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: UNIPROT:P47989 (xanthine oxidase)
8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies were carried out on the inhibitory complex of alloxanthine (1H-pyrazolo[3,4-d]pyrimidine-4,5-diol) with xanthine oxidase, in extension of the work of Williams & Bray [Biochem. J. (1981) 195, 753-760]. By suitable regulation of the reaction conditions, up to 10% of the functional enzyme could be converted into the complex in the Mo(V) oxidation state. The e.p.r. spectrum of the complex was investigated in detail with the help of computer simulation and substitution with stable isotopes. Close structural analogy of the signal-giving species to that of the Very Rapid intermediate in enzyme turnover is shown by g-values (2.0279, 1.9593 and 1.9442) and by coupling to 33S in the cyanide-labile site of the enzyme [A(33S) 0.30, 3.10 and 0.70mT]. However, whereas in the Very Rapid signal there is strong coupling to 17O [Gutteridge & Bray, Biochem. J. (1980) 189, 615-623], instead, in the Alloxanthine signal there is strong coupling to a single nitrogen atom [A(14N) 0.35, 0.35, 0.32 mT]. This is presumed to originate from the 2-position of the heterocyclic ring system. From this work and from earlier kinetic studies it is concluded that alloxanthine, after being bound reversibly at the active centre, reacts slowly with it, in a specific manner, distinct from that in the normal catalytic reaction with substrates. This reaction involves elimination of an oxygen ligand of molybdenum and co-ordination, in this site, of alloxanthine via the N-2 nitrogen atom, to give a complex that is structurally but not chemically closely analogous to that of the Very Rapid species.
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PMID:The structure of the inhibitory complex of alloxanthine (1H-pyrazolo[3,4-d]pyrimidine-4,6-diol) with the molybdenum centre of xanthine oxidase from electron-paramagnetic-resonance spectroscopy. 632 52

The present study investigated the effect of the administration of oxypurinol (40 mg/kg), an inhibitor of xanthine oxidase, on adenosine and adenine nucleotide levels in the rat brain during ischemia and reperfusion. The brains of the animals were microwaved before, at the end of a 20-min period of cerebral ischemia, and after 5, 10, 45, and 90 min of reperfusion. Cerebral ischemia was elicited by four-vessel occlusion with arterial hypotension to 45-50 mm Hg. Adenosine and adenine nucleotide levels in the oxypurinol-pretreated (administered intravenously 20 min before ischemia) rats were compared with those in nontreated animals exposed to the same periods of ischemia and reperfusion. Oxypurinol administration resulted in significantly elevated ATP levels at the end of ischemia and 5 min after ischemia, but not at 10 min after ischemia. ADP levels were also elevated, in comparison with those in the control rats, at the end of the ischemic period. Conversely, AMP levels were significantly reduced at the end of ischemia and during the initial (5 min) period of reperfusion. Adenosine levels were lower in oxypurinol-treated rats, during ischemia, and in the initial reperfusion phase. Oxypurinol administration resulted in a significant increase in the energy charge both during ischemia and after 5 min of reperfusion. Physiological indices, namely, time to recovery of mean arterial blood pressure and time to onset of respiration, were also shortened in the oxypurinol-treated animals. These beneficial effects of oxypurinol may have been a result of its purine-sparing (salvage) effects and of its ability to inhibit free radical formation by the enzyme xanthine oxidase. Preservation of high-energy phosphates during ischemia likely contributes to the cerebroprotective potency of oxypurinol.
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PMID:Oxypurinol-enhanced postischemic recovery of the rat brain involves preservation of adenine nucleotides. 772 3

Xanthine oxidase (XO) activity and hydroxyl radical (.OH) formation are widely proposed mediators of renal reperfusion injury, potentially altering the severity of, and recovery from, postischemic acute renal failure. The goal of this study was to ascertain whether combination XO inhibitor (oxypurinol) and .OH scavenger (Na benzoate) therapy, given at the time of renal ischemia, alters the extent of: (1) tubular necrosis and filtration failure; (2) DNA fragmentation/apoptosis (assessed in situ by terminal deoxynucleotidyl transferase reactivity); (3) early tubular regenerative responses (proliferating cell nuclear antigen expression; (3H)thymidine incorporation); and (4) the rate and/or degree of functional and morphologic repair. The effects of XO inhibition, .OH scavengers, and "catalytic" iron (FeSO4) on human proximal tubular cell proliferation in vitro were also assessed with a newly established cell line (HK-2). Male Sprague-Dawley rats were subjected to 35 min of bilateral renal arterial occlusion with or without oxypurinol/benzoate therapy. These agents did not alter the extent of tubular necrosis or filtration failure, proliferating cell nuclear antigen expression or thymidine incorporation, or the rate/extent of renal functional/morphologic repair. DNA fragmentation did not precede tubular necrosis, and it was unaffected by antioxidant therapy. By 5 days postischemia, both treatment groups demonstrated regenerating epithelial fronds that protruded into the lumina. These structures contained terminal deoxynucleotidyl transferase-reactive, but morphologically intact, cells, suggesting the presence of apoptosis. Oxypurinol and .OH scavengers (benzoate; dimethylthiourea) suppressed in vitro tubular cell proliferation; conversely, catalytic Fe had a growth-stimulatory effect. These results suggest that: (1) XO inhibition/.OH scavenger therapy has no discernible net effect on postischemic acute renal failure; (2) DNA fragmentation does not precede tubular necrosis, suggesting that it is not a primary mediator of ischemic cell death; and (3) antioxidants can be antiproliferative for human tubular cells, possibly mitigating their potential beneficial effects.
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PMID:An evaluation of antioxidant effects on recovery from postischemic acute renal failure. 791 60

Indirect evidence suggests accelerated degradation of endothelium-derived nitric oxide (ENDO) by superoxide anion (O2-) in hypercholesterolemic vessels (HV). To directly measure O2- production by normal vessels (NV) and HV, we used an assay for O2- based on the chemiluminescence (CL) of lucigenin (L). HV (1 mo cholesterol-fed rabbits) produced threefold more O2- than NV (1.47 +/- 0.20 nM/mg tissue/min, n = 7 vs. 0.52 +/- 0.05 nmol/mg tissue/min, n = 8, P < 0.001). Endothelial removal increased O2- production in NV (0.73 +/- 0.08, n = 6, P < 0.05), while decreasing it in HV (0.76 +/- 0.15, n = 5, P < 0.05). There was no difference between denuded HV and denuded NV. Oxypurinol, a noncompetitive inhibitor of xanthine oxidase, normalized O2- production in HV, but had no effect in NV. In separate isometric tension studies treatment with oxypurinol improved acetylcholine induced relaxations in HV, while having no effect on responses in normal vessels. Oxypurinol did not alter relaxations to nitroprusside. Thus, the endothelium is a source of O2- in hypercholesterolemia probably via xanthine oxidase activation. Increased endothelial O2- production in HV may inactivate endothelium-derived nitric oxide and provide a source for other oxygen radicals, contributing to the early atherosclerotic process.
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PMID:Hypercholesterolemia increases endothelial superoxide anion production. 839 Apr 82

The mechanism of allopurinol [4-hydroxypyrazolo(3,4-d)pyrimidine] transport into human erythrocytes was investigated with an inhibitor stop assay. Allopurinol transport could be resolved into two components: (1) a saturable system and (2) a non-saturable process, which most likely represents non-facilitated diffusion. Allopurinol transport had a Km of 268 mumol/L and a Vmax of 28 pmol/microL intracellular volume/sec; the non-saturable component was 0.0195/sec. Mutual inhibition studies showed that the competitive Ki values of hypoxanthine and adenine on allopurinol transport were 120 and 3 mumol/L, respectively. These Ki values as well as the IC50 values of 100-150 mumol/L for hypoxanthine and 3-10 mumol/L for adenine were similar to the corresponding transport Km values of these bases, which are 128 and 8 mumol/L, respectively. The Ki of allopurinol on hypoxanthine transport was 274 mumol/L and thus nearly identical to its Km. Thus in erythrocytes the uricostatic agent allopurinol is an alternative substrate for the purine transport system, but lacks the exceptional high affinity it has for xanthine oxidase. This could explain the paradoxical clinical side effect of allopurinol, namely that it can provoke an attack of gout. Theophylline, a methylated purine, inhibited allopurinol transport with an IC50 of 200-400 mumol/L. Oxypurinol [4,6-dihydroxypyrazolo(3,4-d)pyrimidine], the main metabolite of allopurinol, also inhibited allopurinol transport with an IC50 of 20-40 mumol/L. This is noteworthy, since allopurinol and oxypurinol do not share the same transport system in the kidney.
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PMID:Allopurinol transport in human erythrocytes. 845 64

The reaction mechanism of the molybdoenzyme xanthine oxidase has been further investigated by 13C and 17O ENDOR of molybdenum(V) species and by kinetic studies of exchange of oxygen isotopes. Three EPR signal-giving species were studied: (i) Very Rapid, a transient intermediate in substrate turnover, (ii) Inhibited, the product of an inhibitory side reaction with aldehyde substrates, and (iii) Alloxanthine, a species formed by reaction of reduced enzyme with the inhibitor, alloxanthine. The Very Rapid signal was developed either with [8-13C]xanthine or with 2-oxo-6-methylpurine using enzyme equilibrated with [17O]H2O. The Inhibited signal was developed with 2H13C2HO and the Alloxanthine signal by using [17O]H2O. Estimates of Mo-C distances were made, from the anisotropic components of the 13C-couplings, by corrected dipolar coupling calculations and by back-calculation from assumed possible structures. Estimated distances in the Inhibited and Very Rapid species were about 1.9 and less than 2.4 A, respectively. A Mo-C bond in the Inhibited species is very strongly suggested, presumably associated with side-on bonding to molybdenum of the carbonyl of the aldehyde substrate. For the Very Rapid species, a Mo-C bond is highly likely. Coupling from a strongly coupled 17O, not in the form of an oxo group, and no coupling from other oxygens was detected in the Very Rapid species. No coupled oxygens were detected in the Alloxanthine species. That the coupled oxygen of the Very Rapid species is the one that appears in the product uric acid molecule was confirmed by new kinetic data. It is concluded that this oxygen of the Very Rapid species does not, as frequently assumed, originate from the oxo group of the oxidized enzyme. A new turnover mechanism is proposed, not involving direct participation of the oxo ligand group, and based on that of Coucouvanis et al. [Coucouvanis, D., Toupadakis, A., Lane, J. D., Koo, S. M., Kim, C. G., Hadjikyriacou, A. (1991) J. Am. Chem. Soc. 113, 5271-5282]. It involves formal addition of the elements of the substrate (e.g., xanthine) across the Mo = S double bond, to give a Mo(VI) species. This is followed by attack of a "buried" water molecule (in the vicinity of molybdenum and perhaps a ligand of it) on the bound substrate carbon, to give an intermediate that on intramolecular one-electron oxidation gives the Very Rapid species. The latter, in keeping with the 13C, 17O, and 33S couplings, is presumed to have the 8-CO group of the uric acid product molecule bonded side-on to molybdenum, with the sulfido molybdenum ligand retained, as in the oxidized enzyme.
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PMID:Evidence favoring molybdenum-carbon bond formation in xanthine oxidase action: 17Q- and 13C-ENDOR and kinetic studies. 863 73

Hypercholesterolemic and hypertensive patients have impaired endothelium-dependent vasorelaxation because of decreased nitric oxide activity, but the mechanism underlying this abnormality is unknown. This study sought to determine whether an increased breakdown of nitric oxide by xanthine oxidase-generated superoxide anions could participate in these forms of endothelial dysfunction. We studied vascular responses to intrabrachial infusion of acetylcholine (an endothelium-dependent vasodilator, 7.5 to 30 microg/min) and sodium nitroprusside (a direct smooth muscle dilator, 0.8 to 3.2 microg/min) by strain-gauge plethysmography before and during the combined administration of oxypurinol (300 microg/min), a xanthine oxidase inhibitor, in 20 hypercholesterolemic patients, 20 essential hypertensive patients, and 20 normal subjects. The vasodilator response to acetylcholine was blunted in hypercholesterolemic (highest flow, 8.2+/-8 mL x min(-1) x dL(-1)) and hypertensive (8.5+/-4 mL x min(-1) x dL(-1)) patients compared with control subjects (13.8+/- 6.6 mL x min(-1) x dL(-1)) (both P<.001); however, no differences were observed in the response to sodium nitroprusside. Oxypurinol did not change the response to acetylcholine in control subjects (P=.26) and improved, but did not normalize, its vasodilator effect in hypercholesterolemic patients (P<.01). Oxypurinol did not affect the response to acetylcholine in hypertensive patients (P=.34) and did not modify the response to sodium nitroprusside in any group. These results suggest that xanthine oxidase-generated superoxide anions are partly responsible for the impaired endothelial vasodilator function of hypercholesterolemic patients. In contrast, this mechanism does not appear to play a significant role in essential hypertension.
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PMID:Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. 923 21

The objectives of this study were to (1) determine the time course of neutrophil adhesion to monolayers of human umbilical vein endothelial cells (HUVECs) that were exposed to 60 minutes of anoxia followed by 30 to 600 minutes of reoxygenation and (2) define the mechanisms responsible for both the early (minutes) and late (hours) hyperadhesivity of postanoxic HUVECs to human neutrophils. The results clearly demonstrate that anoxia/reoxygenation (A/R) leads to a biphasic increase in neutrophil adhesion to HUVECs, with peak responses occurring at 30 minutes (phase 1) and 240 minutes (phase 2) after reoxygenation. Oxypurinol and catalase inhibited phase-1 adhesion, suggesting a role for xanthine oxidase and H2O2. In comparison, platelet activating factor (PAF) contributed to both phases of neutrophil adhesion. Anti-intercellular adhesion molecule-1 (ICAM-1) and anti-P-selectin antibodies (monoclonal antibodies [mAbs]) attenuated phase-1 neutrophil adhesion, consistent with roles for constitutively expressed ICAM-1 and enhanced surface expression of preformed P-selectin. Phase-2 neutrophil adhesion was attenuated by an anti-E-selectin mAb, indicating a dominant role of this adhesion molecule in the late phase response. Pretreatment with actinomycin D and cycloheximide or with competing ds-oligonucleotides containing the nuclear factor-kappa B or activator protein-1 cognate DNA sequences significantly attenuated phase-2 response, suggesting a role for de novo macromolecule synthesis. Surface expression of ICAM-1, P-selectin, and E-selectin on HUVECs correlated with the phase-1 and -2 neutrophil adhesion responses. Collectively, these findings indicate that A/R elicits a two-phase neutrophil-endothelial cell adhesion response that involves transcription-independent and transcription-dependent surface expression of different endothelial cell adhesion molecules.
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PMID:Molecular mechanisms of anoxia/reoxygenation-induced neutrophil adherence to cultured endothelial cells. 940 Mar 72

The superoxide (O2.-) scavenging activity and neuroprotective effects of oxypurinol, a xanthine oxidase inhibitor, were compared with those of alpha-phenyl-N-tert-butyl nitrone (PBN). The rate constant for the reaction of oxypurinol with O2.- at pH 7.4 was 1.71 x 10(3) M(-1) s(-1) which was more than 100-fold that of PBN (1.65 x 10 M(-1) s(-1)). Oxypurinol inhibited the release of O2.- from stimulated neutrophils better than did PBN. However, oxypurinol did not attenuate the ischemic neuronal damage in gerbils, while PBN did. These results indicate that neither xanthine oxidase inhibiting activity nor O2.- scavenging activity correlates to the therapeutic efficacy of neuroprotective agents in ischemic-reperfusion injury.
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PMID:Oxypurinol, a xanthine oxidase inhibitor and a superoxide scavenger, did not attenuate ischemic neuronal damage in gerbils. 971 87

Left lung autotransplantation (LLA) results in a chronic attenuation in endothelium-dependent, nitric oxide (NO)-mediated pulmonary vasodilation. We tested the hypothesis that this abnormality involves a decrease in the effective concentration of NO due to inactivation by superoxide anion. Size- and position-matched pulmonary arterial rings were isolated from the right (control) and left (LLA) lungs of seven dogs 1-5 mo post-LLA. The rings were suspended for isometric tension recording and contracted with phenylephrine, and cumulative dose-response curves for ACh or calcium ionophore (A-23187) were generated. Endothelium-dependent relaxation to ACh was inhibited post-LLA, with the maximum vasorelaxation response reduced from 88 +/- 5 to 63 +/- 5% (P < 0. 01) post-LLA. In contrast, after pretreatment with the superoxide anion scavengers tiron or superoxide dismutase (SOD), the dose-response relationships for ACh were similar in control and LLA rings. Oxypurinol, which inhibits superoxide anion production by endothelial xanthine oxidase, also restored the vasorelaxation response to ACh in LLA rings. The pulmonary vasorelaxant response to A-23187 was also attenuated (P < 0.01) post-LLA, and this effect was entirely reversed by pretreatment with tiron, SOD, or oxypurinol. These results indicate that the attenuated responses to these pulmonary vasorelaxants post-LLA involve inactivation of NO by superoxide anion generated by endothelial xanthine oxidase.
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PMID:Superoxide anion scavengers restore NO-mediated pulmonary vasodilation after lung transplantation. 988 15


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