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:1.17.1.4 (xanthine dehydrogenase)
1,236 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xanthine oxidoreductase from bovine milk can be prepared in two interconvertible forms, xanthine oxidase (XO) and xanthine dehydrogenase (XDH), depending on the number of protein cysteines versus cystines. Enzyme forms differ in respect to their oxidizing substrates; XDH prefers NAD to molecular oxygen, whereas XO only reacts significantly with oxygen. The preference for oxidizing substrate is partially explained by thermodynamics. Unlike XDH, the midpoint potential of the FAD, the center at which oxygen and NAD react, is too high in XO to efficiently reduce NAD (Hunt, J., Massey, V., Dunham, W.R., and Sands, R.H. (1993) J. Biol. Chem. 268, 18685-18691). To distinguish between changes in thermodynamics and in substrate binding, samples of both XO and XDH have been prepared in which the native FAD has been replaced with an FAD analog of different redox potential, 1-deaza-FAD or 8-CN-FAD. Reductive titrations indicate that both 1-deaza-XO and 1-deaza-XDH have a flavin midpoint potential similar to native XDH and that 8-CN-XO and 8-CN-XDH each have a flavin potential higher than XO. Both the low potential 1-deaza-XO and the high potential 8-CN-XDH contain essentially no xanthine/NAD activity. However, 1-deaza-XDH does exhibit xanthine/NAD activity, and 8-CN-XO has normal xanthine/oxygen activity. The binding of NAD to oxidized XO and XDH was investigated by ultrafiltration and isothermal titration calorimetry. The Kd for the binding of NAD to XDH was determined to be 280 +/- 145 microM by ultrafiltration and 160 +/- 40 microM by isothermal titration calorimetry. No evidence for the binding of NAD to XO by either method could be obtained. A low flavin midpoint potential is necessary but not sufficient for dehydrogenase activity.
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PMID:Role of the flavin midpoint potential and NAD binding in determining NAD versus oxygen reactivity of xanthine oxidoreductase. 998 90

This study was designed to study xanthine oxidase (XO) and xanthine dehydrogenase (XD) activity in the lung of rats exposed to prolonged restraining immobilization stress. Immobilization caused more than twofold increase of xanthine oxidase activity in the rat lung. The activity of xanthine oxidase decreased in lung homogenates incubated at -20 degrees C for 24 h. The same incubation of homogenates from control rats caused a non-significant increase of the activity. No measurable NAD(+)-dependent xanthine dehydrogenase activity could be established in the lungs of both control rats and rats subjected to immobilization. All rats revealed methylene blue-dependent xanthine dehydrogenase activity which was more than two-times higher in the immobilized animals. Incubation at -20 degrees C for 24 h increased the methylene blue-dependent xanthine dehydrogenase activity in homogenates from control rats and decreased the enzyme activity in homogenates from immobilized rats. A working hypothesis was proposed for the sequence of events explaining the results obtained: XO-catalyzed generation of activated oxygen species may take place in the initiation of lipid peroxidation in the lung of rats immobilized for prolonged periods of time.
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PMID:Pulmonary xanthine oxidase activity of rats exposed to prolonged immobilization stress. 1019 22

The distribution of the Mo-enzymes aldehyde oxidase (AO; EC 1.2.3.1) xanthine dehydrogenase (XDH; EC 1.2.1.37) and nitrate reductase (NAD(P)H NR; EC 1.6.6.1-2) was studied along the longitudinal and transversal axes of maize (Zea mays L. cv. Jubily) nodal roots as affected by nitrogen sources and salinity. Activities of the Mo-enzymes were considerably enhanced under mild saline conditions. The activities of AO and XDH increased following addition of ammonium to the nutrient solution. Immunoblot analysis with antibodies raised against maize AO protein revealed increased levels of AO proteins in root tips of ammonium fed plants. Application of salinity to nitrate fed plants did not affect the enzyme protein level, although it enhanced the activity of the Mo-hydroxylases. The specific activities of the Mo-enzymes were the highest in root tips (0-1 cm segments) while on the transversal axis maximal activity was observed in the stele or vascular cylinder. Activity staining of AO after native PAGE of root extracts revealed four bands of AO proteins (AO1-4) capable of oxidizing a number of aliphatic and aromatic aldehydes. Increased AO activity in maize nodal roots grown with ammonium, and salinity were observed mainly at the AO3 and AO4 bands. Tips and stele contained primarily AO3 and AO4, and only traces of AO1 and AO2. SDS-PAGE of root extracts followed by Western blots revealed, besides the major 150 kD subunit of AO, two polypeptides with molecular masses of 72 and 85 kD located specifically in the cortex. Part of the polymorphism of AO in plant roots may be related to the allocation of distinct isoforms to different regions of the root, although the specific metabolic roles of the different bands have not been established.
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PMID:Distribution of the Mo-enzymes aldehyde oxidase, xanthine dehydrogenase and nitrate reductase in maize (Zea mays L.) nodal roots as affected by nitrogen and salinity. 1077 39

Mammalian xanthine oxidoreductases, which catalyze the last two steps in the formation of urate, are synthesized as the dehydrogenase form xanthine dehydrogenase (XDH) but can be readily converted to the oxidase form xanthine oxidase (XO) by oxidation of sulfhydryl residues or by proteolysis. Here, we present the crystal structure of the dimeric (M(r), 290,000) bovine milk XDH at 2.1-A resolution and XO at 2.5-A resolution and describe the major changes that occur on the proteolytic transformation of XDH to the XO form. Each molecule is composed of an N-terminal 20-kDa domain containing two iron sulfur centers, a central 40-kDa flavin adenine dinucleotide domain, and a C-terminal 85-kDa molybdopterin-binding domain with the four redox centers aligned in an almost linear fashion. Cleavage of surface-exposed loops of XDH causes major structural rearrangement of another loop close to the flavin ring (Gln 423Lys 433). This movement partially blocks access of the NAD substrate to the flavin adenine dinucleotide cofactor and changes the electrostatic environment of the active site, reflecting the switch of substrate specificity observed for the two forms of this enzyme.
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PMID:Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: structure-based mechanism of conversion. 1100 54

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

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

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

Guppy is a popular ornamental fish owing to its diverse body and fin coloration. More than 40 established color varieties have been selectively bred. The complementary DNAs for 2 enzymes that are involved in the de novo synthesis of pteridines and purines, which are important for the production of color pigments, were cloned from the caudal fin. Two cDNA isoforms for 6-pyruvoyl tetrahydropterin synthase (PTPS), with an open reading frame of 130 and 147 amino acids, respectively, were cloned from the Red Tail variety. The deduced amino acid sequence of the longer isoform shows an overall identity of about 65% to the mammalian PTPS sequences. The cDNA for xanthine dehydrogenase (XDH) was cloned from the Yellow Tail variety, and consists of an open reading frame of 1331 amino acids. Although it shows a higher overall identity to bovine aldehyde oxidase (AO; 54%) than to chicken XDH (51%), it has a NAD-binding domain that is specific to XDHs. Northern blot analysis indicated that both PTPS and XDH messenger RNAs were highly expressed in the liver, but absent in the muscle. In the caudal fins, guppy varieties with a higher proportion of xanthophores and erythrophores showed higher expression of PTPS, while XDH mRNA levels were too low to indicate obvious differential expression among the color guppy varieties. The results implied that high expression of PTPS is correlated with the biosynthesis of pteridines in the erythrophores and xanthophores, while the association between the putative guppy XDH with specific chromatophores is less clear.
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PMID:Cloning and tissue expression of 6-pyruvoyl tetrahydropterin synthase and xanthine dehydrogenase from Poecilia reticulata. 1292 12

There is substantial evidence that oxidative stress participates in the pathophysiology of cardiovascular disease. Biochemical, molecular and pharmacological studies further implicate xanthine oxidoreductase (XOR) as a source of reactive oxygen species in the cardiovascular system. XOR is a member of the molybdoenzyme family and is best known for its catalytic role in purine degradation, metabolizing hypoxanthine and xanthine to uric acid with concomitant generation of superoxide. Gene expression of XOR is regulated by oxygen tension, cytokines and glucocorticoids. XOR requires molybdopterin, iron-sulphur centres, and FAD as cofactors and has two interconvertible forms, xanthine oxidase and xanthine dehydrogenase, which transfer electrons from xanthine to oxygen and NAD(+), respectively, yielding superoxide, hydrogen peroxide and NADH. Additionally, XOR can generate superoxide via NADH oxidase activity and can produce nitric oxide via nitrate and nitrite reductase activities. While a role for XOR beyond purine metabolism was first suggested in ischaemia-reperfusion injury, there is growing awareness that it also participates in endothelial dysfunction, hypertension and heart failure. Importantly, the XOR inhibitors allopurinol and oxypurinol attenuate dysfunction caused by XOR in these disease states. Attention to the broader range of XOR bioactivity in the cardiovascular system has prompted initiation of several randomised clinical outcome trials, particularly for congestive heart failure. Here we review XOR gene structure and regulation, protein structure, enzymology, tissue distribution and pathophysiological role in cardiovascular disease with an emphasis on heart failure.
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PMID:Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. 1469 47

Mammalian xanthine dehydrogenase can be converted to xanthine oxidase by modification of cysteine residues or by proteolysis of the enzyme polypeptide chain. Here we present evidence that the Cys(535) and Cys(992) residues of rat liver enzyme are indeed involved in the rapid conversion from the dehydrogenase to the oxidase. The purified mutants C535A and/or C992R were significantly resistant to conversion by incubation with 4,4'-dithiodipyridine, whereas the recombinant wild-type enzyme converted readily to the oxidase type, indicating that these residues are responsible for the rapid conversion. The C535A/C992R mutant, however, converted very slowly during prolonged incubation with 4,4'-dithiodipyridine, and this slow conversion was blocked by the addition of NADH, suggesting that another cysteine couple located near the NAD(+) binding site is responsible for the slower conversion. On the other hand, the C535A/C992R/C1316S and C535A/C992R/C1324S mutants were completely resistant to conversion, even on prolonged incubation with 4,4'-dithiodipyridine, indicating that Cys(1316) and Cys(1324) are responsible for the slow conversion. The crystal structure of the C535A/C992R/C1324S mutant was determined in its demolybdo form, confirming its dehydrogenase conformation.
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PMID:Mechanism of the conversion of xanthine dehydrogenase to xanthine oxidase: identification of the two cysteine disulfide bonds and crystal structure of a non-convertible rat liver xanthine dehydrogenase mutant. 1587 60


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