Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.17.1.4 (xanthine dehydrogenase)
 1,236 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xanthine oxidoreductases (XOR), xanthine dehydrogenase (XDH, EC1.1.1.204) and xanthine oxidase (XO, EC1.2.3.2), are the best-studied molybdenum-containing iron-sulfur flavoproteins. The mammalian enzymes exist originally as the dehydrogenase form (XDH) but can be converted to the oxidase form (XO) either reversibly by oxidation of sulfhydryl residues of the protein molecule or irreversibly by proteolysis. The active form of the enzyme is a homodimer of molecular mass 290 kDa. Each subunit contains one molybdopterin group, two non-identical [2Fe-2S] centers, and one flavin adenine dinucleotide (FAD) cofactor. This review focuses mainly on the role of the two iron-sulfur centers in catalysis, as recently elucidated by means of X-ray crystal structure and site-directed mutagenesis studies. The arrangements of cofactors indicate that the two iron-sulfur centers provide an electron transfer pathway from molybdenum to FAD. However, kinetic and thermodynamic studies suggest that these two iron-sulfur centers have roles not only in the pathway of electron flow, but also as an electron sink to provide electrons to the FAD center so that the reactivity of FAD with the electron acceptor substrate might be thermodynamically controlled by way of one-electron-reduced or fully reduced state.
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PMID:The role of the [2Fe-2s] cluster centers in xanthine oxidoreductase. 1113 37

To investigate the properties of xanthine dehydrogenase/xanthine oxidase (XDH/XO) deficiency in a patient with atypical type I xanthinuria, as indicated by oxypurine data, a cDNA sequence encoding XDH, XDH/XO immunoblot analysis and a competitive PCR assay were performed, and the results were compared with those of normal subjects. The xanthine dehydrogenase cDNA sequence of the patient was consistent with the controls, while immunologically reactive 150 kD XDH/XO protein was not present in the xanthinuric duodenal mucosa, unlike the control duodenal mucosa. In addition, a decrease in XDH/XO messenger RNA was found by competitive PCR. These results suggest that atypical type I xanthinuria is due to a decrease in messenger RNA of XDH/XO. Furthermore, it was considered that this decrease could explain the normal plasma level and near normal urinary excretion of hypoxanthine seen in this case of xanthinuria, though XDH/XO activity and protein were not detected spectrophotometrically and immunologically, respectively.
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PMID:Human xanthine dehydrogenase cDNA sequence and protein in an atypical case of type I xanthinuria in comparison with normal subjects. 1116 12

It has been established that papaverine as well as other xenobiotics (dexamethasone and nitrosodimethylamine) [figure: see text] provoked the thymocyte death like apoptosis. The increase of the quantity of double-strand, single-strand DNA breaks and low molecular weight fragments of DNA preceded cell death. In papaverine-induced process of thymocyte apoptosis the total activity of xanthine oxidase in thymocytes strongly elevated long before their death, the conversion of xanthine dehydrogenase (D-form) to xanthinoxidase (O-form) and accumulation of O-form in the cultural medium took place. Direct stimulating effect of papaverine on O-form of enzyme in thymocyte lysate was revealed. The used digitonin thymocytes were divided into cytoplasmic and structural component fractions. It was shown that about 80% of total xanthinoxidase activity was concentrated in cytoplasma while only 20% of its activity was found in structural components. More higher ratio of xanthinoxidase/xanthindehydrogenase (XO/XDH) was observed and papaverine-induced changes of these enzyme forms activities were expressed more brightly in the structural components, than in the thymocyte cytoplasma. During the process of developing thymocytes apoptosis caused by papaverine the reaction of lipid peroxidation was intensified. XO-hypoxanthin system displaying prooxidant influence on cells increased the cytotoxic effect of papaverine but the presence of allopurinol or catalase and superoxidedismutase decreased it. Besides, cytotoxic action on thymocytes of allopurinol itself as well as hypoxanthin itself was revealed.
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PMID:[Role of xanthine oxidase and xanthine dehydrogenase systems in thymocyte apoptosis, induced by papaverine]. 1120 Apr 84

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant, induced xanthine oxidase and xanthine dehydrogenase (XO/XDH) activities, in addition to ethoxyresorufin-O-dealkylase and methoxyresorufin-O-dealkylase activities in liver of mice. When TCDD was given to mice as a single oral dose of 40 microg/kg, the activities of XO and XDH increased about threefold within 3 days and the increased levels were maintained for 4 weeks. The treatment of mice with 3-methylcholanthrene also induced XO/XDH activities, but phenobarbital and dexamethasone had no effect. The level of aldehyde oxidase, a molybdenum flavoenzyme related to XO/XDH, in mouse liver was also enhanced about 1.5-fold by TCDD treatment. The inducing effect of TCDD and 3-methylcholanthrene was not observed in null mice (AhR(-/-)), which lack the AhR gene. XO and XDH activities were induced by TCDD in heterozygous mice (AhR(+/-)). The lipid peroxidation in liver was stimulated by TCDD. The induction of XO and XDH, which produces reactive oxygen species, may contribute to the various toxicities of TCDD.
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PMID:Aryl hydrocarbon receptor (AhR)-mediated induction of xanthine oxidase/xanthine dehydrogenase activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1124 47

A cDNA coding for feline liver xanthine dehydrogenase (XDH, EC 1.1.204) was amplified by RT-PCR and cloned for determining the sequence. The clones contained an open reading frame of 4002 base pairs encoding 1333 amino acid residues. The calculated molecular weight and isoelectric point were approximately 146 kDa and 7.0. Comparison of the deduced amino acid sequences indicated remarkable high homology, i.e., the amino acid residues of feline XDH shared approximately 90%, 87%, 87% and 86% identity with those of human, bovine, rat and mouse, respectively. The anino acid sequences of two putative iron-sulfur centers, one NAD binding site and one molybdenum binding site were well conserved among mammalian animals.
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PMID:Molecular cloning of a cDNA coding for feline liver xanthine dehydrogenase. 1130 44

Studies have been made on the possible involvement of malondialdehyde (MDA) and (E)-4-hydroxynon-2-enal (HNE), two terminal compounds of lipid peroxidation, in modifying xanthine oxidoreductase activity through interaction with the oxidase (XO) and/or dehydrogenase (XDH) forms. The effect of the two aldehydes on XO (reversible, XO(rev), and irreversible, XO(irr)) and XDH was studied using xanthine oxidase from milk and xanthine oxidoreductase partially purified from rat liver. The incubation of milk xanthine oxidase with these aldehydes resulted in the inactivation of the enzyme following pseudo-first-order kinetics: enzyme activity was completely abolished by MDA (0.5-4 mM), while residual activity (5% of the starting value) associated with an XO(irr) form was always observed when the enzyme was incubated in the presence of HNE (0.5-4 mM). The addition of glutathione to the incubation mixtures prevented enzyme inactivation by HNE. The study on the xanthine oxidoreductase partially purified from rat liver showed that MDA decreases the total enzyme activity, acting only with the XO forms. On the contrary HNE leaves the same level of total activity but causes the conversion of XDH into an XO(irr) form.
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PMID:Mechanisms of action of malondialdehyde and 4-hydroxynonenal on xanthine oxidoreductase. 1133 8

The activity of xanthine oxidoreductases (xanthine oxidase, XO, EC 1.2.3.2 and xanthine dehydrogenase, XDH, EC 1.1.1.204) in partially purified extracts of Gonyaulax polyedra was measured over 24 h both in a light:dark cycle and in constant light. This is the first demonstration of xanthine oxidoreductase in a unicellular alga. The activity of the O2-dependent form (XO) was found to be 15 times higher in light than in darkness. The same time-of-day specific differences persisted in constant light, demonstrating a control of XO by the circadian clock. In contrast, the activity of the NAD-dependent form (XDH) is not under circadian control. Because pharmacological inhibition of XO also blocks the effect of blue light on the Gonyaulax circadian clock, the possible relationship between XO and light reception in this unicellular alga will be discussed.
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PMID:The flavo-enzyme xanthine oxidase is under circadian control in the marine alga Gonyaulax. 1206 1

The molybdenum cofactor (MoCo)-containing enzymes aldehyde oxidase (AO; EC 1.2.3.1) and xanthine dehydrogenase (XDH; EC 1.2.1.37) require for activity a sulfuration step that inserts a terminal sulfur ligand into the MoCo. The tomato flacca mutation was originally isolated as a wilty phenotype due to a lack of abscisic acid (ABA) that is related to simultaneous loss of AO and XDH activities. An expressed sequence tag candidate from tomato was selected on the basis of homology to sulfurases from animals, fungi and the recently isolated Arabidopsis genes LOS5/ABA3. The tomato homologue maps as a single gene to the bottom of chromosome 7, consistent with the genetic location of the flacca mutation. The structure of FLACCA shows a multidomain protein with an N-terminal NifS-like sulfurase domain; a mammal-specific intermediate section; and a C-terminus containing conserved motifs. Prominent among these are molybdopterin oxidoreductases and thioredoxin redox-active centre/iron-sulfur-binding region signatures which may be relevant to the specific sulfuration of MoCo. Indeed, the molecular analysis of flacca identifies the mutation in a highly conserved motif located in the C-terminus. Activity gel assays show that FLACCA is expressed throughout the plant. Transient and stable complementation of flacca and the Arabidopsis aba3 mutants with Aspergillus nidulans hxB and FLACCA yielded full, partial and tissue-specific types of Mo-hydroxylase activities. Restoration of activity in the root alone is sufficient to augment plant ABA content and rectify the wild-type phenotype. Thus the pleiotropic flacca phenotype is due to the loss of activity of enzymes requiring a sulfurated MoCo.
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PMID:The absence of molybdenum cofactor sulfuration is the primary cause of the flacca phenotype in tomato plants. 1216 10

cDNA of rat liver xanthine oxidoreductase (XOR), a molybdenum-containing iron-sulfur flavoprotein, was expressed in a baculovirus-insect cell system. The expressed XOR consisted of a heterogeneous mixture of native dimeric, demolybdo-dimeric, and monomeric forms, each of which was separated and purified to homogeneity. All the expressed forms contained flavin, of which the semiquinone form was stable during dithionite titration after dithiothreitol treatment, indicating that the flavin domains of all the expressed molecules have the intact conformations interconvertible between NAD(+)-dependent dehydrogenase (XDH) and O(2)-dependent oxidase (XO) types. The absorption spectrum and metal analyses showed that the monomeric form lacks not only molybdopterin but also one of the iron-sulfur centers. The reductive titration of the monomer with dithionite showed that the monomeric form required only three electrons for complete reduction, and the redox potential of the iron-sulfur center in the monomeric form is a lower value than that of FAD. In contrast to native or demolybdo-dimeric XDHs, the monomer showed a very slow reductive process with NADH under anaerobic conditions, although the conformation around FAD is a dehydrogenase form, suggesting the important role of the iron-sulfur center in the reductive process of FAD with the reduced pyridine nucleotide.
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PMID:Purification and characterization of multiple forms of rat liver xanthine oxidoreductase expressed in baculovirus-insect cell system. 1235 75

Hypoxia causes up-regulation and activation of xanthine dehydrogenase/xanthine oxidase (XDH/XO) in vitro and in the lungs in vivo. This up-regulation, and the likely corresponding production of reactive oxygen species, may underlie the pathogenesis of an array of disorders. Thus, compounds that prevent hypoxia-induced increase in XDH/XO activity may provide a therapeutic strategy in such disorders. The antioxidant properties of estrogens have been demonstrated in several studies. However, the effect of these compounds on XDH/XO has not been explored previously. The aim of this study was to investigate the effects of estrogen on hypoxia-induced increase in XDH/XO activity. Rat pulmonary artery microvascular endothelial cells were exposed to normoxia or hypoxia in the presence or absence of 17beta- or 17alpha-estradiol. The XDH/XO enzyme and gene promoter activities were measured in different groups of cells. Hypoxia caused a twofold increase in XDH/XO enzymatic and promoter activity. Either of the estradiol stereoisomers prevented the hypoxia-induced increase in XDH/XO enzymatic activity, but not the promoter activity. ICI 182,780, an antagonist of the estrogen receptor, failed to block the inhibitory effect of estradiol on XDH/XO. In conclusion, 17alpha- and 17beta-estradiol modulate the hypoxia-induced regulation of XDH/XO activity at a posttranscriptional level by a receptor-independent mechanism.
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PMID:Estrogen modulates xanthine dehydrogenase/xanthine oxidase activity by a receptor-independent mechanism. 1458 43


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