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

Adenosine and the adenine nucleotides have a potent depressant action on cerebral cortical neurons, including identified corticospinal cells. Other purine and pyrimidine nucleotides were either weakly depressant (inosine and guanosine derivatives) or largely inactive (xanthine, cytidine, thymidine, uridine derivatives). The 5'-triphosphates and to a lesser extent the 5'-diphosphates of all the purine and pyrimidines tested had excitant actions on cortical neurons. Adenosine transport blockers and deaminase inhibitors depressed the firing of cortical neurons and potentiated the depressant actions of adenosine and the adenine nucleotides. Methylxanthines (theophylline, caffeine, and isobutylmethylxanthine) antagonized the depressant effects of adenosine and the adenine nucleotides and enhanced the spontaneous firing rate of cerebral cortical neurons. Intracellular recordings showed that adenosine 5'-monophosphate hyperpolarizes cerebral cortical neurons and suppresses spontaneous and evoked excitatory postsynaptic potentials in the absence of any pronounced alterations in membrane resistance or of the threshold for action potential generation. It is suggested that adenosine depresses spontaneous and evoked activity by inhibiting the release of transmitter from presynaptic nerve terminals. Furthermore, the depressant effects of potentiators and excitant effects of antagonists of adenosine on neuronal firing are consistent with the hypothesis that cortical neurons are subject to control by endogenously released purines.
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PMID:Effects of adenosine and adenine nucleotides on synaptic transmission in the cerebral cortex. 9 18

1. Adenosine and its analogs depress the firing of neurons in various brain regions. The primary mode of action of adenosine in exerting this effect appears to be the depression of transmitter release from presynaptic nerve terminals. This is a result of reduced calcium mobilization. 2. Adenosine uptake inhibitors and deaminase inhibitors depress the firing of central neurons. Adenosine antagonists, caffeine and theophylline, excite central neurons. Adenosine is therefore likely to be released in sufficient quantities to exert an ongoing modulation of synaptic transmission in the intact brain. 3. A number of groups of centrally active drugs inhibit adenosine uptake by brain synaptosomal preparations. These include the benzodiazepines, phenothiazines, various other sedatives and hypnotics, tricyclic antidepressants, non-steroidal anti-inflammatory analgesics, some steroids, diphenylhydantoin, puromycin and toyocamycin. 4. It is proposed that many agents with anxiolytic, sedative, analgesic or anti-convulsant actions may achieve their effects by inhibiting adenosine uptake and thus potentiating extracellular adenosine levels. 5. Morphine also elevates extracellular adenosine levels but achieves this by enhancing adenosine release.
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PMID:The effect of various centrally active drugs on adenosine uptake by the central nervous system. 612 37

Adenosine (Ado) has been shown to suppress several functional responses of human polymorphonuclear leukocytes (PMNs). The current study investigated whether endogenous Ado regulates the biosynthesis of leukotriene (LT)B4 in ligand-stimulated PMNs. Measurements of Ado in PMN resuspended in Hanks' buffered salt solution (HBSS) or plasma showed a cell concentration- and time-dependent accumulation of the nucleoside. The removal of endogenous Ado with either Ado deaminase or the blockade of its action by the Ado A2a receptor antagonist, 8-(3-chlorostyryl) caffeine, markedly increased LTB4 biosynthesis upon ligand stimulation in HBSS. Similarly, LTB4 synthesis by ligand-stimulated PMNs in plasma (containing recombinant LTA4 hydrolase to allow the conversion of protein-bound LTA4) was strongly enhanced by addition of Ado deaminase. Addition of red blood cells to suspensions of PMNs in plasma mimicked the effect of adding Ado deaminase and LTA4 hydrolase in enhancing LTB4 biosynthesis upon ligand stimulation. This effect of red blood cells on LTB4 biosynthesis was blocked by dipyridamole, an inhibitor of Ado transport, or captopril, an inhibitor of LTA4 hydrolase. These results demonstrate that endogenous Ado efficiently downregulates ligand-stimulated LTB4 biosynthesis in PMN suspensions, pointing out a potentially important regulatory function of Ado in inflammatory exudates. These results also unveil a dual role for red blood cells in upregulating LTB4 biosynthesis, namely, the removal of endogenous Ado and the conversion of LTA4 released by activated PMNs.
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PMID:Suppression of leukotriene B4 biosynthesis by endogenous adenosine in ligand-activated human neutrophils. 933 81

This study examined the ability of an adenosine kinase inhibitor (5'-amino-5'-deoxyadenosine; NH2dAD), an adenosine deaminase inhibitor (2'-deoxycoformycin), and combinations of these agents to produce a peripheral modulation of the pain signal in the low concentration formalin model. Drugs were administered in combination with 0.5% formalin, or into the contralateral hindpaw to test for systemic effects, and episodes of flinching behaviors determined. Coadministration of NH2dAD 0.1-100 nmol with formalin produced antinociception as revealed by an inhibition of flinching behaviors. This action was peripherally mediated as it was not seen following contralateral administration of the NH2dAD, and was due to accumulation of adenosine and activation of cell surface adenosine receptors as it was blocked by the adenosine receptor antagonist caffeine. Antinociception was intensity-dependent, as it was not seen when higher concentrations of formalin (0.75%, 1.5%) were used. The coadministration of the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine revealed the presence of an inhibitory tone of adenosine when the intrinsic antinociceptive effect of NH2dAD was obscured by the solvent or the stimulus intensity. 2'-Deoxycoformycin 0.1-100 nmol did not produce any intrinsic effect, but 100 nmol coadministered with low concentrations of NH2dAD, which lacked an intrinsic effect, augmented antinociception by NH2dAD. Again, this was a peripheral rather than a systemic response. The combined action of the adenosine kinase and deaminase inhibitors was completely reversed by coadministration of caffeine. Antinociception with NH2dAD is observed at higher concentrations of formalin in second trial experiments. This study demonstrates a peripheral antinociceptive action mediated by endogenous adenosine which accumulates following the peripheral inhibition of adenosine kinase; this action is due to activation of an adenosine A1 receptor.
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PMID:Peripheral antinociceptive effect of an adenosine kinase inhibitor, with augmentation by an adenosine deaminase inhibitor, in the rat formalin test. 951 63

Adenosine (Ado) is an important autocrine modulator of neutrophil functions. In this study, we determined the effects of endogenous Ado on fMet-Leu-Phe (fMLP)-induced phospholipase D (PLD) activity in neutrophils. The removal of extracellular Ado by Ado deaminase (ADA) or the blockade of its action by the A2a receptor antagonists 8-(3-chlorostyryl) caffeine (CSC) or CGS15943 markedly increased fMLP-induced PLD activation. The concentration-dependent stimulatory effects of CSC and CGS15943 were abolished by a pretreatment of neutrophil suspensionswith ADA. In contrast, the selective A2a receptor agonist CGS21680 suppressed fMLP-induced PLD activation. Furthermore, inhibition by CGS21680 of fMLP-induced PLD activity was reversed by CSC or CGS15943. The removal of Ado by ADA or the blockade of its action by CSC or CGS15943, markedly increased the membrane recruitment of cytosolic protein kinase Calpha (PKCalpha), RhoA, and ADP-ribosylation factor (ARF) in response to fMLP. As shown for PLD activity, the stimulatory effect of Ado receptor antagonists on PLD cofactors translocation was abolished by a pretreatment of the cells with ADA. Moreover, the membrane translocation of both PKCalpha, RhoA, and ARF in response to fMLP was attenuated by CGS21680 and this effect of the A2a receptor agonist was antagonized by CSC or CGS15943. These data demonstrate that Ado released by neutrophils in the extracellular milieu inhibits PLD activation by blocking membrane association of ARF, RhoA, and PKCalpha through Ado A2a receptor occupancy. (Blood. 2000;95:519-527)
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PMID:Adenosine receptor occupancy suppresses chemoattractant-induced phospholipase D activity by diminishing membrane recruitment of small GTPases. 1062 57

Because micromolar concentrations of adenosine (Ado) have been documented recently in the interstitial fluid of carcinomas growing in animals, we examined the effects of low concentrations of Ado on the growth of cultured human carcinoma cells. Ado alone had little effect upon cell growth. In the presence of one of a number of Ado deaminase (ADA) inhibitors, Ado led to significant growth inhibition of all cell lines tested. Similar effects were found when ATP, ADP, or AMP was substituted for Ado. Surprisingly, the ADA inhibitor coformycin (CF) had a much greater potentiating effect than did 2'-deoxycoformycin (DCF), although DCF is a more potent ADA inhibitor. The growth inhibition of the Ado/CF combination was not abrogated by pyrimidines or caffeine, a nonspecific Ado receptor blocker. Toxicity was prevented by the addition of the Ado transport inhibitor dipyridamole or the Ado kinase inhibitor 5'-amino 5'-deoxyadenosine. S-Adenosylhomocysteine hydrolase is not involved because neither homocysteine thiolactone nor an S-adenosylhomocysteine hydrolase inhibitor (adenosine dialdehyde) potentiated toxicity of the Ado/CF combination. Unexpectedly, substitution of 2'-deoxyadenosine (the toxic moiety in congenital ADA deficiency) for Ado, did not lead to equivalent toxicity. The Ado/CF combination inhibited DNA synthesis and brought about morphological changes consistent with apoptosis. Together, these findings indicate that the Ado-mediated killing proceeds via an intracellular route that requires the action of Ado kinase. The enhanced cofactor activity of CF may be attributable to its being a more potent inhibitor of AMP deaminase than is DCF.
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PMID:Adenosine-mediated killing of cultured epithelial cancer cells. 1076 76

Sudden unexpected death in epilepsy (SUDEP) is a significant cause of mortality in people with epilepsy. Two postulated causes for SUDEP, cardiac and respiratory depression, can both be explained by overstimulation of adenosine receptors. We hypothesized that SUDEP is a consequence of a surge in adenosine as a result of prolonged seizures combined with deficient adenosine clearance; consequently, blockade of adenosine receptors should prevent SUDEP. Here we induced impaired adenosine clearance in adult mice by pharmacologic inhibition of the adenosine-removing enzymes, adenosine kinase and deaminase. Combination of impaired adenosine clearance with kainic acid-induced seizures triggered sudden death in all animals. Most importantly, the adenosine receptor antagonist caffeine, when given after seizure onset, increased survival from 23.75 +/- 1.35 min to 54.86 +/- 6.59 min (p < 0.01). Our data indicate that SUDEP is due to overactivation of adenosine receptors and that caffeine treatment after seizure onset might be beneficial.
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PMID:A novel mouse model for sudden unexpected death in epilepsy (SUDEP): role of impaired adenosine clearance. 1967 57

Purine nucleotide catabolism is common to most organisms and involves a guanine deaminase to convert guanine to xanthine in animals, invertebrates, and microorganisms. Using metabolomic analysis of mutants, we demonstrate that Arabidopsis thaliana uses an alternative catabolic route employing a highly specific guanosine deaminase (GSDA) not reported from any organism so far. The enzyme is ubiquitously expressed and deaminates exclusively guanosine and 2'-deoxyguanosine but no other aminated purines, pyrimidines, or pterines. GSDA belongs to the cytidine/deoxycytidylate deaminase family of proteins together with a deaminase involved in riboflavin biosynthesis, the chloroplastic tRNA adenosine deaminase Arg and a predicted tRNA-specific adenosine deaminase 2 in A. thaliana. GSDA is conserved in plants, including the moss Physcomitrella patens, but is absent in the algae and outside the plant kingdom. Our data show that xanthosine is exclusively generated through the deamination of guanosine by GSDA in A. thaliana, excluding other possible sources like the dephosphorylation of xanthosine monophosphate. Like the nucleoside hydrolases NUCLEOSIDE HYDROLASE1 (NSH1) and NSH2, GSDA is located in the cytosol, indicating that GMP catabolism to xanthine proceeds in a mostly cytosolic pathway via guanosine and xanthosine. Possible implications for the biosynthetic route of purine alkaloids (caffeine and theobromine) and ureides in other plants are discussed.
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PMID:Plant purine nucleoside catabolism employs a guanosine deaminase required for the generation of xanthosine in Arabidopsis. 2413 Jan 59