Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steady state and time-resolved fluorescence studies on native, desulpho and deflavo xanthine oxidase (XO) have been carried out to investigate the conformational changes associated with the replacement of the molybdenum double bonded sulphur by oxygen and the removal of the flavin adenine dinucleotide (FAD). The steady state quenching experiments of the intrinsic tryptophan residues of the enzyme show that all the nine tryptophans are accessible to neutral quencher, acrylamide, in the native as well as desulpho and deflavo enzymes. However, the number of the tryptophan residues accessible to the ionic quenchers, potassium iodide and cesium chloride, increases upon removal of the FAD centre from the enzyme. This indicates that two tryptophan residues move out from the core of the enzyme to the solvent upon the removal of the FAD. The time-resolved fluorescence studies were carried out on the native, desulpho and deflavo XO by means of the time-correlated single photon counting technique, and the data were analysed by discrete exponential and maximum entropy methods. The results show that the fluorescence decay curve fitted best to a three-exponential model with lifetimes tau(1)=0.4, tau(2)=1.4 and tau(3)=3.0 ns for the native and desulpho XO, and tau(1)=0.7, tau(2)=1.7 and tau(3)=4.8 ns for the deflavo XO. The replacement of the molybdenum double bonded sulphur by oxygen in the desulpho enzyme does not cause any significant change of the lifetime components. However, removal of the FAD centre causes a significant change in the shortest and longest lifetime components indicating a conformational change in the deflavo XO possibly in the flavin domain. Decay-associated emission spectra at various emission wavelengths have been used to determine the origin of the lifetimes. The results show that tau(1) and tau(3) of the native and desulpho XO originate from the tryptophan residues which are completely or partially accessible to the solvent but tau(2) corresponds to those residues which are buried in the core of the enzyme and not exposed to the solvent. For deflavo enzyme, tau(2) is red shifted compared to the native enzyme indicating the movement of tryptophan residues from the core of the enzyme to the solvents.
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PMID:Steady state and picosecond time-resolved fluorescence studies on native, desulpho and deflavo xanthine oxidase. 1101 18

A series of 1-phenylpyrazoles was evaluated for inhibitory activity against xanthine oxidase in vitro. Of the compounds prepared, 1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid (Y-700) had the most potent enzyme inhibition and displayed longer-lasting hypouricemic action than did allopurinol in a rat model of hyperuricemia induced by the uricase inhibitor potassium oxonate.
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PMID:Synthesis and structure-activity relationships of 1-phenylpyrazoles as xanthine oxidase inhibitors. 1129 82

Ethylenediaminetetraacetic acid (EDTA) is an inhibitor of iodide (I-) oxidation that is catalyzed by horseradish peroxidase (HRP). HRP-mediated iodine (I2) reduction and triiodide (I3+) disappearance occur in the presence of this inhibitor. It is interesting that in the presence of EDTA, HRP produces superoxide radical, a reactive oxygen species that is required for iodine reduction. Substitution of potassium superoxide (KO2) or a biochemical superoxide generating system (xanthine/xanthine oxidase) for HRP and H2O2 in the reaction mixture also can reduce iodine to iodide. Thus, iodine reduction mediated by HRP occurs because HRP is able to mediate the formation of superoxide in the presence of EDTA and H2O2. Although superoxide is able to mediate iodine reduction directly, other competing reactions appear to be more important. For example, high concentrations (mM range) of EDTA are required for efficient iodine reduction in this system. Under such conditions, the concentration (microM range) of contaminating EDTA-Fe(III) becomes catalytically important. In the presence of superoxide, EDTA-Fe(III) is reduced to EDTA-Fe(II), which is able to reduce iodine and form triiodide rapidly. Also of importance is the fact that EDTA-Fe(II) reacts with hydrogen peroxide to form hydroxyl radical. Hydroxyl radical involvement is supported by the fact that a wide variety of hydroxyl radical (OH) scavengers can inhibit HRP dependent iodine reduction in the presence of EDTA and hydrogen peroxide.
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PMID:Iodide oxidation and iodine reduction mediated by horseradish peroxidase in the presence of ethylenediaminetetraacetic acid (EDTA): the superoxide effect. 1137 Jul 64

We examined the effect of N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on extracellular potassium ion concentration ([K(+)](o))-enhanced hydroxyl radical (.OH) generation due to 1-methyl-4-phenylpyridinium ion (MPP(+)) was examined in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused through a microdialysis probe to detect the generation of.OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Induction of KCl (20, 70 and 140 mM) increased MPP(+)-induced.OH formation trapped as 2,3-dihydroxybenzoic acid (DHBA) in a concentration dependent manner. However, the application of L-NAME (5 mg/kg i.v.) abolished the [K(+)](o) depolarization-induced.OH formation with MPP(+). Dopamine (DA; 10 microM) also increased the levels of DHBA due to MPP(+). However, the effect of DA after application of L-NAME did not change the levels of DHBA. On the other hand, the application of allopurinol (20 mg/kg i.v., 30 min prior to study), a xanthine oxidase (XO) inhibitor was abolished the both [K(+)](o)- and DA-induced.OH generation. Moreover, when iron(II) was administered to MPP(+) then [K(+)](o) (70 mM)-pretreated animals, a marked increase in the level of DHBA. However, when corresponding experiments were performed with L-NAME-pretreated animals, the same results were obtained. Therefore, NOS activation may be no relation to Fenton-type reaction via [K(+)](o) depolarization-induced.OH generation. The present results suggest that [K(+)](o)-induced depolarization augmented MPP(+)-induced.OH formation by enhancing NO synthesis.
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PMID:Nitric oxide enhances MPP(+)-induced hydroxyl radical generation via depolarization activated nitric oxide synthase in rat striatum. 1138 16

In an earlier communication, we have shown that Tephrosia purpurea ameliorates benzoyl peroxide-induced oxidative stress in murine skin (Saleem et al. 1999). The present study was designed to investigate a chemopreventive efficacy of T purpurea against N-diethylnitrosamine-initiated and potassium bromate-mediated oxidative stress and toxicity in rat kidney. A single intraperitoneal dose of N-diethylnitrosamine (200 mg/kg body weight) one hr prior to the dose of KBrO3 (125 mg/kg body weight) increases microsomal lipid peroxidation and the activity of xanthine oxidase and decreases the activities of renal antioxidant enzymes viz., catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase, phase II metabolizing enzymes such as glutathione-S-transferase and quinone reductase and causes depletion in the level of renal glutathione content. A sharp increase in blood urea nitrogen and serum creatinine has also been observed. Prophylactic treatment of rats with T. purpurea at doses of 5 mg/kg body weight and 10 mg/kg body weight prevented N-diethylnitrosamine-initiated and KBrO3 promoted renal oxidative stress and toxicity. The susceptibility of renal microsomal membrane for iron ascorbate-induced lipid peroxidation and xanthine oxidase activities were significantly reduced (P<0.01). The depleted levels of glutathione, the inhibited activities of antioxidant enzymes, phase II metabolizing enzymes and the enhanced levels of serum creatinine and blood urea nitrogen were recovered to a significant level (P<0.01). All the antioxidant enzymes were recovered dose-dependently. Our data indicate that T purpurea besides a skin antioxidant can be a potent chemopreventive agent against renal oxidative stress and carcinogenesis induced by N-diethylnitrosamine and KBrO3.
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PMID:Tephrosia purpurea ameliorates N-diethylnitrosamine and potassium bromate-mediated renal oxidative stress and toxicity in Wistar rats. 1145 68

We examined the effect of NG-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, on extracellular potassium ion concentration ([K+]o) and induced hydroxyl free radical (.OH) generation by an in vivo microdialysis technique. A flexibly mounted microdialysis technique was used to detect the generation of .OH in in-vivo rat hearts. The microdialysis probe was implanted in the left ventricular myocardium of anesthetized rats and tissue was perfused with Ringer's solution through the microdialysis probe at a rate of 1.0 microl/min. To measure the level of .OH, sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused directly through a microdialysis probe to detect the generation of .OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (2,3-DHBA). Induction of high-concentration [K+]o (20, 70 and 140 mM) significantly increased formation of .OH trapped as 2,3-DHBA in a concentration-dependent manner. However, the application of L-NAME (50 mg/kg, i.v.) and allopurinol, a xanthine oxidase inhibitor, abolished the [K+]o depolarization-induced .OH generation. Tyramine (1.0 mM) increased the level of 2,3-DHBA. However, the application of L-NAME did not change the level of 2,3-DHBA. On the other hand, pretreatment with allopurinol (10 mg/kg, i.v.) abolished the KCl- or tyramine-induced .OH generation. Moreover, when iron (II) was administered to [K+]o (70 mM)-pretreated animals, there was a marked increased in the level of 2,3-DHBA. However, the application of L-NAME was not related to a Fenton-type reaction via [K+]o depolarization-induced .OH generation. To examine the effect of L-NAME on ischemic/reperfused rat myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion by left anterior descending coronary artery branch (LAD). When the heart was reperfused, a marked elevation of the level of 2,3-DHBA was observed. However, L-NAME attenuated .OH generation by ischemic/reperfused rat heart. These results suggest that NOS inhibition is associated with a cardioprotective effect due to the suppression of [K+]o depolarization-induced .OH generation.
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PMID:Nitric oxide induces hydroxyl radical generation in rat hearts via depolarization-induced nitric oxide synthase activation. 1148 40

We previously reported enhanced expression of the p67(phox) and gp91(phox) components of NAD(P)H oxidase in angiotensin (Ang) II-induced hypertension, suggesting de novo assembly in response to Ang II. To examine the direct involvement of NAD(P)H oxidases in Ang II-induced O(2)(-) production, we designed a chimeric peptide that inhibits p47(phox) association with gp91(phox) in NAD(P)H oxidase (gp91ds-tat). This was achieved by linking a 9-amino acid peptide (aa) derived from HIV-coat protein (tat) to a 9-aa sequence of gp91(phox) (known to interact with p47(phox)). As a control, we constructed a chimera containing tat and a scrambled gp91 sequence (scramb-tat). We found that gp91ds-tat decreased O(2)(-) levels in aortic rings treated with Ang II (10 pmol/L) but had no effect on either the O(2)(-)-generating enzyme xanthine oxidase or potassium superoxide-generated O(2)(-). We infused vehicle, Ang II (0.75 mg. kg(-1). d(-1)), Ang II+gp91ds-tat (10 mg. kg(-1). d(-1)), or Ang II+scramb-tat intraperitoneally in C57Bl/6 mice and measured systolic blood pressure (SBP) on days 0, 3, 5, and 7 of infusion. SBP increased by day 3 in mice given Ang II and Ang II+scramb-tat but was significantly lower with Ang II+gp91-tat. On day 7, SBP was still significantly inhibited in mice given Ang II+gp91ds-tat, whereas Ang II-induced O(2)(-) production was inhibited throughout the aorta as detected by dihydroethidium staining, consistent with the ability of this inhibitor to block the various vascular NAD(P)H oxidase isoforms. These data support the hypothesis that inhibition of the interaction of p47(phox) and gp91(phox) (or its homologues) can block O(2)(-) production and attenuate blood pressure elevation in mice.
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PMID:Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. 1153 1

Mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels have been suggested as triggers and end effectors in myocardial ischemic preconditioning. However, the intracellular mechanism regulating mitoK(ATP) channels remains unclear. In the present study, mitoK(ATP) channels from bovine ventricular myocardium were reconstituted using planar lipid bilayers, and the effect of superoxide (O(2-.)) on the activity of these reconstituted channels was examined. After incorporation, a potassium-selective current was recorded. The mean conductance of this current was 56 pS at 150 mmol/L KCl, which was substantially inhibited by 1 mmol/L MgATP. 5-Hydroxydecanoate (5-HD, 10 to 100 micromol/L), a selective mitoK(ATP) antagonist, reduced the open state probability (NPo) of these channels in a concentration-dependent manner, whereas diazoxide (10 micromol/L), a selective mitoK(ATP) agonist, significantly increased channel activity. HMR-1098 (100 micromol/L), a selective sarcolemmal K(ATP) antagonist, had no effect on the activity of reconstituted channels. Addition of xanthine/xanthine oxidase (100 micromol/L per 0.038 U/mL), an O(2-.)-generating system, resulted in a marked activation of mitoK(ATP) channels; the NPo of the channels was increased from 0.60+/-0.10 to 1.94+/-0.02. This O(2)(-.)-induced channel activation was completely abolished by pretreatment with 5-HD (100 micromol/L) or a sulfhydryl alkylating compound, N-ethylmaleimide (2 mmol/L). It is concluded that myocardial mitoK(ATP) channels can be reconstituted into lipid bilayers and that O(2-.) activates these channels. The effect of O(2-.) may be associated with its direct action on the sulfhydryl groups of the channel protein.
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PMID:Characteristics and superoxide-induced activation of reconstituted myocardial mitochondrial ATP-sensitive potassium channels. 1173 83

1. Modulation of K+ channel activities by cellular oxidative stress has emerged as a significant determinant of vasomotor function in multiple disease states. 2. Evidence from in vitro and in vivo studies suggest that superoxide (O2-) and hydrogen peroxide (H2O2) enhance BKCa channel activity in rat and cat cerebral arterioles; however, activity is decreased by peroxynitrite (ONOO-) in rat cerebral arteries. The mechanisms of changes in BKCa channel properties are not fully understood and may involve oxidation of cysteine residues that are located in the cell membranes. 3. Studies further suggest that O2- increases KATP channel activity in guinea-pig cardiac myocytes, but decreases opening in cerebral vasculature. Both H2O2 and ONOO- enhance KATP channel activity in the myocardium and in coronary, renal, mesenteric and cerebral vascular beds. Alteration of KATP channels by free radicals may be due to oxidation of SH groups or changes in the cytosolic concentration of ATP. 4. It does appear that O2- produced by either reaction of xanthine and xanthine oxidase or elevated levels of glucose reduces Kv channel activity and the impairments can be partially restored by free radical scavengers, superoxide dismutase and catalase. 5. Thus, redox modulation of potassium channel activity is an important mechanism regulating cell vascular smooth muscle membrane potential.
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PMID:Oxidative stress and potassium channel function. 1198 41

This review examines the influence of endogenous and exogenous carbon monoxide (CO) on the cerebral circulation. Although CO generated from neuronal heme oxygenase can modulate neurotransmission, evidence supporting its role in cerebral vasodilation is limited. In newborn piglets, heme oxygenase is enriched in microvessels and contributes to hypoxic vasodilation. Low CO concentrations dilate piglet arterioles by opening calcium-activated potassium channels. With inhalation of CO and formation of carboxyhemoglobin, cerebral vasodilation can be greater than that occurring with hypoxic hypoxia at equivalent reductions of arterial oxygen content. This additional vasodilation is probably attributable to additional release of hypoxic vasodilators secondary to increased oxyhemoglobin affinity, although direct effects of CO on cerebral arterioles may also occur. When CO exposure is prolonged, cerebral endothelium undergoes oxidant stress as evident by nitrotyrosine formation. As CO levels increase, modest decreases in oxygen consumption are detectable, which may reflect CO or nitric oxide interactions with cytochrome oxidase in regions with very low oxygen availability. If subsequent CO concentration increases sufficiently to depress cardiac function and limit cerebral perfusion, cerebral oxygen consumption becomes further reduced, and oxidant stress becomes amplified by leukocyte sequestration and xanthine oxidase activity with consequent lipid peroxidation. Specific regions of the brain, such as central white matter, globus pallidus, and hippocampus, are selectively vulnerable to CO toxicity, but whether the mechanisms involved in selective injury differ from other forms of hypoxia-ischemia needs to be clarified.
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PMID:Cerebrovascular effects of carbon monoxide. 1200 79


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