Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 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

Aldehyde oxidases are molybdo-flavoenzymes structurally related to xanthine oxidoreductase. They catalyze the oxidation of aldehydes or N-heterocycles of physiological, pharmacological, and toxicological relevance. Rodents are characterized by four aldehyde oxidases as follows: AOX1 and aldehyde oxidase homologs 1-3 (AOH1, AOH2, and AOH3). Humans synthesize a single functional aldehyde oxidase, AOX1. Here we define the structure and the characteristics of the aldehyde oxidase genes and proteins in chicken and dog. The avian genome contains two aldehyde oxidase genes, AOX1 and AOH, mapping to chromosome 7. AOX1 and AOH are structurally very similar and code for proteins whose sequence was deduced from the corresponding cDNAs. AOX1 is the ortholog of the same gene in mammals, whereas AOH represents the likely ancestor of rodent AOH1, AOH2, and AOH3. The dog genome is endowed with two structurally conserved and active aldehyde oxidases clustering on chromosome 37. Cloning of the corresponding cDNAs and tissue distribution studies demonstrate that they are the orthologs of rodent AOH2 and AOH3. The vestiges of dog AOX1 and AOH1 are recognizable upstream of AOH2 and AOH3 on the same chromosome. Comparison of the complement and the structure of the aldehyde oxidase and xanthine oxidoreductase genes in vertebrates and other animal species indicates that they evolved through a series of duplication and inactivation events. Purification of the chicken AOX1 protein to homogeneity from kidney demonstrates that the enzyme possesses retinaldehyde oxidase activity. Unlike humans and most other mammals, dog and chicken are devoid of liver aldehyde oxidase activity.
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PMID:Avian and canine aldehyde oxidases. Novel insights into the biology and evolution of molybdo-flavoenzymes. 1667 19

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

Most acetaldehyde is generated in the liver by alcohol dehydrogenase (ADH) during ethanol metabolism. Polymorphic variants of these genes encode enzymes with altered kinetic properties, and pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde. Two additional pathways of acetaldehyde generation are by the cytochrome P450 2E1 (CYP2E1) and catalase. While the amount of ethanol oxidized by these enzymes comprises a small fraction of total body ethanol clearance, the local formation of acetaldehyde by these enzymes may have important effects. Additional sources of acetaldehyde include other minor enzymes (nitric oxide synthase, other cytochrome P450s, P450 reductase, xanthine oxidoreductase) as well as non-enzymatic pathways (formation of hydroxyethyl radicals from the reaction of ethanol with hydroxyl radical, and its subsequent decomposition to acetaldehyde). Acetaldehyde may have effects locally (in the cells generating it), or when delivered to other cells by the blood stream or saliva, or by diffusion from the lumen of the gastrointestinal tract. The ultimate determinants of acetaldehyde toxicity include rates of its formation, rates of oxidation, and the capacity of cellular systems to prevent or repair chemical effects of acetaldehyde (e.g. formation of protein adducts or modification of nucleic acid bases).
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PMID:Acetaldehyde generating enzyme systems: roles of alcohol dehydrogenase, CYP2E1 and catalase, and speculations on the role of other enzymes and processes. 1759 Sep 84

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

Mammalian aldehyde oxidases are a small group of proteins belonging to the larger family of molybdo-flavoenzymes along with xanthine oxidoreductase and other bacterial enzymes. The two general types of reactions catalyzed by aldehyde oxidases are the hydroxylation of heterocycles and the oxidation of aldehydes into the corresponding carboxylic acids. Different animal species are characterized by a different complement of aldehyde oxidase genes. Humans contain a single active gene, while marsupials and rodents are characterized by four such genes clustering at a short distance on the same chromosome. At present, little is known about the physiological relevance of aldehyde oxidases in humans and other mammals, although these enzymes are known to play a role in the metabolism of drugs and compounds of toxicological importance in the liver. The present article provides an overview of the current knowledge of genetics, evolution, structure, enzymology, tissue distribution and regulation of mammalian aldehyde oxidases.
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PMID:Mammalian aldehyde oxidases: genetics, evolution and biochemistry. 1806 86

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


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