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)

Ischemic stroke is caused by obstruction of blood flow to the brain, resulting in energy failure that initiates a complex series of metabolic events, ultimately causing neuronal death. One such critical metabolic event is the activation of phospholipase A2 (PLA2), resulting in hydrolysis of membrane phospholipids and release of free fatty acids including arachidonic acid, a metabolic precursor for important cell-signaling eicosanoids. PLA2 enzymes have been classified as calcium-dependent cytosolic (cPLA2) and secretory (sPLA2) and calcium-independent (iPLA2) forms. Cardiolipin hydrolysis by mitochondrial sPLA2 disrupts the mitochondrial respiratory chain and increases production of reactive oxygen species (ROS). Oxidative metabolism of arachidonic acid also generates ROS. These two processes contribute to formation of lipid peroxides, which degrade to reactive aldehyde products (malondialdehyde, 4-hydroxynonenal, and acrolein) that covalently bind to proteins/nucleic acids, altering their function and causing cellular damage. Activation of PLA2 in cerebral ischemia has been shown while other studies have separately demonstrated increased lipid peroxidation. To the best of our knowledge no study has directly shown the role of PLA2 in lipid peroxidation in cerebral ischemia. To date, there are very limited data on PLA2 protein by Western blotting after cerebral ischemia, though some immunohistochemical studies (for cPLA2 and sPLA2) have been reported. Dissecting the contribution of PLA2 to lipid peroxidation in cerebral ischemia is challenging due to multiple forms of PLA2, cardiolipin hydrolysis, diverse sources of ROS arising from arachidonic acid metabolism, catecholamine autoxidation, xanthine oxidase activity, mitochondrial dysfunction, activated neutrophils coupled with NADPH oxidase activity, and lack of specific inhibitors. Although increased activity and expression of various PLA2 isoforms have been demonstrated in stroke, more studies are needed to clarify the cellular origin and localization of these isoforms in the brain, their responses in cerebral ischemic injury, and their role in oxidative stress.
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PMID:Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. 1644 52

Although the majority of oxidative metabolic reactions are mediated by the CYP superfamily of enzymes, non-CYP-mediated oxidative reactions can play an important role in the metabolism of xenobiotics. The (major) oxidative enzymes, other than CYPs, involved in the metabolism of drugs and other xenobiotics are: the flavin-containing monooxygenases, the molybdenum hydroxylases (aldehyde oxidase and xanthine oxidase), the prostaglandin H synthase, the lipoxygenases, the amine oxidases (monoamine, polyamine, diamine and semicarbazide-sensitive amine oxidases) and the alcohol and aldehyde dehydrogenases. In a similar manner to CYPs, these oxidative enzymes can also produce therapeutically active metabolites and reactive/toxic metabolites, modulate the efficacy of therapeutically active drugs or contribute to detoxification. Many of them have been shown to be important in endobiotic metabolism, and, consequently, interactions between drugs and endogenous compounds might occur when they are involved in drug metabolism. In general, most non-CYP oxidative enzymes appear to be noninducible or much less inducible than the CYP system, although some of them may be as inducible as some CYPs. Some of these oxidative enzymes exhibit polymorphic expression, as do some CYPs. It is possible that the contribution of non-CYP oxidative enzymes to the overall metabolism of xenobiotics is underestimated, as most investigations of drug metabolism in discovery and lead optimisation are performed using in vitro test systems optimised for CYP activity.
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PMID:Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics. 1712 8

Previous studies showed that cytosolic and microsomal fractions from rat ventral prostate are able to biotransform ethanol to acetaldehyde and 1-hydroxyethyl radicals via xanthine oxidase and a non P450 dependent pathway respectively. Sprague Dawley male rats were fed with a Lieber and De Carli diet containing ethanol for 28 days and compared against adequately pair-fed controls. Prostate microsomal fractions were found to exhibit CYP2E1-mediated hydroxylase activity significantly lower than in the liver and it was induced by repetitive ethanol drinking. Ethanol drinking led to an increased susceptibility of prostatic lipids to oxidation, as detected by t-butylhydroperoxide-promoted chemiluminiscence emission and increased levels of lipid hydroperoxides (xylenol orange method). Ultrastructural alterations in the epithelial cells were observed. They consisted of marked condensation of chromatin around the perinuclear membrane, moderate dilatation of the endoplasmic reticulum and an increased number of epithelial cells undergoing apoptosis. The prostatic alcohol dehydrogenase activity of the stock rats was 4.84 times lower than that in the liver and aldehyde dehydrogenase activity in their microsomal, cytosolic and mitochondrial fractions was either not detectable or significantly less intense than in the liver. A single dose of ethanol led to significant acetaldehyde accumulation in the prostate. The results suggest that acetaldehyde accumulation in prostate tissue might result from both acetaldehyde produced in situ but also because of its low aldehyde dehydrogenase activity and its poor ability to metabolize acetaldehyde arriving via the blood. Acetaldehyde, 1-hydroxyethyl radical and the oxidative stress produced may lead to epithelial cell injury.
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PMID:Biochemical and ultrastructural alterations in the rat ventral prostate due to repetitive alcohol drinking. 1729 12

Flavonoids, one of the most numerous and best studied groups of plant polyphenols, are well known to exhibit various biological and pharmacological effects. Functional artificial polymeric flavonoids, flavonoid polymers and amine containing polymer-flavonoid conjugates have been developed. The acid-catalyzed polymerization of catechin and aldehydes proceeds regioselectively to produce catechin-aldehyde polycondensates. Peroxidases and laccases catalyze the oxidative coupling of flavonoids and oxidative conjugation with polyamines. The resulting polymers show much higher antioxidant activities than the flavonoid monomers. In addition, these polymeric flavonoids efficiently inhibit disease related enzymes, such as xanthine oxidase, collagenase, elastase, hyaluronidase and tyrosinase. Based on these results, the molecular design for amplification of the biological and pharmacological properties of flavonoids is proposed.
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PMID:Artificial polymeric flavonoids: synthesis and applications. 1742 27

The reduction of acetaldehyde back to ethanol via NAD-linked alcohol dehydrogenase is an important mechanism for keeping acetaldehyde levels low following ethanol ingestion. However, this does not remove acetaldehyde from the body, but just delays its eventual removal. Acetaldehyde is removed from the body primarily by oxidation to acetate via a number of NAD-linked aldehyde dehydrogenase (ALDH) enzymes. There are nineteen known ALDHs in humans, but only a few of them appear to be involved in acetaldehyde oxidation. There are many analogous enzymes in other organisms. Genetic polymorphisms of several ALDHs have been identified in humans that are responsible for several hereditary defects in the metabolism of normal endogenous substrates. The best known ALDH genetic polymorphism is in ALDH2 gene, which encodes a mitochondrial enzyme primarily responsible for the oxidation of the ethanol-derived acetaldehyde. This common polymorphism is known to dominantly inhibit its enzymatic activity resulting in reduced ability to clear acetaldehyde in both homozygote and heterozygote individuals. These individuals are generally protected against alcohol abuse but are susceptible to oesophageal cancer. For those enzymes that are capable of reacting with acetaldehyde, they may do so at the expense of their normal substrates, resulting in abnormal accumulation of these substrates. Examples of this are the aldehydes of the biogenic amines, dopamine, noradrenaline, adrenaline, serotonin and long chain lipid aldehydes such as nonenal. Not all of these enzymes are capable of efficient oxidation of acetaldehyde; however, it is possible that acetaldehyde may function as an inhibitor of these enzymes as well. The aldehydes whose metabolism is interfered with may also serve as inhibitors of ALDHs as well. However, this aspect of aldehyde function has not been extensively studied. A number of other mechanisms for the removal of acetaldehyde exist. For example, reaction of acetaldehyde with protein or nucleic acids is responsible for the disappearance of a small amount of acetaldehyde, but may be responsible for some pathological effects of acetaldehyde. There are a few other enzymes such as aldehyde oxidase, xanthine oxidase, cytochrome P450 oxidase and glyceraldehyde-3-phosphate dehydrogenase that are capable of oxidizing acetaldehyde. However, these enzymes account for only a small fraction of the total activity.
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PMID:Removal of acetaldehyde from the body. 1759 Sep 85

Glucose oxidase, horseradish peroxidase, xanthine oxidase, and carbonic anhydrase have been adsorbed to colloidal gold sols with good retention of enzymatic activity. Adsorption of xanthine oxidase on colloidal gold did not result in a change in enzymatic activity as determined by active site titration with the stoichiometric inhibitor pterin aldehyde and by measurement of the apparent Michaelis constant (K'(M)). Gold sols with adsorbed glucose oxidase, horseradish peroxidase, and xanthine oxidase have also been electrodeposited onto conducting matrices (platinum gauze and/or glassy carbon) to make enzyme electrodes. These electrodes retained enzymatic activity and, more importantly, gave an electrochemical response to the enzyme substrate in the presence of an appropriate electron transfer mediator. Our results demonstrate the utility of colloidal gold as a biocompatible enzyme immobilization matrix suitable for the fabrication of enzyme electrodes.
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PMID:Colloidal gold as a biocompatible immobilization matrix suitable for the fabrication of enzyme electrodes by electrodeposition. 1860 Nov 42

In an effort to develop novel anti-tumor, or cancer chemopreventive agents, a series of 2',5'-dialkoxylchalcones were prepared by Claisen-Schmidt condensation of appropriate acetophenones with suitable aromatic aldehyde. In vitro screening revealed low micromolar activity (IC(50)) against several human cancer cell lines. Selective compound 10 induced an accumulation of A549 cells in the G(2)/M phase arrest which was well correlated with inhibitory activity against tubulin polymerization. Cytotoxic compounds 3 and 12 showed significant inhibitory effects on NO production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophage-like cells while cytotoxic compound 10 revealed potent inhibitory effect on TNF-alpha formation in RAW 264.7 cells in response to LPS. Compounds 3 and 10 also showed significant inhibitory effects on xanthine oxidase. The present results suggested that compounds 3 and 10 were potential to be served as cancer chemopreventive agents.
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PMID:Synthesis and cytotoxic, anti-inflammatory, and anti-oxidant activities of 2',5'-dialkoxylchalcones as cancer chemopreventive agents. 1860 46

Mouse aldehyde oxidase (mAOX1) forms a homodimer and belongs to the xanthine oxidase family of molybdoenzymes which are characterized by an essential equatorial sulfur ligand coordinated to the molybdenum atom. In general, mammalian AOs are characterized by broad substrate specificity and an yet obscure physiological function. To define the physiological substrates and the enzymatic characteristics of mAOX1, we established a system for the heterologous expression of the enzyme in Escherichia coli. The recombinant protein showed spectral features and a range of substrate specificity similar to the native protein purified from mouse liver. The EPR data of recombinant mAOX1 were similar to those of AO from rabbit liver, but differed from the homologous xanthine oxidoreductase enzymes. Site-directed mutagenesis of amino acids Val806, Met884 and Glu1265 at the active site resulted in a drastic decrease in the oxidation of aldehydes with no increase in the oxidation of purine substrates. The double mutant V806E/M884R and the single mutant E1265Q were catalytically inactive enzymes regardless of the aldehyde or purine substrates tested. Our results show that only Glu1265 is essential for the catalytic activity by initiating the base-catalyzed mechanism of substrate oxidation. In addition, it is concluded that the substrate specificity of molybdo-flavoenzymes is more complex and not only defined by the three characterized amino acids in the active site.
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PMID:Site directed mutagenesis of amino acid residues at the active site of mouse aldehyde oxidase AOX1. 1940 76

Alcohol drinking is known to lead to deleterious effects on prostate epithelial cells from humans and experimental animals. The understanding of the mechanisms underlying these effects is relevant to intraprostatic ethanol treatment of benign prostatic hyperplasia and to shed some light into the conflictive results linking alcohol consumption to prostate cancer. In previous studies, we provided evidence about the presence in the rat ventral prostate of cytosolic and microsomal metabolic pathways of ethanol to acetaldehyde and 1-hydroxyethyl radical and about the low levels of alcohol dehydrogenase and aldehyde dehydrogenase. Acetaldehyde accumulation in prostate tissue and oxidative stress promotion were also observed. In this study, we report that in the ventral prostate cytosolic fraction, xanthine oxidoreductase is able to metabolize acetaldehyde to acetyl radical. The identification of the acetyl was performed by GC-MS of the silylated acetyl-PBN adduct. Reference adduct was generated chemically. Formation of acetyl was also observed using pure xanthine oxidase. The generation of acetyl by the prostate cytosol was inhibited by allopurinol, oxypurinol, diphenyleneiodonium chloride, folate, and ellagic acid. Results suggest that metabolism of ethanol to acetaldehyde and to 1-hydroxyethyl and acetyl radicals could be involved in the deleterious effects of alcohol drinking on prostate epithelial cells.
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PMID:Rat ventral prostate xanthine oxidase-mediated metabolism of acetaldehyde to acetyl radical. 1973 71

Mammalian xanthine oxidase (XO) and Desulfovibrio gigas aldehyde oxidoreductase (AOR) are members of the XO family of mononuclear molybdoenzymes that catalyse the oxidative hydroxylation of a wide range of aldehydes and heterocyclic compounds. Much less known is the XO ability to catalyse the nitrite reduction to nitric oxide radical (NO). To assess the competence of other XO family enzymes to catalyse the nitrite reduction and to shed some light onto the molecular mechanism of this reaction, we characterised the anaerobic XO- and AOR-catalysed nitrite reduction. The identification of NO as the reaction product was done with a NO-selective electrode and by electron paramagnetic resonance (EPR) spectroscopy. The steady-state kinetic characterisation corroborated the XO-catalysed nitrite reduction and demonstrated, for the first time, that the prokaryotic AOR does catalyse the nitrite reduction to NO, in the presence of any electron donor to the enzyme, substrate (aldehyde) or not (dithionite). Nitrite binding and reduction was shown by EPR spectroscopy to occur on a reduced molybdenum centre. A molecular mechanism of AOR- and XO-catalysed nitrite reduction is discussed, in which the higher oxidation states of molybdenum seem to be involved in oxygen-atom insertion, whereas the lower oxidation states would favour oxygen-atom abstraction. Our results define a new catalytic performance for AOR-the nitrite reduction-and propose a new class of molybdenum-containing nitrite reductases.
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PMID:Nitrite reduction by xanthine oxidase family enzymes: a new class of nitrite reductases. 2117 May 63


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