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:3.1.3.5 (5'-nucleotidase)
3,167 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine is a product of complete dephosphorylation of adenine nucleotides which takes place in various compartments of the cell. This nucleoside is a significant signal molecule engaged in regulation of physiology and modulation of the function of numerous cell types (i.e. neurons, platelets, neutrophils, mast cells and smooth muscle cells in bronchi and vasculature, myocytes etc.). As part a of purinergic signaling system, adenosine mediates neurotransmission, conduction, secretion, vasodilation, proliferation and cell death. Most of the effects of adenosine help to protect cells and tissues during stress conditions such as ischemia or anoxia. Adenosine receptors and nucleoside transporters are targets for potential drugs in many pathophysiological situations. The adenosine-producing system in vertebrates involves a cascade dephosphorylating ATP and ending with 5'-nucleotidase (EC 3.1.3.5) localized either on the membrane or inside the cell. In this paper the cytoplasmic variants of 5'-nucleotidase are broadly characterized as well as their clinical relevance. The role of AMP-selective 5'-nucleotidase (cN-I) in the heart, skeletal muscle and brain is highlighted. cN-I action is crucial during ischemia and important for the efficacy of some nucleoside-based drugs and in the regulation of the substrate pool for nucleic acids synthesis. Inhibitors used in studying the roles of cytoplasmic and membrane-bound 5'-nucleotidases are also described.
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PMID:Adenosine as a metabolic regulator of tissue function: production of adenosine by cytoplasmic 5'-nucleotidases. 1677 Apr 41

Adenosine is an important modulator of the nervous system that has been implicated in the pathophysiology of schizophrenia. We studied peripheral adenosine metabolism by determining the activity of serum adenosine deaminase, which converts adenosine into inosine, and 5'-nucleotidase, which converts AMP into adenosine, in 26 DSM-IV male schizophrenic patients under antipsychotic monotherapy and 26 healthy volunteers balanced for age and race. Schizophrenic patients treated either with typical antipsychotics or clozapine showed increased serum adenosine deaminase activity compared to controls (controls=18.96+/-4.61 U/l; typical=25.09+/-10.98 U/l; clozapine=30.32+/-10.83 U/l; p<0.05, ANOVA) and 5'-nucleotidase activity was also increased in patients on clozapine. After adjusting for confounding factors, adenosine deaminase, but not 5'-nucleotidase, alterations remained significant particularly in the clozapine group. This result suggests that either altered adenosine metabolism is present in schizophrenic patients or is influenced by treatment with antipsychotics, particularly clozapine.
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PMID:Increased serum adenosine deaminase activity in schizophrenic receiving antipsychotic treatment. 1728 63

Pentylenetetrazol (PTZ) is commonly used as a convulsant drug. The enhanced seizure susceptibility induced by kindling is probably attributable to plastic changes in the synaptic efficacy. Adenosine and guanosine act both as important neuromodulators and neuroprotectors with mostly inhibitory effects on neuronal activity. Adenosine and guanosine can be released per se or generated from released nucleotides (ATP, ADP, AMP, GTP, GDP, and GMP) that are metabolized and rapidly converted to adenosine and guanosine. The aim of this study was to evaluate nucleotide hydrolysis by ecto- and soluble nucleotidases (hippocampal slices and CSF, respectively) after PTZ-kindling (stages 3, 4, or 5 seizures) or saline treatment in rats. Additionally, the levels of purines in rat cerebrospinal fluid (CSF), as well as ecto-NTPDases (1, 2, 3, 5, 6 and 8) and ecto- 5'-nucleotidase expression were determined. Ecto-enzyme assays demonstrated that ATP, AMP, GDP, and GMP hydrolysis enhanced when compared with controls. In addition, there was an increase of ADP, GDP, and GMP hydrolysis by soluble nucleotidases in PTZ-kindling rats compared to control group. The HPLC analysis showed a marked increase in PTZ-kindled CSF concentrations of GTP, ADP, and uric acid, but GDP, AMP, and hypoxanthine concentrations were decreased. Such alterations indicate that the modulatory role of purines in CNS could be affected by PTZ-kindling. However, the physiological significance of these findings remains to be elucidated.
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PMID:Pentylenetetrazol kindling alters adenine and guanine nucleotide catabolism in rat hippocampal slices and cerebrospinal fluid. 1754 58

Adenosine, an endogenous neuroprotective agent, can be produced in the synaptic cleft from adenosine triphosphate (ATP) hydrolysis via the concerted action of two enzymes: ATP diphosphohydrolase and 5'-nucleotidase. The aim of the present study was to investigate such enzymatic activities in the hippocampus of rats subjected to single (2- or 10-minute) or double (2+10 minute, with a 24-hour interval in between, named preconditioned group) ischemic episodes. Ischemia was produced by four-vessel occlusion method. Histological analysis showed no cell death in 2-minute ischemia, and up to 90% of pyramidal CA(1) cell loss in the 10-minute ischemic group. As predicted, double ischemic rats displayed a significant cytoprotective effect (around 60%). Preconditioned rats presented a delayed enhancement in ATP diphosphohydrolase activity (for ATP and adenosine diphosphate hydrolysis) after 48 hours of reperfusion. 5'-nucleotidase activity was increased immediately after ischemic insult (for all groups) and after a late reperfusion period (48 hours). We suggest that preconditioning causes delayed changes in enzymatic activities that would conceivably lead to increased adenosine production. This effect could be related to cytoprotection seen in preconditioned rats.
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PMID:Nucleotide hydrolysis in rats submitted to global cerebral ischemia: a possible link between preconditioning and adenosine production. 1789 2

Enteropathogenic Escherichia coli (EPEC) triggers a large release of adenosine triphosphate (ATP) from host intestinal cells and the extracellular ATP is broken down to adenosine diphosphate (ADP), AMP, and adenosine. Adenosine is a potent secretagogue in the small and large intestine. We suspected that ecto-5'-nucleotidase (CD73, an intestinal enzyme) was a critical enzyme involved in the conversion of AMP to adenosine and in the pathogenesis of EPEC diarrhea. We developed a nonradioactive method for measuring ecto-5'-nucleotidase in cultured T84 cell monolayers based on the detection of phosphate release from 5'-AMP. EPEC infection triggered a release of ecto-5'-nucleotidase from the cell surface into the supernatant medium. EPEC-induced 5'-nucleotidase release was not correlated with host cell death but instead with activation of phosphatidylinositol-specific phospholipase C (PI-PLC). Ecto-5'-nucleotidase was susceptible to inhibition by zinc acetate and by alpha,beta-methylene-adenosine diphosphate (alpha,beta-methylene-ADP). In the Ussing chamber, these inhibitors could reverse the chloride secretory responses triggered by 5'-AMP. In addition, alpha,beta-methylene-ADP and zinc blocked the ability of 5'-AMP to stimulate EPEC growth under nutrient-limited conditions in vitro. Ecto-5'-nucleotidase appears to be the major enzyme responsible for generation of adenosine from adenine nucleotides in the T84 cell line, and inhibitors of ecto-5'-nucleotidase, such as alpha,beta-methylene-ADP and zinc, might be useful for treatment of the watery diarrhea produced by EPEC infection.
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PMID:Ecto-5'-nucleotidase and intestinal ion secretion by enteropathogenic Escherichia coli. 1840 37

Venoms of Heloderma horridum and Heloderma suspectum were analyzed for the possible presence of purine and pyrimidine nucleosides. Adenosine, cytidine, guanosine, hypoxanthine, inosine, and uridine were found in mug quantities. These amounts are much smaller than those seen in many elapid or viperine venoms, but greater and more varied than those found in crotaline venoms. While their contribution to the hypotension induced by Heloderma venoms may be minor, venom nucleosides nonetheless act in concert with kallikreins/hemorrhagins, alkaline phosphomonoesterase, 5'-nucleotidase, helodermin, helospectins, helothermine, and serotonin. The use of nucleosides as toxins is therefore a generalized squamate strategy, rather than the exclusive province of snakes. Both Heloderma venoms were found to be devoid of NADase and phosphodiesterase activities. Enzymes to release endogenous purines in the prey, are not significant components of Heloderma venoms.
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PMID:Nucleoside composition of Heloderma venoms. 1843 May 99

Adenosine has been shown to exert direct antihypertrophic effects on the heart, and plasma adenosine levels have been shown to be elevated in patients with heart failure. It has therefore been proposed that endogenously synthesized adenosine may function as a cardiac antihypertrophic factor. The present study was aimed to determine whether the adenosine system is altered in a potential adaptive manner following phenylephrine-induced hypertrophy in cultured neonatal rat ventricular myocytes. Phenylephrine produced significant hypertrophy as determined by cell size and atrial natriuretic peptide gene expression, which was accompanied by significantly increased gene and protein expression of adenosine A(1), A(2a), and A(3) receptors. These effects and the hypertrophic response were prevented by the alpha(1)-adrenoceptor antagonist prazosin as well as pharmacological agonists for all adenosine receptor subtypes. The upregulation of adenosine receptors by phenylephrine was also abrogated by adenosine 5'-(alpha,beta-methylene)diphosphate, an inhibitor of ectosolic 5'-nucleotidase. Moreover, phenylephrine significantly increased production of adenosine from myocytes in the presence of a nucleoside transport and adenosine deaminase inhibitor, the combination of which abrogated the hypertrophic effect of phenylephrine. The latter effect was reversed by adenosine receptor antagonists. Phenylephrine also produced a significant upregulation in expression levels of equilibrative nucleoside transporter 1 although expression levels of equilibrative nucleoside transporter 2 were unaffected. Taken together, our results suggest an adaptive upregulation of the adenosine system to phenylephrine-induced cardiomyocyte hypertrophy that serves to limit the hypertrophic effect of alpha(1-)adrenoceptor activation.
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PMID:Compensatory upregulation of the adenosine system following phenylephrine-induced hypertrophy in cultured rat ventricular myocytes. 1996 59

The vascular ectonucleotidases CD39[ENTPD1 (ectonucleoside triphosphate diphosphohydrolase-1), EC 3.6.1.5] and CD73[EC 3.1.3.5] generate adenosine from extracellular nucleotides. CD39 activity is critical in determining the response to ischemia-reperfusion injury (IRI), and CD39 null mice exhibit heightened sensitivity to renal IRI. Adenosine has multiple mechanisms of action in the vasculature including direct endothelial protection, antiinflammatory and antithrombotic effects and is protective in several models of IRI. Mice transgenic for human CD39 (hCD39) have increased capacity to generate adenosine. We therefore hypothesized that hCD39 transgenic mice would be protected from renal IRI. The overexpression of hCD39 conferred protection in a model of warm renal IRI, with reduced histological injury, less apoptosis and preserved serum creatinine and urea levels. Benefit was abrogated by pretreatment with an adenosine A2A receptor antagonist. Adoptive transfer experiments showed that expression of hCD39 on either the vasculature or circulating cells mitigated IRI. Furthermore, hCD39 transgenic kidneys transplanted into syngeneic recipients after prolonged cold storage performed significantly better and exhibited less histological injury than wild-type control grafts. Thus, systemic or local strategies to promote adenosine generation and signaling may have beneficial effects on warm and cold renal IRI, with implications for therapeutic application in clinical renal transplantation.
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PMID:Transgenic overexpression of CD39 protects against renal ischemia-reperfusion and transplant vascular injury. 2097 15

This review focuses on the potential role of site- and event-selective adenosinergic drugs in the treatment of cardiovascular diseases. Adenosine is released from the myocardium and vessels in response to various forms of stress and acts on four receptor subtypes (A1, A2A, A2B and A3). Adenosine is an important endogenous substance with important homeostatic activity in the regulation of cardiac function and circulation. Adenosine receptors are also involved in the modulation of various cellular events playing crucial role in physiological and pathological processes of the cardiovascular system. These actions are associated to activation of distinct adenosine receptor subtypes, therefore drugs targeting specific adenosine receptors might be promising therapeutic tools in treatment of several disorders including various forms of cardiac arrhythmia, myocardial ischemia-reperfusion injury, angina pectoris, chronic heart failure, etc. Recently, in addition to subtype-specific adenosine receptor agonists and antagonists, a number of substances that enhance adenosine receptor activation locally at the site where the release of endogenous adenosine is the most intensive have been developed. Thus global actions of adenosine receptor agonists and antagonists, as well as desensitization or down-regulation following chronic administration of these orthosteric compounds can possibly be avoided. We discuss the chemical, pharmacological and clinical features of these compounds: (1) inhibitors of membrane adenosine transporters (NBTI, dipyridamole), (2) inhibitors of adenosine deaminase (coformycin, EHNA), (3) inhibitors of adenosine kinase (tubercidin, aristeromycin), (4) inhibitors of AMP deaminase (GP3269), (5) activators of 5'-nucleotidase (methotrexate), (6) adenosine regulators (acadesine) and (7) allosteric adenosine receptor modulators (PD81723, LUF6000). The development of this type of substances might offer a novel therapeutic approach for treating cardiovascular diseases in the near future.
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PMID:Novel trends in the treatment of cardiovascular disorders: site- and event- selective adenosinergic drugs. 2129 68

Nucleotides and nucleosides play an important role in neurodevelopment acting through specific receptors. Ectonucleotidases are the major enzymes involved in controlling the availability of purinergic receptors ligands. ATP is co-released with several neurotransmitters and is the most important source of extracellular adenosine by catabolism exerted by ectonucleotidases. The main ectonucleotidases are named NTPDases (1-8) and 5'-nucleotidase. Adenosine is a powerful modulator of neurotransmitter release. Caffeine blocks adenosine receptor activity as well as adenosine-mediated neuromodulation. Considering the susceptibility of the immature brain to caffeine and the need for correct purinergic signaling during fetal development, we have analyzed the effects of caffeine exposure during gestational and lactational periods on nucleotide degradation and ectonucleotidase expression from the hippocampi of 7-, 14- and 21-days-old rats. Nucleotides hydrolysis was assessed by colorimetric determination of inorganic phosphate released. Ectonucleotidases expression was performed by RT-PCR. ATP and ADP hydrolysis displayed parallel age-dependent decreases in both control and caffeine-treated groups. AMP hydrolysis increased with caffeine treatment in 7-days-old rats (75%); although there was no significant difference in AMP hydrolysis between control (non caffeine-treated) rats and 14- or 21-days caffeine-treated rats. ADP hydrolysis was not affected by caffeine treatment. Caffeine treatment in 7- and 14-days-old rats decreased ATP hydrolysis when compared to the control group (19% and 60% decrease, respectively), but 21-days-treated rats showed an increase in ATP hydrolysis (39%). Expression levels of NTPDase 1 and 5 decreased in hippocampi of caffeine-treated rats. The expression of 5'-nucleotidase was not affected after caffeine exposure. The changes observed in nucleotide hydrolysis and ectonucleotidases expression could promote subtle effects on normal neural development considering the neuromodulatory role of adenosine.
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PMID:Profile of nucleotide catabolism and ectonucleotidase expression from the hippocampi of neonatal rats after caffeine exposure. 2184 69


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