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)

In the presence of 0.5 millimolar allopurinol (4-hydroxypyrazolo [3,4-d]pyrimidine), an inhibitor of NAD:xanthine oxidoreductase (EC 1.2.3.2), intact attached nodules of cowpea (Vigna unguiculata L. Walp. cv Vita 3) formed [(15)N]xanthine from (15)N(2) at rates equivalent to those of ureide synthesis, confirming the direct assimilation of fixed nitrogen into purines. Xanthine accumulated in nodules and was exported in increasing amounts in xylem of allopurinol-treated plants. Other intermediates of purine oxidation, de novo purine synthesis, and ammonia assimilation did not increase and, over the time course of experiments (4 hours), allopurinol had no effect on nitrogenase (EC 1.7.99.2) activity. Negligible (15)N-labeling of asparagine from (15)N(2) was observed, suggesting that the significant pool (up to 14 micromoles per gram of nodule fresh weight) of this amide in cowpea nodules was not formed directly from fixation but may have accumulated as a consequence of phloem delivery.
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PMID:Pathways of Nitrogen Assimilation in Cowpea Nodules Studied using N(2) and Allopurinol. 1666 67

Hydrophilic interaction chromatography (HILIC) interfaced with an Orbitrap Fourier transform mass spectrometer (FT-MS) was used to carry out metabolomic profiling of the classical Drosophila mutation, rosy (ry). This gene encodes a xanthine oxidase/dehydrogenase. In addition to validating the technology by detecting the same changes in xanthine, hypoxanthine, urate and allantoin that have been reported classically, completely unsuspected changes were detected in each of the tryptophan, arginine, pyrimidine and glycerophospholipid metabolism pathways. The rosy mutation thus ramifies far more widely than previously detected.
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PMID:Metabolomic profiling of Drosophila using liquid chromatography Fourier transform mass spectrometry. 1865 38

Tobacco (cv. Xanthi nn) plants were watered with allopurinol [4-hydroxypyrazolo (3,4-d) pyrimidine, HPP], a xanthine oxidoreductase (XOR) inhibitor, to investigate its effects on infection by Tobacco mosaic virus engineered to express the green fluorescent protein (TMV.GFP). TMV.GFP infection was monitored by examination of inoculated leaves under UV light, by confocal scanning laser microscopy and by epifluorescence microscopy. Susceptibility to TMV.GFP was enhanced in HPP-treated plants. This was seen as a statistically significant increase in numbers of infection sites per leaf and in the number of infected cells per infection site. Two hypotheses are discussed to explain the enhanced susceptibility. The inhibition exerted by HPP against XOR activity could provoke either (i) an increased adenine and guanine nucleotide pool, which could facilitate viral RNA synthesis or (ii) it could cause changes in IAA/auxin levels, which has been proposed to influence TMV susceptibility in tobacco.
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PMID:Allopurinol, an inhibitor of purine catabolism, enhances susceptibility of tobacco to Tobacco mosaic virus. 1867 60

Xanthine oxidoreductase is a ubiquitous cytoplasmic protein that catalyzes the final two steps in purine catabolism. We have previously investigated the catalytic mechanism of the enzyme by rapid reaction kinetics and x-ray crystallography using the poor substrate 2-hydroxy-6-methylpurine, focusing our attention on the orientation of substrate in the active site and the role of Arg-880 in catalysis. Here we report additional crystal structures of as-isolated, functional xanthine oxidase in the course of reaction with the pterin substrate lumazine at 2.2 A resolution and of the nonfunctional desulfo form of the enzyme in complex with xanthine at 2.6 A resolution. In both cases the orientation of substrate is such that the pyrimidine subnucleus is oriented opposite to that seen with the slow substrate 2-hydroxy-6-methylpurine. The mechanistic implications as to how the ensemble of active site functional groups in the active site work to accelerate reaction rate are discussed.
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PMID:Substrate Orientation and Catalysis at the Molybdenum Site in Xanthine Oxidase: CRYSTAL STRUCTURES IN COMPLEX WITH XANTHINE AND LUMAZINE. 1910 52

Oxygen is the essential molecule for all aerobic organisms, and plays predominant role in ATP generation, namely, oxidative phosphorylation. During this process, reactive oxygen species (ROS) including superoxide anion (O(2)(-)) and hydrogen peroxide (H(2)O(2)) are produced as by-products, while it seems indispensable for signal transduction pathways that regulate cell growth and reduction-oxidation (redox) status. However, during times of environmental stress ROS levels may increase dramatically, resulting in significant damage to cell structure and functions. This cumulated situation of ROS is known as oxidative stress, which may, however, be utilized for eradicating cancer cells. It is well known that oxidative stress, namely over-production of ROS, involves in the initiation and progression of many diseases and disorders, including cardiovascular diseases, inflammation, ischemia-reperfusion (I/R) injury, viral pathogenesis, drug-induced tissue injury, hypertension, formation of drug resistant mutant, etc. Thus, it is reasonable to counter balance of ROS and to treat such ROS-related diseases by inhibiting ROS production. Such therapeutic strategies are described in this article, that includes polymeric superoxide dismutase (SOD) (e.g., pyran copolymer-SOD), xanthine oxidase (XO) inhibitor as we developed water soluble form of 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP), heme oxygenase-1 (HO-1) inducers (e.g., hemin and its polymeric form), and other antioxidants or radical scavengers (e.g., canolol). On the contrary, because of its highly cytotoxic nature, ROS can also be used to kill cancer cells if one can modulate its generation selectively in cancer. To achieve this goal, a unique therapeutic strategy was developed named as "oxidation therapy", by delivering cytotoxic ROS directly to the solid tumor, or alternatively inhibiting the antioxidative enzyme system, such as HO-1 in tumor. This anticancer strategy was examined by use of O(2)(-) or H(2)O(2)-generating enzymes (i.e., XO and d-amino acid oxidase [DAO] respectively), and by discovering the inhibitor of HO-1 (i.e., zinc protoporphyrin [ZnPP] and its polymeric derivatives). Further for the objective of tumor targeting and thus reducing side effects, polymer conjugates or micellar drugs were prepared by use of poly(ethylene glycol) (PEG) or styrene maleic acid copolymer (SMA), which utilize EPR (enhanced permeability and retention) effect for tumor-selective delivery. These macromolecular drugs further showed superior pharmacokinetics including much longer in vivo half-life, particularly tumor targeted accumulation, and thus remarkable antitumor effects. The present review concerns primarily our own works, in the direction of "Controlling oxidative stress: Therapeutic and delivery strategy" of this volume.
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PMID:Therapeutic strategies by modulating oxygen stress in cancer and inflammation. 1924 31

In vascular system, superoxide anion (O2(-)) generated by xanthine oxidase (XO) is known to regulate vascular tonus by reacting with, and thus consuming nitric oxide (NO), which determines vasorelaxation. We previously reported the remarkable antihypertensive effect of a potent XO inhibitor, 4-amino -6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP). However, AHPP is insoluble in water, which hamper its in vivo application. Therefore, in this study we prepared a water soluble polymeric conjugate of AHPP, by using a styrene maleic acid copolymer (SMA, SMA-AHPP). SMA-AHPP showed similar inhibitory activity against XO (K(i)=0.25 microM) comparable to native AHPP (K(i)=0.17 microM), while exhibiting good water-solubility, which now made it possible for systemic injection. In vivo experiments were carried out to examine the antihypertensive effect of SMA-AHPP using the spontaneously hypertensive rats (SHR) by i.v. injection (15, 30 mg/kg) or by oral administration (100 mg/kg) of SMA-AHPP. The results showed significantly reduced blood pressures (up to 30% reduction) of SHR rats; this antihypertensive effect continued for at least 24 h after SMA-AHPP administration. These findings strongly suggest the potential value of SMA-AHPP as an antihypertensive agent with sustained in vivo activity, which warrants further investigations.
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PMID:SMA-copolymer conjugate of AHPP: a polymeric inhibitor of xanthine oxidase with potential antihypertensive effect. 1933 63

Aldehyde oxidase 1 (AOX1) is a major member of the xanthine oxidase family belonging to the class of complex molybdo-flavoenzymes and plays an important role in the nucleophilic oxidation of N-heterocyclic aromatic compounds and various aldehydes. The enzyme has been well known to show remarkable species differences. Comparing the rabbit and monkey enzymes, the former showed extremely high activity toward cinchonidine and methotrexate, but the latter exhibited only marginal activities. In contrast, monkey had several times greater activity than did rabbit toward zonisamide and (+)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine [(S)-RS-8359]. In this report, we tried to confer high cinchonidine oxidation activity comparable with that of rabbit AOX1 to monkey AOX1. The chimera proteins prepared by restriction enzyme digestion and recombination methods between monkey and rabbit AOX1s indicated that the sequences from Asn993 to Ala1088 of rabbit AOX1 are essential for the activity. The kinetic parameters were then measured using monkey AOX1 mutants prepared by site-directed mutagenesis. The monkey V1085A mutant acquired the high cinchonidine oxidation activity. Inversely, the reciprocal rabbit A1081V mutant lost the activity entirely: amino acid 1081 of rabbit AOX1 corresponding to amino acid 1085 of monkey AOX1. Thus, cinchonidine oxidation activity was drastically changed by mutation of a single residue in AOX1. However, this might be true for bulky substrates such as cinchonidine but not for small substrates. The mechanism of substrate-dependent species differences in AOX1 activity toward bulky substrates is discussed.
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PMID:A single amino acid substitution confers high cinchonidine oxidation activity comparable with that of rabbit to monkey aldehyde oxidase 1. 1991 May 15

Recent studies showed that c-Src and phosphatidylinositol 3 (PI3) kinase mediate the oxidative stress-induced disruption of tight junctions in Caco-2 cell monolayers. The present study evaluated the roles of PI3 kinase and Src kinase in the oxidative stress-induced activation of focal adhesion kinase (FAK) and acceleration of cell migration. Oxidative stress, induced by xanthine and xanthine oxidase system, rapidly increased phosphorylation of FAK on Y397, Y925, and Y577 in the detergent-insoluble and soluble fractions and increased its tyrosine kinase activity. The PI3 kinase inhibitors, wortmannin and LY294002, and the Src kinase inhibitor, 4-amino-5[chlorophyll]-7-[t-butyl]pyrazolo[3-4-d]pyrimidine, attenuated tyrosine phosphorylation of FAK. Oxidative stress induced phosphorylation of c-Src on Y418 by a PI3 kinase-dependent mechanism, whereas oxidative stress-induced activation of PI3 kinase was independent of Src kinase activity. Hydrogen peroxide accelerated Caco-2 cell migration in a concentration-dependent manner. Promotion of cell migration by hydrogen peroxide was attenuated by LY294002 and PP2. Reduced expression of FAK by siRNA attenuated hydrogen peroxide-induced acceleration of cell migration. The expression of constitutively active c-Src(Y527F) enhanced cell migration, whereas the expression of dominant negative c-Src(K296R/Y528F) attenuated hydrogen peroxide-induced stimulation of cell migration. Oxidative stress-induced activation of c-Src and FAK was associated with a rapid increase in the tyrosine phosphorylation and the levels of paxillin and p130(CAS) in actin-rich, detergent-insoluble fractions. This study shows that oxidative stress activates FAK and accelerates cell migration in an intestinal epithelium by a PI3 kinase- and Src kinase-dependent mechanism.
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PMID:Hydrogen peroxide activates focal adhesion kinase and c-Src by a phosphatidylinositol 3 kinase-dependent mechanism and promotes cell migration in Caco-2 cell monolayers. 2037 26

The detrimental role of superoxide anion (O(2)(-)) has been well documented in the pathogenesis of ischemia-reperfusion (I/R) injury. Our and other studies suggested that one critical source of O(2)(-) generation may be xanthine oxidase (XO). We thus hypothesized that I/R injury could be protected by inhibiting XO activity, which would reduce the amount of O(2)(-) and hence reduce pathogenic consequences. Among various XO inhibitors, we previously found 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP) exhibited potent XO inhibitory activity. Here, we report that the covalent conjugate of AHPP with amphipathic styrene-maleic acid copolymer (SMA-AHPP) showed protective effect against I/R-induced injury in a rat hepatic I/R model. Liver ischemia was induced by occluding both the portal vein and the hepatic artery for 30 min, and followed by reperfusion. SMA-AHPP was administered via the tail vein two hours before ischemia was initiated. A remarkable increase of liver enzymes in plasma (aspartate aminotransferase, AST; alanine aminotransferase, ALT and lactate dehydrogenase, LDH) was detected three hours after reperfusion, whereas prior injection of SMA-AHPP greatly suppressed this increase of AST, ALT and LDH. Moreover, induction of inflammatory cytokines, i.e. tumor necrosis factor-alpha (TNF-alpha), interleukin-12 (IL-12) and monocyte chemotactic protein-1 (MCP-1) by I/R were significantly inhibited by SMA-AHPP treatment. Accordingly, cytotoxic effect or apoptosis in the liver caused by I/R was clearly reduced by SMA-AHPP pretreatment. Furthermore, thiobarbituric acid-reactive substance assay showed a significant decrease of lipid peroxidation in rat liver after the administration of SMA-AHPP, which is parallel with the decreased XO activity after SMA-AHPP treatment, indicating the involvement of reactive oxygen species generated by XO. In addition, SMA-AHPP was found to bind to albumin, thus to exhibit prolonged in vivo (plasma) half-life. These results suggest that SMA-AHPP exerted a potent cytoprotective effect against I/R injury in rat liver, by inhibiting XO activity and the subsequent generation of O(2)(-).
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PMID:Tissue protective effect of xanthine oxidase inhibitor, polymer conjugate of (styrene-maleic acid copolymer) and (4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine), on hepatic ischemia-reperfusion injury. 2040 81

A series of pyrazolo[3,4-d]pyrimidine analogues 3, 4, 5a-f, 6a-f with various amines and ester groups at C-4 and N-1 were synthesized and evaluated for antitumour activity. They were also evaluated for xanthine oxidase inhibitory activity, with most compounds having no significant impact. Compound 5e had the strongest activity against human hepatoma carcinoma cells 7402 and 7221, with half-maximal inhibitory concentration values of 4.55 and 6.28, respectively. Structure-activity relationship studies indicate that chlorine atoms in the structure of 4-((4-(substituted amides)phenyl)amino pyrazolo[4,3-d]pyrimidine analogues is crucial for antitumour activity.
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PMID:Synthesis and biological evaluation of pyrazolo[4,3-d]pyrimidine analogues. 2385 Nov 16


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