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)

Conceptualization of the gastrointestinal tract as the "motor" that drives sepsis and multiple-system organ failure has only recently been appreciated. Most of the investigation into the pathophysiology of gut-derived sepsis involves using animal models; however, some of the findings are already being corroborated in human studies. The gastrointestinal tract is a dynamic organ whose function as a front-line defense against infection needs to be appreciated. The development of lethal sepsis is a function of the microbial load and virulence, the status of the gastrointestinal barrier, and the magnitude of the host defense response. In assuming care of a critically ill patient, we must be judicious in the use of antibiotics in order to prevent intestinal overgrowth of potential pathogens. Providing proper nutrition by an enteral route (when possible) not only satisfies caloric needs but regulates the microflora and maintains the integrity of the mucosal barrier. Burn patients should receive enteral nutrition early, the first day if possible. This not only will protect the intestinal mucosa but also will blunt the hypermetabolic response following thermal injury. Lastly, the patient should not receive an excessive amount of narcotic or sedative, for these drugs have an inhibitory effect on gastrointestinal motility, encouraging bacterial overgrowth. In the near future, new therapeutic modalities may soon become available to protect and treat the compromised gastrointestinal barrier. These modalities may include, but certainly are not limited to, the use of glutamine and xanthine oxidase inhibitors to prevent stress-related injury to the gastrointestinal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of the gastrointestinal tract in the development of burn sepsis. 151 4

Our previous studies established that human neutrophils could damage and probably kill hyphae of Aspergillus fumigatus and Rhizopus oryzae in vitro, primarily by oxygen-dependent mechanisms active at the cell surface. These studies were extended, again quantitating hyphal damage by reduction in uptake of (14)C-labeled uracil or glutamine. Neither A. fumigatus nor R. oryzae hyphae were damaged by neutrophils from patients with chronic granulomatous disease, confirming the importance of oxidative mechanisms in damage to hyphae. In contrast, neutrophils from one patient with hereditary myeloperoxidase deficiency damaged R. oryzae but not A. fumigatus hyphae. Cell-free, in vitro systems were then used to help determine the relative importance of several potentially fungicidal products of neutrophils. Both A. fumigatus and R. oryzae hyphae were damaged by the myeloperoxidase-hydrogen peroxide-halide system either with reagent hydrogen peroxide or enzymatic systems for generating hydrogen peroxide (glucose oxidase with glucose, or xanthine oxidase with either hypoxanthine or acetaldehyde). Iodide with or without chloride supported the reaction, but damage was less with chloride alone as the halide cofactor. Hydrogen peroxide alone damaged hyphae only in concentrations >/=1 mM, but 0.01 mM hypochlorous acid, a potential product of the myeloperoxidase system, significantly damaged R. oryzae hyphae (a 1 mM concentration was required for significant damage to A. fumigatus hyphae). Damage to hyphae by the myeloperoxidase system was inhibited by azide, cyanide, catalase, histidine, and tryptophan, but not by superoxide dismutase, dimethyl sulfoxide, or mannitol. Photoactivation of the dye rose bengal resulted in hyphal damage which was inhibited by histidine, tryptophan, and 1,4-diazobicyclo(2,2,2)octane. Lysates of neutrophils or separated neutrophil granules did not affect A. fumigatus hyphae, but did damage R. oryzae hyphae. Similarly, three preparations of cationic proteins purified from human neutrophil granules were more active in damaging R. oryzae than A. fumigatus hyphae. This damage, as with the separated granules and whole cell lysates, was inhibited by the polyanion heparin. Damage to R. oryzae hyphae by neutrophil cationic proteins was enhanced by activity of the complete myeloperoxidase system or by hydrogen peroxide alone in subinhibitory concentrations. These data support the importance of oxidative products in general and the myeloperoxidase system in particular in damage to hyphae by neutrophils. Cationic proteins may also contribute significantly to neutrophil-mediated damage to R. oryzae hyphae.
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PMID:Damage to Aspergillus fumigatus and Rhizopus oryzae hyphae by oxidative and nonoxidative microbicidal products of human neutrophils in vitro. 629 3

The rate of purine de novo synthesis from sodium formate in developing rat brain falls in the late gestational stages to birth, rises again in the 1st week of life and then decreases rapidly to the 3rd week, and continues declining up to 8 weeks of life (adulthood). The changes in the overall purine biosynthetic rate with respect to time are similar to those in the activity of the rate-limiting enzyme [amidophosphoribosyltransferase (phosphoribosyl diphosphate amidotransferase; EC 2.4.2.14)]. Azaserine [O-diazoacetyl-L-serine], a known inhibitor of glutamine requiring metabolic steps, inhibits purine de novo synthesis by more than 90%. This confirms that the method used to assess purine de novo synthesis in fact does so. The effects of virazole [1-beta-ribofuranosyl-1-H,1,2,4-triazole-3-carboxamide], an inhibitor of IMP dehydrogenase (EC 1.2.1.14), and of alanosine [L-2-amino-3-(hydroxynitrosamino)propanoic acid] an inhibitor of adenylosuccinate synthetase (EC 6.3.4.4), on the rate of purine de novo synthesis were investigated in liver and brain tissue. The effect of the xanthine oxidase inhibitor allopurinol [4-hydroxypyrazolo(3,4-d)pyrimidine] was also investigated in liver tissue. The biosynthesis of the purines which were extruded into the incubation medium as well as those which remained in the tissue was studied. Only inhibitory effects were observed, and these were confined to the purines remaining in the tissue. Allopurinol was completely inert from this viewpoint. The results are compared with those of other workers using lymphoid cells, and emphasize the differences in the control of de novo purine synthesis in different tissues and under different conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Purine de novo synthesis in liver and developing rat brain, and the effect of some inhibitors of purine nucleotide interconversion. 662 51

The effect of storage at - 80 degrees C for 1-28 days on the activity of 12 enzymes in intact liver tissue, liver extract and isolated hepatic microsomes was investigated. To find optimal conditions for tissue homogenization for this study the effects of three types of homogenization on the activity of 10 enzymes from different cell compartments were compared. The activities of glucokinase and phosphofructokinase decreased markedly during storage of both supernatant and liver tissue. Storage of liver tissue increased the activity of mitochondrial enzymes or isoenzymes. While this effect can be explained by additional disintegration of liver tissue caused by freezing and thawing for enzymes like glutamine dehydrogenase, other mechanisms may be involved in the prolonged increase observed in the activity of citrate synthase and xanthine oxidase during storage. The activity of a number of enzymes from the cytosol, mitochondria and microsomes decreased more markedly in the stored liver samples than in the stored supernatant or in the stored microsomal pellet. Cytochrome P 450 content remained stable throughout the whole storage period in both intact liver tissue and isolated microsomes.
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PMID:The effect of storage at - 80 degrees C on the activities of cytoplasmic, mitochondrial and microsomal enzymes in rat liver. 706 80

We have developed a unique rat AGML model produced by ischemia/reperfusion plus 0.2% ammonia (I/R.NH3), either treatment which would not induce mucosal injury when used alone. The effects of troxipide and other gastric mucosal defensive drugs were investigated with this I/R.NH3-induced AGML model and other AGML models in rats. The following results were obtained: 1) Like allopurinol, troxipide at 50-200 mg/kg, p.o. dose-dependently prevented I/R.NH3-induced development of AGML and also the ischemia/reperfusion-induced increase of gastric mucosal thiobarbituric acid (TBA)-reactive substances; 2) Troxipide at 10(-6)-10(-4) M, like allopurinol, inhibited concentration-dependently in vitro xanthine oxidase activity in gastric mucosal homogenates; 3) Troxipide at 50-200 mg/kg, p.o. inhibited AGMLs induced by bleeding plus 0.2% ammonia and by 1.0% ammonia alone; and 4) Troxipide and sofalcone were similar in preventing all AGMLs tested and also the increase of mucosal TBA-reactive substances, but somewhat differed from teprenone, cetraxate hydrochloride, azulene plus L-glutamine and sucralfate. These findings suggest that troxipide may inhibit I/R.NH3-induced AGML development by preventing generation of oxygen free radicals and by protecting against mucosal fragility due to reduced energy metabolism from poor blood flow and also against ammonia-induced disruption of the gastric mucosal barrier. Therefore, troxipide may be highly effective for various AGMLs with multifactor involvement.
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PMID:[Preventive effects of troxipide on a newly developed model of acute gastric mucosal lesion (AGML) induced by ischemia/reperfusion plus ammonia in the rat]. 795 22

The feeding of a protein hydrolysate based 'elemental' diet supplemented with added glutamine did not provide superior protection to the small intestine of dogs subjected to therapeutic pelvic irradiation. Comparison of diets with and without the added glutamine showed significant protection of the intestine from radiation injury. Both histological examination and electron microscopy showed lack of tissue injury with both diets. The activity of the free radical generating enzymes, scavengers, and antioxidants were similar in the intestinal mucosa of dogs fed either diet. After radiation, however, the activity of xanthine oxidase, superoxide dismutase, and glutathione peroxidase were significantly (p < 0.002) higher in the intestine of dogs fed elemental diet without the added glutamine. If the activities of these enzymes are important in the protection of the intestine from radiation injury, then the addition of extra glutamine may provide no benefit.
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PMID:Protection from radiation injury by elemental diet: does added glutamine change the effect? 812 94

We have expressed, purified, and analyzed the iron-containing superoxide dismutase (FeSOD) of Escherichia coli with mutations directed at tyrosine position 34 to introduce phenylalanine (SODY34F), serine (SODY34S), or cysteine (SODY34C). FeSOD and mutant enzymes were purified from SOD-deficient cells using a GST-FeSOD fusion protein intermediate which was subsequently cleaved with thrombin and repurified. Specific activities were measured using the xanthine-xanthine oxidase method and gave 3148 u/mg for wild-type FeSOD. The SODY34S mutation virtually inactivates the enzyme (42 u/mg); mutation to cysteine greatly reduces activity (563 u/mg), but the SODY34F mutant retains nearly 40% of the activity of wild type (1205 u/mg). Fusion protein intermediates were also shown to be active and were demonstrated to protect SOD-deficient E. coli cells from the induced effects of oxidative stress, with growth rates directly proportional to the specific activities of the expressed mutant enzymes. SODY34F exhibited decreased thermal stability, reduced activity at high pH, and a pronounced increase in sensitivity to the inhibitor sodium azide compared with wild-type FeSOD. These results suggest that tyrosine at position 34 is multifunctional and plays a structural role (probably through hydrogen bonding to glutamine at position 69) in maintaining the integrity of the active site, a stabilizing role at high pH, and a steric role in obstructing access to the active site of both substrate and inhibitor molecules.
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PMID:The conserved residue tyrosine 34 is essential for maximal activity of iron-superoxide dismutase from Escherichia coli. 912 14

The use of NSAIDs (non-steroidal anti-inflammatory drugs), although of great therapeutic value clinically, is limited by their tendency to cause mucosal damage in the gastrointestinal tract. In the small intestine, the effects these drugs have been shown to produce include inhibition of cyclo-oxygenase, mitochondrial dysfunction and free radical-induced oxidative changes, all of which contribute to the mucosal damage seen. Glutamine is a fuel preferentially used by enterocytes and is known to contribute to maintaining the integrity of these cells. In the present study, we investigated the effect of glutamine on indomethacin-induced changes in the small intestinal mucosa. Rats were given 2% glutamine or glutamic acid or isonitrogenous amino acids, glycine or alanine, in the diet for 7 days. Indomethacin was then administered orally at a dose of 40 mg/kg of body weight. After 1 h, the small intestine was removed and used for the measurement of parameters of oxidative stress and mitochondrial and BBM (brush border membrane) function. Evidence of oxidative stress was found in the mucosa of the small intestine of drug-treated rats, as indicated by significantly increased activity of xanthine oxidase (P < 0.001) and myeloperoxidase (P < 0.001), with corresponding decreases in the levels of several free radical scavenging enzymes and alpha-tocopherol (P < 0.001 in all cases). Levels of products of peroxidation were also significantly elevated (P < 0.001 for all the parameters measured). In addition, oxidative stress was evident in isolated intestinal mitochondria and BBMs (P < 0.001 for all the parameters measured), with associated alterations in function of these organelles (P < 0.001 for all the parameters measured). Supplementation of the diet with glutamine or glutamic acid prior to treatment with indomethacin produced significant amelioration in all the effects produced by the drug in the small intestine (P < 0.001 for all the parameters measured). Glycine and alanine were found to be much less effective in these respects.
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PMID:Oral glutamine attenuates indomethacin-induced small intestinal damage. 1512 85

Glutamine synthetase (GS) is an astrocytic enzyme that is essential for the glutamate-glutamine cycle between neurons and astrocytes. To measure the effects of oxidative stress on the activity of GS in astrocytes, astrocyte-rich primary cultures from the brains of wild-type and glutathione peroxidase-1 deficient mice (GPx1(-/-)) were exposed to a chronic hydrogen peroxide-generating system consisting of xanthine oxidase, hypoxanthine and superoxide dismutase. The specific activity of GS was strongly diminished by chronic exposure to hydrogen peroxide in astrocytes cultured from both mouse lines. After 60 min of oxidative stress in the presence of 5 mU/mL, 10 mU/mL and 20 mU/mL of xanthine oxidase, the specific GS activity of wild-type astrocytes was reduced to 47%, 22% and 13% of the initial activity, respectively. For all activities of xanthine oxidase applied, astrocytes from GPx1(-/-) mice experienced a significantly greater rate of GS inactivation compared to their wild-type counterparts. These results confirm that GS is sensitive to inactivation by chronic peroxide stress in viable astrocytes and show that glutathione peroxidase-1 helps to protect GS from inactivation by oxidative stress.
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PMID:Glutathione peroxidase-1 contributes to the protection of glutamine synthetase in astrocytes during oxidative stress. 1646 22

Quinaldine 4-oxidase (Qox), which catalyzes the hydroxylation of quinaldine to 1H-4-oxoquinaldine, is a heterotrimeric (LMS)2 molybdo-iron/sulfur flavoprotein belonging to the xanthine oxidase family. Variants of Qox were generated by site-directed mutagenesis. Replacement in the large subunit at E736, which is presumed to be located close to the molybdenum, by aspartate (QoxLE736D) resulted in a marked decrease in kcat app for quinaldine, while Km app was largely unaffected. Although a minor reduction of the glutamine substituted variant QoxLE736Q by quinaldine occurred, its activity was below detection, indicating that the carboxylate group of E736 is crucial for catalysis. Replacement of cysteine ligands C40, C45, or C60 (FeSII) and of the C120 or C154 ligands to FeSI in the small subunit of Qox by serine led to decreased iron contents of the protein preparations. Substitutions C40S and C45S (Fe1 of FeSII) suppressed the characteristic FeSII EPR signals and significantly reduced catalytic activity. In QoxSC154S (Fe1 of FeSI), the g-factor components of FeSI were drastically changed. In contrast, Qox proteins with substitutions of C48 and C60 (Fe2 of FeSII), and of the C120 ligand at Fe2 of FeSI, retained considerable activity and showed less pronounced changes in their EPR parameters. Taken together, the properties of the Qox variants suggest that Fe1 of both FeSI and FeSII are the reducible iron sites, whereas the Fe2 ions remain in the ferric state. The location of the reducible iron sites of FeSI and FeSII appears to be conserved in enzymes of the xanthine oxidase family.
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PMID:Spectroscopic and biochemical studies on protein variants of quinaldine 4-oxidase: Role of E736 in catalysis and effects of serine ligands on the FeSI and FeSII clusters. 1714 79


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