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)

The molybdenum cofactor prepared by denaturing xanthine oxidase by heat treatment or other methods was partially purified by anaerobic gel filtration in the presence of sodium dithionite, with little loss of activity. A range of products with different elution volumes was obtained. This behaviour is apparently related to association of the molybdenum cofactor with various residual peptides. E.p.r. signals from molybdenum (V) in the active cofactor, present either in crude preparations or in purified fractions, may be generated in dimethyl sulphoxide solution by controlled oxidation carried out on the molybdenum cofactor alone or in the presence of added thiols. The g-values of the spectra suggest that in the oxidized cofactor molybdenum has one terminal oxygen ligand and four ligands from thiolate groups. It is proposed that two of these are from the organic part of the cofactor and two from cysteine residues in the protein or in residual peptides. A signal generated in high yield with little loss of cofactor activity in the presence of thiophenol has g parallel = 2.0258 and g = 1.9793. It is suggested that in this species two cysteine residues have been replaced by two thiophenol molecules. The possible usefulness of the thiophenol complex in further purification of the molybdenum cofactor is discussed.
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PMID:Studies by electron-paramagnetic-resonance spectroscopy of the environment of the metal in the molybdenum cofactor of molybdenum-containing enzymes. 609 19

The stoichiometry of reducing equivalents per protomer for the complex molybdoflavoprotein xanthine oxidase has been re-examined by reductive titrations with sodium dithionite and anaerobic reoxidation with cytochrome c and phenazine methosulfate of dithionite- or photo-reduced enzyme. It is found that 8.0 +/- 0.1 reducing equivalents are taken up (or given up) by the enzyme, a value of 2 eq greater than expected on the basis of the known oxidation-reduction centers in the enzyme. The reaction of reduced xanthine oxidase with [14C]iodoacetate indicates that, in the reduced form of the enzyme, additional cysteine residues are available for reaction. These results, in conjunction with the observation that reaction of oxidized enzyme with sulfite results in the appearance of an additional equivalent of thiol capable of reacting with 5,5'-dithiobis-(2-nitrobenzoic acid) or iodoacetate, indicate the presence of a disulfide linkage in the enzyme that can be reduced by dithionite or photochemically employing EDTA and 5-deazaflavin. Neither xanthine nor lumazine, however, is capable of reducing this oxidation-reduction center, suggesting that the disulfide does not play a role in the catalytic reactions of the enzyme. These results resolve discrepancies in the literature which indicated that greater than 6 reducing equivalents were consistently needed to bring about the complete reduction of xanthine oxidase.
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PMID:The presence of a reducible disulfide bond in milk xanthine oxidase. 628 47

The activation of N2-methyl-9-hydroxyellipticinium acetate (4) by a peroxidase--H2O2 system leads to the formation of an omicron-quinone (7a). This omicron-quinone is not directly generated from the starting material but through a quinone imine intermediate (6) which is subsequently oxidized. This reaction is highly dependent on pH values. The omicron-quinone 7a is easily protonated (7b), gives an addition product with methanol (9), and is reduced by cysteine. The omicron-quinone 7b has a rather low inhibitory effect against L1210 leukemia cell multiplication but acts as an electron carrier and dramatically augments the oxygen consumption in xanthine oxidase-NADH and rat liver microsomes-NADPH systems.
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PMID:omicron-Quinone formation in the biochemical oxidation of the antitumor drug N2-methyl-9-hydroxyellipticinium acetate. 683 91

X-ray absorption spectra have been recorded for the molybdenum K-edge region of xanthine oxidase. Both the absorption edge and the extended fine structure (e.x.a.f.s.) regions were investigated. Spectra were obtained for samples of the desulpho enzyme as well as for mixtures of this with the active enzyme. The spectrum of the pure active form was then obtained by difference. The desulpho enzyme shows a pronounced step in the absorption edge, of a type previously associated terminal oxygen ligands. In the active enzyme this step has decreased markedly. Satisfactory simulations of the e.x.a.f.s. spectrum of the desulpho enzyme could be obtained by assuming the molybdenum to be bonded to two terminal oxygen atoms (Mo = O about .175 nm), two sulphur atoms (presumably from cysteine residues, Mo-S about .0250 nm) and one sulphur atom (presumably from a methionine residue, Mo-S about 0.290 nm). E.x.a.f.s. of the active enzyme differed appreciably from this. In keeping with earlier proposals [Gutteridge, Tanner & Bray (1978) Biochem. J. 175, 887-897], the spectrum of the active enzyme could be simulated if a sulphur atom at about 0.225 nm (i.e. presumably a terminal sulphur atom) replaced one of the terminal oxygen atoms of the desulpho from, with small changes in the other bond distances. Validity of the interpretative procedures, which involved phase shift and amplitude calculations ab initio, was demonstrated by using low molecular weight compounds of known structure.
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PMID:X-ray absorption spectroscopy of xanthine oxidase. The molybdenum centres of the functional and the desulpho forms. 689 37

Reductive activation of misonidazole and misondiazole acetate, a simple derivative, in the presence of xanthine oxidase causes inactivation of the enzyme. The inactivation is not accompanied by binding of the misonidazole to the enzyme. The nitroreductase activity of xanthine oxidase is inhibited as measured by the reduction of 3,5-dinitrobenzonitrile (DNBN). Cysteine does not appear to protect against the enzyme inactivation by misonidazole but, by itself, cysteine has a strong stimulating effect on the reduction of DNBN. The possible significance of these reactions to the toxicity of misonidazole are discussed.
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PMID:Reductive activation of nitroaromatics and enzyme inhibition: misonidazole and xanthine oxidase. 689 6

Steady-state radiolysis, pulse radiolysis and epr studies, combined with enzyme activity measurements, were carried out on the mechanism by which radical attack, through one-electron oxidation, inactivates xanthine oxidase. Electron transfer to both the N3 and Br2- radical species was used to initiate oxidative damage on the enzyme. Inactivation was found to occur to a greater extent at low than at high pH and is associated with the initial formation of a tryptophanyl radical which converts by a known intramolecular pathway to a tyrosyl radical with a rate constant of 5 x 10(3) S-1. The tyrosyl radical in turn slowly loses around half of its absorbance at an intramolecular rate constant of 350S-1 and is consistent with the establishment of a radical equilibrium with cysteine residue(s). The sequence of reactions could be repeated several times on the same irradiated sample implying that restitution of the implied cysteinyl radical occurs leading to other damage in the protein. N3+Trp/N-->Trp/N-->Tyr/O<-->Cys/S-->?. Epr evidence implies that inactivation of the enzyme from the above sequence of reactions arises in part from alternations to Fe/S center I in the enzyme.
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PMID:Inactivation of xanthine oxidase by oxidative radical attack. 749 May 3

The direct neurotoxic action of the beta-amyloid protein, the major constituent of senile plaques, may represent the underlying cause of neuronal degeneration observed in Alzheimer's disease. The apoptotic-mediated neuronal death induced by beta-amyloid appears to reside in its ability to form Ca(2+)-permeable pores in neuronal membranes resulting in an excessive influx of Ca2+ and the induction of neurotoxic cascades. It is possible that during beta-amyloid exposure a Ca(2+)-mediated increase in free radical generation may exceed the defensive capacity of cells and thus lead to cell death. Consequently, in the present study we have investigated the effect of a panoply of antioxidants and inhibitors of free radical formation on the development of beta-amyloid neurotoxicity. Acute exposure of rat hippocampal neurons to "aged" beta-amyloid25-35 peptide (5-50 microM) induced a slow, concentration-dependent apoptotic neurotoxicity (25-85%) during a 6 day exposure. Co-incubation of cultures with beta-amyloid25-35 peptide (25 microM) and inhibitors of nitric oxide synthase and/or xanthine oxidase (NG-monomethyl-L-arginine [1 mM), N omega-nitro-L-arginine [1 mM], oxypurinol [100 microM], allopurinol [100 microM]), important mediators of nitric oxide, superoxide, and hydroxyl radical formation, did not attenuate beta-amyloid neurotoxicity. Similarly, a reduction in free radical generation by selective inhibition of phospholipase-A2 cyclooxygenase, and lipoxygenase activities with quinacrine (0.5 microM), indomethacin (50 microM), and nor-dihydroguaiaretic acid (0.5 microM), respectively, did not reduce the proclivity of beta-amyloid to induce cell death. Exposure of cultures to catalase (25 U/ml) and/or superoxide dismutase (10 U/ml) as well as the free radical scavengers vitamin E (100 microM), vitamin C (100 microM), glutathione (100 microM), L-cysteine (100 microM), N-acetyl-cysteine (100 microM), deferoxamine (5 microM), or haemoglobin (35 micrograms/ml) failed to attenuate the neurotoxic action of beta-amyloid. On the other hand, pre-treatment of cultures with subtoxic concentrations of beta-amyloid peptide significantly increased the vulnerability of neurons to H2O2 exposure and suggest that beta-amyloid peptide renders neurons more sensitive to free radical attack. However, a potential beta-amyloid-mediated increase in free radical formation is not a proximate cause of the neurotoxic mechanism of beta-amyloid in vitro.
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PMID:Inhibitors of free radical formation fail to attenuate direct beta-amyloid25-35 peptide-mediated neurotoxicity in rat hippocampal cultures. 753 47

Nitric oxide which was released in aqueous solutions (> or = 10 microM) of direct NO-donors such as 3-morpholinesydnonimine (SIN-1) and S-nitroso-N-acetyl-penicillamine (SNAP) consumed avidly sulfhydryl groups of N-acetylcysteine > cysteine > glutathione. In case of SIN-1 generation of nitrites run in parallel to disappearance of sulfhydryl groups of N-acetylcysteine and glutathione, however, for a pair of SIN-1 and cysteine the rate of formation of nitrites was much slower than the rate of consumption of sulfhydryl groups. We infer that kinetics of formation and breakdown of S-nitrosothiols varies depending on the type of a thiol which reacts with a NO-donor. Indirect NO-donors such as glyceryl trinitrate (GTN), molsidomine (MSD) or sodium nitroprusside (NaNP) at concentrations < 100 microM did not consume sulfhydryl groups of cysteine unless pretreated with the xanthine/xanthine oxidase system. We suppose that in this last case superoxide anions react with nitric oxide to form peroxynitrites with a higher potency than nitric oxide itself to destroy sulfhydryl groups. We conclude that out of three studied thiols N-acetylcysteine is the best substrate for the formation of S-nitrosothiols, while S-nitrosocysteine is the slowest releaser of nitric oxide. Moreover, unlike SIN-1 and SNAP, NaNP is not a direct NO-donor but behaves rather like GTN. Minute amounts of nitric oxide released either from NaNP or GTN gain from superoxide anions an amplification as SH-scavengers.
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PMID:In vitro generation and decomposition of S-nitrosothiols from direct and indirect nitric oxide donors. 755 May 51

Superoxide radical (O2-.), generated by the xanthine-xanthine oxidase system, induces significant amount (20%) of single-strand breaks in plasmid pBR322 DNA. This is almost completely inhibited by its specific scavenger, superoxide dismutase. The biological antioxidants, at near physiological concentrations show great variation in their modulation of DNA damage induced by O2-.. The thiols glutathione, cysteine and dithiothreitol do not protect DNA, instead they greatly enhance the strand-breaking activity of this free radical. However, the lipid soluble antioxidants tannic acid, butein, canthaxanthin, beta-carotene and lipoate offered significant protection to plasmid DNA against O2-.. Since O2-. is the most abundant reactive oxygen species generated, the above mentioned modulating abilities of biological antioxidants may have significant biological implications.
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PMID:Variation in the modulation of superoxide-induced single-strand breaks in plasmid pBR322 DNA by biological antioxidants. 766 83

Asbestos fibers cause dose-dependent, persistent increases in mRNA levels of c-jun and c-fos proto-oncogenes in rat pleural mesothelial (RPM) cells, the progenitor cells of asbestos-induced mesothelioma (N. Heintz, Y. M. W. Janssen, and B. T. Mossman. Proc. Natl. Acad. Sci. USA, 90: 3299-3303, 1993). Here we report that addition of N-acetyl-L-cysteine decreases asbestos-mediated induction of c-fos and c-jun mRNA levels in a dose-dependent fashion. Exposure of RPM cells to asbestos causes depletion of total cellular glutathione, a response that can be abolished by pretreatment with N-acetyl-L-cysteine. Pretreatment of cells with buthionine sulfoximine, an agent which diminishes glutathione pools, increases the magnitude of induction of c-fos and c-jun mRNA by asbestos. To determine whether asbestos-induced effects on proto-oncogene expression could be attributed to extracellular generation of active oxygen species (AOS), RPM cells were exposed to H2O2 or xanthine and xanthine oxidase, a generating system of AOS. These oxidant stresses did not decrease cellular glutathione levels nor alter mRNA levels of c-fos or c-jun. However, increased mRNA levels of manganese-containing superoxide dismutase and heme oxygenase were observed, indicating that RPM cells respond to AOS by increased expression of genes encoding antioxidant enzymes. These data indicate that the signaling pathways leading to c-fos/c-jun proto-oncogene induction by asbestos are not triggered directly by formation of extracellular AOS. However, intracellular thiol levels appear to influence the expression of c-fos and c-jun, suggesting a redox-sensitive component in the signaling cascade which modulates gene expression of c-fos and c-jun by asbestos.
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PMID:Induction of c-fos and c-jun proto-oncogene expression by asbestos is ameliorated by N-acetyl-L-cysteine in mesothelial cells. 774 7


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