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)

Some sterically hindered N-substituted derivatives of daunorubicin are known to be poor substrates for NADH dehydrogenase, NADPH cytochrome P450 reductase and xanthine oxidase. In consequence, poor oxygen radical generation by these compounds is observed. In this study we examined a new family of sugar-N-substituted derivatives of daunorubicin bearing a bulky substituent introduced on the nitrogen atom through the amidine spacer. These compounds were found to be very active in radical formation catalyzed by all three studied enzymes. Thus, the introduction of a heterocyclic ring, even if it is bulky but flexible, on the nitrogen atom of daunosamine moiety through the one-atom spacer (amidine group), does not induce the steric hindrance effect on the interaction of daunorubicin derivatives with these flavoprotein enzymes.
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PMID:The ability of new formamidine sugar-modified derivatives of daunorubicin to stimulate free radical formation in three enzymatic systems: NADH dehydrogenase, NADPH cytochrome P450 reductase and xanthine oxidase. 1096 87

S-Nitrosoglutathione (GSNO) undergoes spontaneous degradation that generates several nitrogen-containing compounds and oxidized glutathione derivatives. We identified glutathione sulfonic acid, glutathione disulfide S-oxide (GS(O)SG), glutathione disulfide S-dioxide, and GSSG as the major decomposition products of GSNO. Each of these compounds and GSNO were tested for their efficacies to modify rat brain neurogranin/RC3 (Ng) and neuromodulin/GAP-43 (Nm). Among them, GS(O)SG was found to be the most potent in causing glutathiolation of both proteins; four glutathiones were incorporated into the four Cys residues of Ng, and two were incorporated into the two Cys residues of Nm. Ng and Nm are two in vivo substrates of protein kinase C; their phosphorylations by protein kinase C attenuate the binding affinities of both proteins for calmodulin. When compared with their respective unmodified forms, the glutathiolated Ng was a poorer substrate and glutathiolated Nm a better substrate for protein kinase C. Glutathiolation of these two proteins caused no change in their binding affinities for calmodulin. Treatment of [(35)S]cysteine-labeled rat brain slices with xanthine/xanthine oxidase or a combination of xanthine/xanthine oxidase with sodium nitroprusside resulted in an increase in cellular level of GS(O)SG. These treatments, as well as those by other oxidants, all resulted in an increase in thiolation of proteins; among them, thiolation of Ng was positively identified by immunoprecipitation. These results show that GS(O)SG is one of the most potent glutathiolating agents generated upon oxidative stress.
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PMID:Glutathiolation of proteins by glutathione disulfide S-oxide derived from S-nitrosoglutathione. Modifications of rat brain neurogranin/RC3 and neuromodulin/GAP-43. 1106 Mar 8

Free radicals are highly reactive molecules implicated in the pathology of traumatic brain injury and cerebral ischemia, through a mechanism known as oxidative stress. After brain injury, reactive oxygen and reactive nitrogen species may be generated through several different cellular pathways, including calcium activation of phospholipases, nitric oxide synthase, xanthine oxidase, the Fenton and Haber-Weiss reactions, by inflammatory cells. If cellular defense systems are weakened, increased production of free radicals will lead to oxidation of lipids, proteins, and nucleic acids, which may alter cellular function in a critical way. The study of each of these pathways may be complex and laborious since free radicals are extremely short-lived. Recently, genetic manipulation of wild-type animals has yielded species that over- or under-express genes such as, copper-zinc superoxide dismutase, manganese superoxide dismutase, nitric oxide synthase, and the Bcl-2 protein. The introduction of the species has improved the understanding of oxidative stress. We conclude here that substantial experimental data links oxidative stress with other pathogenic mechanisms such as excitotoxicity, calcium overload, mitochondrial cytochrome c release, caspase activation, and apoptosis in central nervous system (CNS) trauma and ischemia, and that utilization of genetically manipulated animals offers a unique possibility to elucidate the role of free radicals in CNS injury in a molecular fashion.
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PMID:Free radical pathways in CNS injury. 1106 54

Nitration of proteins by peroxynitrite may alter protein function. We hypothesized that reactive nitrogen species modulate fibronectin-induced fibroblast migration. To test this hypothesis, we evaluated fibroblast migration induced by fibronectin incubated with and without peroxynitrite. Peroxynitrite attenuated fibronectin-induced fibroblast migration in a dose-dependent manner but did not attenuate complement-activated serum-induced fibroblast migration. The reducing agents, deferoxamine and dithiothreitol (DTT), and L-tyrosine reversed the inhibition by peroxynitrite. PAPA-NONOate, a nitric oxide (NO) donor, and superoxide generated by the action of xanthine oxidase on lumazine or xanthine, also showed an inhibitory effect on fibroblast migration. The peroxynitrite generator, 3-morpholinosydnonimine (SIN-1), caused a concentration-dependent inhibition of fibroblast migration. Peroxynitrite reduced fibronectin binding to fibroblasts and resulted in nitrotyrosine formation. These findings are consistent with nitration of tyrosine by peroxynitrite with subsequent inhibition of fibronectin binding to fibroblasts and suggest that peroxynitrite may play a role in regulation of fibroblast migration.
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PMID:Reactive oxygen and nitrogen metabolites modulate fibronectin-induced fibroblast migration in vitro. 1113 92

The aim of this work was to characterize the products of metabolic activation of the antitumor drug ledakrin (Nitracrine) in model metabolic systems, where formation of drug-DNA adducts was previously discovered. The metabolic products obtained in different biological systems were compared with those obtained in experiments where chemical reducing agents were applied. Therefore, activation products were obtained in the presence of the microsomal fraction of rat liver and in the experiments with the reducing agents dithiothreitol, hydrazine hydrate, and SnCl(2). Furthermore, transformations of the drug with oxidoreductase enzymes DT-diaphorase and xanthine oxidase were observed. The ledakrin transformation products were separated and analyzed by HPLC with diode array detection. Structural studies of the products were performed by means of ESI-MS and NMR. Proton, carbon, and nitrogen assignments were made based upon DQF-COSY, ROESY, TOCSY, HSQC, and HMBC experiments. It was demonstrated during the reduction of ledakrin that a key metabolite, a compound with an additional five-membered ring attached to positions 1 and 9 of the acridine core and with the retained 9-aminoalkyl side chain, was formed in all the systems that were studied. It was determined that the reactive nitrogen atoms of this additional ring underwent further transformations resulting in the formation of a six-membered ring produced by the addition of a carbon atom to the dihydropyrazoloacridine ring. Furthermore, it was observed that positions 2 and 4 of ledakrin's acridine ring are susceptible to nucleophilic substitution as revealed by the studies with dithiothreitol. Additionally, although most products from the reduction of ledakrin were extremely unstable, 1-aminoacridinone, produced enzymatically and with dithiothreitol, exhibited persistent stability under the studied conditions.
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PMID:Products of metabolic activation of the antitumor drug ledakrin (nitracrine) in vitro. 1117 May 2

The Janus face of nitric oxide (NO) has prompted a debate as to whether NO plays a deleterious or protective role in tissue injury. There are a number of reactive nitrogen oxide species, such as N2O3 and ONOO-, that can alter critical cellular components under high local concentrations of NO. However, NO can also abate the oxidation chemistry mediated by reactive oxygen species such as H2O2 and O2- that occurs at physiological levels of NO. In addition to the antioxidant chemistry, NO protects against cell death mediated by H2O2, alkylhydroperoxides, and xanthine oxidase. The attenuation of metal/peroxide oxidative chemistry, as well as lipid peroxidation, appears to be the major chemical mechanisms by which NO may limit oxidative injury to mammalian cells. In addition to these chemical and biochemical properties, NO can modulate cellular and physiological processes to limit oxidative injury, limiting processes such as leukocyte adhesion. This review will address these aspects of the chemical biology of this multifaceted free radical and explore the beneficial effect of NO against oxidative stress.
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PMID:Mechanisms of the antioxidant effects of nitric oxide. 1139 76

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 found previously that the nitric oxide donor DEA/NO enhanced lipid peroxidation, DNA fragmentation, and cytotoxicity in human bronchial epithelial cells (BEAS-2B) when they were cultured in LHC-8 medium containing the superoxide-generating system hypoxanthine/xanthine oxidase (HX/XO). We have now discovered that DEA/NO's prooxidant action can be reversed by raising the L-tyrosine concentration from 30 to 400 microM. DEA/NO also protected the cells when they were cultured in Dulbecco's Modified Eagle's Medium (DMEM), whose standard concentration of L-tyrosine is 400 microM. Similar trends were seen with the colon adenoma cell line CaCo-2. Since HPLC analysis of cell-free DMEM or LHC-8 containing 400 microM L-tyrosine, DEA/NO, and HX/XO revealed no evidence of L-tyrosine nitration, our data suggest the existence of an as-yet uncharacterized mechanism by which L-tyrosine can influence the biochemical and toxicological effects of reactive nitrogen species.
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PMID:L-tyrosine and nitric oxide synergize to prevent cytotoxic effects of superoxide. 1152 74

The title compounds were prepared and tested as xanthine oxidase (XO) inhibitors. Results evidenced that potency was related to the position of the oxygen atom in the 2-linear chain and that it grew with distance from the sulfur atom until it became equipotent to 2-n-hexylthiohypoxanthine. Enzymatic oxidation on C(2) occurred in the 8-alkylthiohypoxanthines. On the contrary, oxidation on C(8) did not occur in the 2-alkythioderivatives, demonstrating that the chain forced these molecules to form a complex with molybdenum(VI) involving only the N(3) and N(9) nitrogen atoms.
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PMID:2-Alkyloxyalkylthiohypoxanthines as new potent inhibitors of xanthine oxidase. 1176 31

We hypothesized that in hyperhomocysteinemia (HHcy), flow-induced arteriolar constriction is due to an enhanced generation of reactive oxygen and/or nitrogen species, causing an impairment of nitric oxide (NO) and prostaglandin mediation of the response. Changes in diameter of isolated, pressurized (at 80 mm Hg) gracilis muscle arterioles (diameter approximately 170 microm) from control and methionine diet-induced HHcy rats were measured by videomicroscopy. Increases in intraluminal flow (from 0 to 25 microL/min) resulted in NO- and prostaglandin-mediated dilations of control arterioles (maximum, control, 30+/-4 microm) but elicited significant constrictions of HHcy arterioles (maximum, HHcy, -32+/-3 microm), which were abolished by the thromboxane A(2) receptor blocker SQ 29,548. Intraluminal administration of superoxide dismutase plus catalase did not affect flow-mediated dilations of control arterioles, but in HHcy arterioles, it reversed the flow-induced constrictions to dilations (maximum 18+/-4 microm), which were abolished by an NO synthase inhibitor. Flow-induced constrictions of HHcy arterioles were prevented by the presence of the xanthine oxidase inhibitor oxypurinol [but not by the NAD(P)H-oxidase inhibitor diphenyleneiodonium] and by urate, a known peroxynitrite scavenger. Also, authentic peroxynitrite elicited arteriolar constrictions (-31+/-8 microm) that were eliminated by urate and SQ 29,548. Thus, we suggest that in HHcy, xanthine oxidase-derived superoxide scavenges NO released to flow, forming peroxynitrite, which promotes release of thromboxane A(2), resulting in arteriolar constriction.
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PMID:Xanthine oxidase-derived reactive oxygen species convert flow-induced arteriolar dilation to constriction in hyperhomocysteinemia: possible role of peroxynitrite. 1178 57


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