and epithelial cells.
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PMID:Peroxynitrite enhances the ability of Salmonella dublin to invade T84 monolayers. 1209 42

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are signal-transducing molecules that regulate the activities of a variety of proteins. In the present investigation, we have compared the effects of superoxide (O2-), nitric oxide (NO), and hydrogen peroxide (H2O2) on the activities of three highly homologous serine/threonine phosphatases, protein phosphatase type 1 (PP1), protein phosphatase type 2A (PP2A), and calcineurin (protein phosphatase type 2B). Although superoxide, generated from xanthine/xanthine oxidase or paraquat, and NO, generated from (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide or sodium nitroprusside, potently inhibited the phosphatase activity of calcineurin in neuroblastoma cell lysates, they had relatively little effect on the activities of PP1 or PP2A. In contrast, H2O2 inhibited the activities of all three phosphatases in lysates but was not a potent inhibitor for any of the enzymes. Calcineurin inactivated by O2-, NO, and H2O2 could be partially reactivated by the reducing agent ascorbate or by the thiol-specific reagent dithiothreitol (DTT). Maximal reactivation was achieved by the addition of both reagents, which suggests that ROS and RNS inhibit calcineurin by oxidizing both a catalytic metal(s) and a critical thiol(s). Reactivation of H2O2-treated PP1 also required the combination of both ascorbate and DTT, whereas PP2A required only DTT for reactivation. These results suggest that, despite their highly homologous structures, calcineurin is the only major Ser/Thr phosphatase that is a sensitive target for inhibition by superoxide and nitric oxide and that none of the phosphatases are sensitive to inhibition by hydrogen peroxide.
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PMID:Differential susceptibilities of serine/threonine phosphatases to oxidative and nitrosative stress. 1214 65

The effect of reactive oxygen/nitrogen species (ROS/RNS)(hydrogen peroxide -- H(2)O(2), superoxide anion radical O(2)*- and hydroxyl radical *OH -- the reaction products of hypoxanthine/xanthine oxidase system), nitric oxide (NO* from sodium nitroprusside -- SNP), and peroxynitrite (ONOO(-) from 3-morpholinosydnonimine -- SIN-1) on insulin mitogenic effect was studied in L6 muscle cells after one day pretreatment with/or without antioxidants. ROS/RNS inhibited insulin-induced mitogenicity (DNA synthesis). Insulin (0.1 microM), however, markedly improved mitogenicity in the muscle cells treated with increased concentrations (0.1, 0.5, 1 mM) of donors of H(2)O(2), O(2)*-, *OH, ONOO(-) and NO*. Cell viability assessed by morphological criteria was also monitored. Massive apoptosis was induced by 1 mM of donors of H(2)O(2) and ONOO(-), while NO* additionally induced necrotic cell death. Taken together, these results have shown that ROS/RNS provide a good explanation for the developing resistance to the growth promoting activity of insulin in myoblasts under conditions of oxidative or nitrosative stress. Cell viability showed that neither donor induced cell death when given below 0.5 mM. In order to confirm the deleterious effects of ROS/RNS prior to the subsequent treatment with ROS/RNS plus insulin one day pretreatment with selected antioxidants (sodium ascorbate - ASC (0.01, 0.1, 1 mM), or N-acetylcysteine - NAC (0.1, 1, 10 mM) was carried out. Surprisingly, at a low dose (micromolar) antioxidants did not abrogate and even worsened the concentration-dependent effects of ROS/RNS. In contrast, pretreatment with millimolar dose of ASC or NAC maintained an elevated mitogenicity in response to insulin irrespective of the ROS/RNS donor type used.
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PMID:Preconditioning with millimolar concentrations of vitamin C or N-acetylcysteine protects L6 muscle cells insulin-stimulated viability and DNA synthesis under oxidative stress. 1215 Oct 57

The impact of nitric oxide (NO) synthesis on different biological cascades can rapidly change dependent on the rate of NO formation and composition of the surrounding milieu. With this perspective, we used diaminonaphthalene (DAN) and diaminofluorescein (DAF) to examine the nitrosative chemistry derived from NO and superoxide (O2-) simultaneously generated at nanomolar to low micromolar per minute rates by spermine/NO decomposition and xanthine oxidase-catalyzed oxidation of hypoxanthine, respectively. Fluorescent triazole product formation from DAN and DAF increased as the ratio of O2- to NO approached equimolar, then decreased precipitously as O2- exceeded NO. This pattern was also evident in DAF-loaded MCF-7 carcinoma cells and when stimulated macrophages were used as the NO source. Cyclic voltammetry analysis and inhibition studies by using the N2O3 scavenger azide indicated that DAN- and DAF-triazole could be derived from both oxidative nitrosylation (e.g., DAF radical + NO) and nitrosation (NO+ addition). The latter mechanism predominated with higher rates of NO formation relative to O2-. The effects of oxymyoglobin, superoxide dismutase, and carbon dioxide were examined as potential modulators of reactant availability for the O2- + NO pathway in vivo. The findings suggest that the outcome of NO biosynthesis in a scavenger milieu can be focused by O2- toward formation of NO adducts on nucleophilic residues (e.g., amines, thiols, hydroxyl) through convergent mechanisms involving the intermediacy of nitrogen dioxide. These modifications may be favored in microenvironments where the rate of O2- production is temporally and spatially contemporaneous with nitric oxide synthase activity, but not in excess of NO generation.
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PMID:Focusing of nitric oxide mediated nitrosation and oxidative nitrosylation as a consequence of reaction with superoxide. 1217 14

It is established, that in rat organism nitrites and nitrates can be restored in nitrogen oxide due to nitrate and nitrite reductase activity of xanthine oxidase system. The rat thymocytes were shown in the experiment in vitro to have nitrate reductase activity, which was activated by hypoxanthine and inhibited by allopurinol. As a result of thymocytes apoptosis, provoked by papaverine, there is an essential increase of nitrate reductase activity of xanthine oxidase. The comparative research of thymocytes destruction character under the action of sodium nitroprusside (NP), N-nitrosodimethylamine (NDMA), NaNO2 and NaNO3 has been revealed, that their cytotoxicity, is dose-dependent and it decreases in order of these compounds mentioning. Synergism is revealed at the action on thymocytes of NP combined with sodium nitrite. These data as the results of investigation of EPR-spectrometry as well as use of thymocytes, containing a trap--complex of diethyldithiocarbamate-iron (DETK-Fe), allow to assume, that cytotoxic effect of NP is caused by the action of liberated from it. Cytotoxic action of nitrate is connected with reducibility to nitrite which influences on the cells independently, and nitrite action doesn't depend on its transformation to NO. The death of thymocytes caused by N-nitrosodimethylamine is not a result of its denitrozation.
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PMID:[The role of xanthine oxidase in the cytotoxic action of nitrates and nitrites]. 1219 68


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