The Experts below are selected from a list of 363 Experts worldwide ranked by ideXlab platform
Letizia Polito - One of the best experts on this subject based on the ideXlab platform.
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Xanthine Oxidoreductase in Drug Metabolism: Beyond a Role as a Detoxifying Enzyme.
Current medicinal chemistry, 2016Co-Authors: Maria Giulia Battelli, Letizia Polito, Massimo Bortolotti, Andrea BolognesiAbstract:The enzyme xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism in the highest Uricotelic primates. XOR is an enzyme with dehydrogenase activity that, in mammals, may be converted into oxidase activity under a variety of pathophysiologic conditions. XOR activity is highly regulated at the transcriptional and post-translational levels and may generate reactive oxygen and nitrogen species, which trigger different consequences, ranging from cytotoxicity to inflammation. The low specificity for substrates allows XOR to metabolize a number of endogenous metabolites and a variety of exogenous compounds, including drugs. The present review focuses on the role of XOR as a drug-metabolizing enzyme, specifically for drugs with anticancer, antimicrobial, antiviral, immunosuppressive or vasodilator activities, as well as drugs acting on metabolism or inducing XOR expression. XOR has an activating role that is essential to the pharmacological action of quinone drugs, cyadox, antiviral nucleoside analogues, allopurinol, nitrate and nitrite. XOR activity has a degradation function toward thiopurine nucleotides, pyrazinoic acid, methylxanthines and tolbutamide, whose half-life may be prolonged by the use of XOR inhibitors. In conclusion, to avoid potential drug interaction risks, such as a toxic excess of drug bioavailability or a loss of drug efficacy, caution is suggested in the use of XOR inhibitors, as in the case of hyperuricemic patients affected by gout or tumor lysis syndrome, when it is necessary to simultaneously administer therapeutic substances that are activated or degraded by the drug-metabolizing activity of XOR.
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Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme
Biochimica et biophysica acta, 2014Co-Authors: Maria Giulia Battelli, Andrea Bolognesi, Letizia PolitoAbstract:The enzyme xanthine oxidoreductase (XOR) catalyses the last step of purine degradation in the highest Uricotelic primates as a rate-limiting enzyme in nucleic acid catabolism. Although XOR has been studied for more than a century, this enzyme continues to arouse interest because its involvement in many pathological conditions is not completely known. XOR is highly evolutionarily conserved; moreover, its activity is very versatile and tuneable at multiple-levels and generates both oxidant and anti-oxidant products. This review covers the basic information on XOR biology that is essential to understand its enzymatic role in human pathophysiology and provides a comprehensive catalogue of the experimental and human pathologies associated with increased serum XOR levels. The production of radical species by XOR oxidase activity has been intensively studied and evaluated in recent decades in conjunction with the cytotoxic consequences and tissue injuries of various pathological conditions. More recently, a role has emerged for the activity of endothelium-bound enzymes in inducing the vascular response to oxidative stress, which includes the regulation of pro-inflammatory and pro-thrombotic activities of endothelial cells. The possible physiological functions of circulating XOR and the products of its enzyme activity are presented here together with their implications in cardiovascular and metabolic diseases.
Andrea Bolognesi - One of the best experts on this subject based on the ideXlab platform.
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Xanthine Oxidoreductase in Drug Metabolism: Beyond a Role as a Detoxifying Enzyme.
Current medicinal chemistry, 2016Co-Authors: Maria Giulia Battelli, Letizia Polito, Massimo Bortolotti, Andrea BolognesiAbstract:The enzyme xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism in the highest Uricotelic primates. XOR is an enzyme with dehydrogenase activity that, in mammals, may be converted into oxidase activity under a variety of pathophysiologic conditions. XOR activity is highly regulated at the transcriptional and post-translational levels and may generate reactive oxygen and nitrogen species, which trigger different consequences, ranging from cytotoxicity to inflammation. The low specificity for substrates allows XOR to metabolize a number of endogenous metabolites and a variety of exogenous compounds, including drugs. The present review focuses on the role of XOR as a drug-metabolizing enzyme, specifically for drugs with anticancer, antimicrobial, antiviral, immunosuppressive or vasodilator activities, as well as drugs acting on metabolism or inducing XOR expression. XOR has an activating role that is essential to the pharmacological action of quinone drugs, cyadox, antiviral nucleoside analogues, allopurinol, nitrate and nitrite. XOR activity has a degradation function toward thiopurine nucleotides, pyrazinoic acid, methylxanthines and tolbutamide, whose half-life may be prolonged by the use of XOR inhibitors. In conclusion, to avoid potential drug interaction risks, such as a toxic excess of drug bioavailability or a loss of drug efficacy, caution is suggested in the use of XOR inhibitors, as in the case of hyperuricemic patients affected by gout or tumor lysis syndrome, when it is necessary to simultaneously administer therapeutic substances that are activated or degraded by the drug-metabolizing activity of XOR.
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Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme
Biochimica et biophysica acta, 2014Co-Authors: Maria Giulia Battelli, Andrea Bolognesi, Letizia PolitoAbstract:The enzyme xanthine oxidoreductase (XOR) catalyses the last step of purine degradation in the highest Uricotelic primates as a rate-limiting enzyme in nucleic acid catabolism. Although XOR has been studied for more than a century, this enzyme continues to arouse interest because its involvement in many pathological conditions is not completely known. XOR is highly evolutionarily conserved; moreover, its activity is very versatile and tuneable at multiple-levels and generates both oxidant and anti-oxidant products. This review covers the basic information on XOR biology that is essential to understand its enzymatic role in human pathophysiology and provides a comprehensive catalogue of the experimental and human pathologies associated with increased serum XOR levels. The production of radical species by XOR oxidase activity has been intensively studied and evaluated in recent decades in conjunction with the cytotoxic consequences and tissue injuries of various pathological conditions. More recently, a role has emerged for the activity of endothelium-bound enzymes in inducing the vascular response to oxidative stress, which includes the regulation of pro-inflammatory and pro-thrombotic activities of endothelial cells. The possible physiological functions of circulating XOR and the products of its enzyme activity are presented here together with their implications in cardiovascular and metabolic diseases.
Maria Giulia Battelli - One of the best experts on this subject based on the ideXlab platform.
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Xanthine Oxidoreductase in Drug Metabolism: Beyond a Role as a Detoxifying Enzyme.
Current medicinal chemistry, 2016Co-Authors: Maria Giulia Battelli, Letizia Polito, Massimo Bortolotti, Andrea BolognesiAbstract:The enzyme xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism in the highest Uricotelic primates. XOR is an enzyme with dehydrogenase activity that, in mammals, may be converted into oxidase activity under a variety of pathophysiologic conditions. XOR activity is highly regulated at the transcriptional and post-translational levels and may generate reactive oxygen and nitrogen species, which trigger different consequences, ranging from cytotoxicity to inflammation. The low specificity for substrates allows XOR to metabolize a number of endogenous metabolites and a variety of exogenous compounds, including drugs. The present review focuses on the role of XOR as a drug-metabolizing enzyme, specifically for drugs with anticancer, antimicrobial, antiviral, immunosuppressive or vasodilator activities, as well as drugs acting on metabolism or inducing XOR expression. XOR has an activating role that is essential to the pharmacological action of quinone drugs, cyadox, antiviral nucleoside analogues, allopurinol, nitrate and nitrite. XOR activity has a degradation function toward thiopurine nucleotides, pyrazinoic acid, methylxanthines and tolbutamide, whose half-life may be prolonged by the use of XOR inhibitors. In conclusion, to avoid potential drug interaction risks, such as a toxic excess of drug bioavailability or a loss of drug efficacy, caution is suggested in the use of XOR inhibitors, as in the case of hyperuricemic patients affected by gout or tumor lysis syndrome, when it is necessary to simultaneously administer therapeutic substances that are activated or degraded by the drug-metabolizing activity of XOR.
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Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme
Biochimica et biophysica acta, 2014Co-Authors: Maria Giulia Battelli, Andrea Bolognesi, Letizia PolitoAbstract:The enzyme xanthine oxidoreductase (XOR) catalyses the last step of purine degradation in the highest Uricotelic primates as a rate-limiting enzyme in nucleic acid catabolism. Although XOR has been studied for more than a century, this enzyme continues to arouse interest because its involvement in many pathological conditions is not completely known. XOR is highly evolutionarily conserved; moreover, its activity is very versatile and tuneable at multiple-levels and generates both oxidant and anti-oxidant products. This review covers the basic information on XOR biology that is essential to understand its enzymatic role in human pathophysiology and provides a comprehensive catalogue of the experimental and human pathologies associated with increased serum XOR levels. The production of radical species by XOR oxidase activity has been intensively studied and evaluated in recent decades in conjunction with the cytotoxic consequences and tissue injuries of various pathological conditions. More recently, a role has emerged for the activity of endothelium-bound enzymes in inducing the vascular response to oxidative stress, which includes the regulation of pro-inflammatory and pro-thrombotic activities of endothelial cells. The possible physiological functions of circulating XOR and the products of its enzyme activity are presented here together with their implications in cardiovascular and metabolic diseases.
Lily Vardimon - One of the best experts on this subject based on the ideXlab platform.
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Weak mitochondrial targeting sequence determines tissue-specific subcellular localization of glutamine synthetase in liver and brain cells.
Journal of Cell Science, 2010Co-Authors: Gideon D. Matthews, Noa Gur, Werner J.h. Koopman, Ophry Pines, Lily VardimonAbstract:Evolution of the Uricotelic system for ammonia detoxification required a mechanism for tissue-specific subcellular localization of glutamine synthetase (GS). In Uricotelic vertebrates, GS is mitochondrial in liver cells and cytoplasmic in brain. Because these species contain a single copy of the GS gene, it is not clear how tissue-specific subcellular localization is achieved. Here we show that in chicken, which utilizes the Uricotelic system, the GS transcripts of liver and brain cells are identical and, consistently, there is no difference in the amino acid sequence of the protein. The N-terminus of GS, which constitutes a 'weak' mitochondrial targeting signal (MTS), is sufficient to direct a chimeric protein to the mitochondria in hepatocytes and to the cytoplasm in astrocytes. Considering that a weak MTS is dependent on a highly negative mitochondrial membrane potential (DeltaPsi) for import, we examined the magnitude of DeltaPsi in hepatocytes and astrocytes. Our results unexpectedly revealed that DeltaPsi in hepatocytes is considerably more negative than that of astrocytes and that converting the targeting signal into 'strong' MTS abolished the capability to confer tissue-specific subcellular localization. We suggest that evolutional selection of weak MTS provided a tool for differential targeting of an identical protein by taking advantage of tissue-specific differences in DeltaPsi.
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A single glutamine synthetase gene produces tissue-specific subcellular localization by alternative splicing.
FEBS letters, 2005Co-Authors: Gideon D. Matthews, Robert M. Gould, Lily VardimonAbstract:Glutamine synthetase (GS) plays a key role in two major biochemical pathways: In liver GS catalyzes ammonia detoxification, whereas in neural tissues it also functions in recycling of the neurotransmitter glutamate. In most species the GS gene gives rise to a cytoplasmic protein in both liver and neural tissues. However, in species that utilize the ureosmotic or Uricotelic system for ammonia detoxification, the enzyme is cytoplasmic in neural tissues, but mitochondrial in liver cells. Since most vertebrates have a single copy of the GS gene, it is not clear how tissue-specific subcellular localization is achieved. Here we show that in the ureosmotic elasmobranch, Squalus acanthias (spiny dogfish), two different GS transcripts are generated by tissue-specific alternative splicing. The liver transcript contains an alternative exon that is not present in the neural one. This exon leads to acquisition of an upstream in-frame start codon and formation of a mitochondrial targeting signal (MTS). Therefore, the liver product is targeted to the mitochondria while the neural one is retained in the cytoplasm. These findings present a mechanism in which alternative splicing of an MTS-encoding exon is used to generate tissue-specific subcellular localization.
Hans Briegel - One of the best experts on this subject based on the ideXlab platform.
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protein catabolism in mosquitoes ureotely and uricotely in larval and imaginal aedes aegypti
Journal of Insect Physiology, 2001Co-Authors: Petra Von Dungern, Hans BriegelAbstract:Catabolism of excess dietary protein by Aedes aegypti was investigated during larval development, during and after metamorphosis. Activity profiles were established for xanthine dehydrogenase (XDH, Uricotelic pathway) and arginase (ureotelic pathway). Both enzymes are active at all times during the life-cycle. During the aquatic larval and pupal instars, XDH and arginase activities increase with body size. Maximal activities of these two enzyme systems coincide with the time of metamorphic restructuring. Both enzymes are found in the fatbody tissue: XDH activity is found in 80% of the tissue, while arginase activity is distributed equally between abdominal fatbody and the thorax. This might indicate a role for arginase other than catabolic, such as energy metabolism. Arginase activity is high in the aquatic instars and low in sugar-fed females but increases after blood-feeding. XDH activity, also high in larvae and pupae, increases markedly after a blood meal. Larval excretion is characterized by the ureotelic pathway. The pupae as closed systems excrete neither uric acid nor urea; urate accumulates during larval and pupal periods, is conserved throughout metamorphosis, and is finally voided with the meconium by the teneral imago. This presents a form of transient storage–excretion.
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Enzymatic analysis of Uricotelic protein catabolism in the mosquito Aedes aegypti.
Journal of insect physiology, 2001Co-Authors: Petra Von Dungern, Hans BriegelAbstract:Excess protein ingested by blood meals of mosquitoes is catabolized by a Uricotelic pathway. We have established enzyme activity profiles for xanthine dehydrogenase (XDH), the enzyme that catalyzes uric acid synthesis, and related it to intestinal proteolytic activities in female Aedes aegypti mosquitoes.During the first day after eclosion the meconium containing urate and urea of larval/pupal origin is discharged, together with XDH activity. Females of constant body size and of defined age were given measured blood meals by enema. XDH activity and uric acid synthesis correlate with the size of the blood meals. Upon completion of protein digestion and catabolism, XDH is excreted in an active form and its activity returns to the residual level. Maximal XDH activity always precedes intestinal proteolytic activities by a few hours. Regulation of XDH activity appears to be purely metabolic, independent of endocrine factors.Small females fed identical volumes of blood produce fewer eggs than their larger sisters and consequently catabolize a higher proportion of blood protein to uric acid.Old females are less fecund and show smaller investments of protein into yolk than younger ones. Despite reduced XDH activities, they excrete equal amounts of urate as young females. Obviously in young females XDH activity is in excess of biochemical requirements.
