Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolism of endogenous adenosine and 2-deoxy-adenosine was studied in cultures of fetal mouse calvaria. Adenosine deamination was the most important pathway of metabolism. This was blocked by erythro-2-(2-hydroxy-3-nonyl)adenine (1 microM). Albumin in the medium could not account for the deaminase activity. The disappearance of adenosine from the medium was not influenced by two inhibitors of adenosine transport, dipyridamole and dilazep, but was competitively inhibited by 2-deoxy-adenosine. During culture there was a net increase in adenosine and inosine, possibly originating from damaged cells.
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PMID:Metabolism of adenosine and 2'-deoxy-adenosine by fetal mouse calvaria in culture. 698 23

Because adenine nucleotide catabolites may be important during postischemic lung reperfusion, we examined the pathway of adenosine monophosphate (AMP) degradation in ischemic lung tissue. Once the pattern of degradation is known, pharmacological interventions can be considered, offering new methods of reducing lung reperfusion injury. For this purpose we used the isolated rabbit lung. Rabbit lungs were flushed in situ with a modified Krebs Henseleit solution (60 ml/kg). The lungs were removed and stored deflated, immersed in saline solution at 37 degrees C. At regular times, biopsies were taken, and adenine nucleotides, nucleosides, and bases were measured in these biopsies using high performance liquid chromatography (HPLC). During lung ischemia, a very significant increase of inosine monophosphate (IMP) was found. Adenosine levels on the other hand did not increase. Hypoxanthine was the major end catabolite of ischemic lung tissue (constituting 92% of the nucleoside and purine base fraction at 4 hours ischemia). To further determine the pathway of AMP degradation, 400 mM of the adenosine deaminase inhibitor erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA) was added to the lung flush solution. During ischemia, adenosine triphosphate (ATP) breakdown was unaltered but adenosine became the major catabolite (2.8 times the concentration of hypoxanthine at 4 hours ischemia). These data suggest that: 1) in rabbit lung tissue, dephosphorylation of AMP to adenosine is more important than deamination to IMP; 2) hypoxanthine is the major end catabolite of ischemic lung tissue. By inhibiting the enzyme deaminase, reduced hypoxanthine levels and increased adenosine levels were obtained. Pharmacological interventions are now available to interfere with the formation of adenine nucleosides and bases in ischemic lung tissue. The importance of adenine nucleotide catabolites to postischemic lung reperfusion injury is discussed.
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PMID:Pattern of AMP degradation in ischemic rabbit lung tissue. 773 34

Endogenous adenosine in the extracellular space inhibits neuronal activity. The roles of adenosine kinase, S-adenosylhomocysteine-hydrolase and adenosine deaminase activities in the regulation of the adenosine levels were investigated in rat hippocampal slices. Iodotubercidin, an inhibitor of adenosine kinase, added to the perfusion fluid at 5 microM increased the release of adenosine from the slices more than 2-fold. Iodotubercidin treatment caused inhibition of population spike discharges and hyperpolarization of pyramidal cells, mimicking the effects of exogenously applied adenosine. Adenosine dialdehyde, an inhibitor of S-adenosylhomocysteine hydrolase, and erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), an inhibitor of adenosine deaminase had little or no effect on the parameters tested. The action of iodotubercidin was greater during deaminase inhibition. The A1-receptor antagonist DPCPX had actions opposite to those of adenosine and blocked the electrophysiological effects of exogenous adenosine and of iodotubercidin. Thus adenosine kinase activity is a significant factor in the regulation of adenosine levels in the hippocampus.
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PMID:Inhibition of adenosine kinase increases endogenous adenosine and depresses neuronal activity in hippocampal slices. 783 17

Adenosine (Ado) is a potent vasodilator that has occasionally been shown to cause vasoconstriction. Constrictor responses are generally attributed to A1-receptor stimulation or interactions with the renin-angiotensin system. We describe a previously unreported vasoconstrictor action of Ado and inosine (Ino) in hamster cheek pouch arterioles and examine the mechanism by which these nucleosides induce constriction. Arterioles were dissected from male Golden hamster cheek pouches, transferred to a 37 degrees C tissue chamber, and cannulated at both ends. Changes of luminal diameter in response to Ado were measured to generate cumulative concentration-response curves. The concentration-response curves were biphasic: 10(-6) M Ado elicited an intense, transient constriction, and higher concentrations induced dilator responses. Pretreatment with 8(p-sulfophenyl)theophylline, an Ado receptor antagonist, inhibited the dilator responses but did not alter the constriction. Inhibition of Ado uptake with S-(4-nitrobenzyl)-6-thio-inosine eliminated the constrictor response without altering dilator responses. Similar effects were found after pretreatment with an Ado deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride. Finally, Ino, a metabolite of Ado, induced constrictions of similar magnitude to those seen with Ado, but at higher concentrations. The constrictor response was focal in nature, suggesting discrete sites of action of Ado. Methylene blue staining after Ado application revealed degranulated mast cells closely associated with the vessel wall, indicating a possible role for mast cell degranulation in the constrictor response. Supporting this idea were the observations that inhibition of degranulation by 10 microM cromolyn blocked the constrictor response, and compound 48/80 (a mast cell secretagogue) caused constriction similar to that elicited by Ado.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nucleoside-induced arteriolar constriction: a mast cell-dependent response. 820 2

The anabolism of 1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, a selective inhibitor of human immunodeficiency virus (HIV), was characterized in human T-lymphoblastoid CD4+ CEM cells. 1592U89 was ultimately anabolized to the triphosphate (TP) of the guanine analog (-)-carbovir (CBV), a potent inhibitor of HIV reverse transcriptase. However, less than 2% of intracellular 1592U89 was converted to CBV, an amount insufficient to account for the CBV-TP levels observed. 1592U89 was anabolized to its 5'-monophosphate (MP) by the recently characterized enzyme adenosine phosphotransferase, but neither its diphosphate (DP) nor its TP was detected. The MP, DP, and TP of CBV were found in cells incubated with either 1592U89 or CBV, with CBV-TP being the major phosphorylated species. We confirmed that CBV is phosphorylated by 5'-nucleotidase and that mycophenolic acid increased the formation of CBV-TP from CBV 75-fold. However, mycophenolic acid did not stimulate 1592U89 anabolism to CBV-TP. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) did not inhibit CBV-TP formation from CBV or 1592U89, whereas the adenylate deaminase inhibitor 2'-deoxycoformycin selectively inhibited 1592U89 anabolism to CBV-TP and reversed the antiviral activity of 1592U89. 1592U89-MP was not a substrate for adenylate deaminase but was a substrate for a distinct cytosolic deaminase that was inhibited by 2'-deoxycoformycin-5'-MP. Thus, 1592U89 is phosphorylated by adenosine phosphotransferase to 1592U89-MP, which is converted by a novel cytosolic enzyme to CBV-MP. CBV-MP is then further phosphorylated to CBV-TP by cellular kinases. This unique activation pathway enables 1592U89 to overcome the pharmacokinetic and toxicological deficiencies of CBV while maintaining potent and selective anti-HIV activity.
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PMID:Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. 914 76

Extracellular adenosine (Ado) and ATP stimulate astrocyte proliferation through activation of P(1) and P(2) purinoceptors. Extracellular GTP and guanosine (Guo), however, that do not bind strongly to these receptors, are more effective mitogens than ATP and Ado. Exogenous Guo, like GTP and 5'-guanosine-betagamma-imidotriphosphate (GMP-PNP), dose-dependently stimulated proliferation of rat cultured astrocytes; potency order GMP-PNP > GTP > or = Guo. The mitogenic effect of Guo was independent of the extracellular breakdown of GTP to Guo, because GMP-PNP, a GTP analogue resistant to hydrolysis, was the most mitogenic. In addition to a direct effect on astrocytes, Guo exerts its proliferative activity involving Ado. Exogenous Guo, indeed, enhanced the extracellular levels of endogenous Ado assayed by HPLC in the medium of cultured astrocytes. Culture pretreatment with Ado deaminase (ADA), that converts Ado into inosine, reduced but did not abolish Guo-induced astrocyte proliferation whereas erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), that inhibits ADA activity, amplified Guo effect. Moreover, the mitogenic activity of Guo was partly inhibited by 8-cyclopentyl-1,3-dipropylxanthine and alloxazine, antagonists of Ado A(1) and A(2B) receptors, respectively. Also microglia seem to be a target for the action of Guo. Indeed, the mitogenic effect of Guo on astrocytes was: i) increased proportionally to the number of microglial cells present in the astrocyte cultures; ii) amplified when purified cultures of astrocytes were supplemented with conditioned medium deriving from Guo-pretreated microglial cultures. These data indicate that the mitogenic effects exerted by exogenous Guo on rat astrocytes are mediated via complex mechanisms involving extracellular Ado and microglia-derived soluble factors.
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PMID:Cultured astrocyte proliferation induced by extracellular guanosine involves endogenous adenosine and is raised by the co-presence of microglia. 1064 47


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