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

---

Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have demonstrated that high concentrations of adenosine interact with both a cell surface receptor and with an intracellular site to evoke relaxation of the guinea-pig aorta. The intracellular action of adenosine was investigated in the present study. The purine sensitive 'P-site' did not appear to be involved since other P-site agonists did not consistently evoke relaxation. A major interaction with intracellular S-adenosylhomocysteine hydrolase also appeared unlikely since 1-homocysteine had only minor effects on adenosine-evoked responses. Inhibition of adenosine deaminase attenuated responses evoked by high concentrations of adenosine. The deaminated metabolite of adenosine, inosine, also evoked aortic relaxation. These responses were mediated solely via an intracellular site since they were blocked by an inhibitor of nucleoside-facilitated diffusion but were unaffected by an adenosine receptor antagonist. These results indicate that a major part of the intracellular effect of adenosine is mediated by its deaminated metabolite inosine.
...
PMID:Evidence that the intracellular effects of adenosine in the guinea-pig aorta are mediated by inosine. 395 72

S-Adenosylhomocysteine (SAH) hydrolase was purified 25-fold from bakers' yeast by chemical methods and column chromatography. The purified enzyme could readily synthesize SAH from adenosine and homocysteine, but could hydrolyze only negligible amounts of SAH. The purified enzyme showed no activity towards S-adenosylmethionine, methylthioadenosine, or adenosine. Several nucleotides, sulfhydryl compounds, and ribose could not replace adenosine or homocysteine in the reaction mixture. SAH could be hydrolyzed by SAH hydrolase if commercial adenosine deaminase was included in the reaction mixture. Under these conditions l-homocysteine could act as a product inhibitor. A number of compounds structurally similar to adenosine and homocysteine were found to inhibit synthesis of SAH from adenosine and homocysteine. The strongest inhibitors were adenine, adenosine-3'-monophosphate, adenosine-2'-monophosphate, adenosine diphosphate, adenosine triphosphate, and adenosine-5'-monophosphate. The biosynthetic and hydrolytic activity of SAH hydrolase in yeast cell ghosts was similar to the activity of the enzyme in vitro.
...
PMID:Partial purification and characterization of S-adenosylhomocysteine hydrolase isolated from Saccharomyces cerevisiae. 456 9

Low concentrations (10-50 microM) of adenosine (EC50 = 17 microM) or chloroadenosine (EC50 = 23 microM) prevent the division of PC12 cells. This inhibition is not mimicked by guanosine, inosine, 3',5' dideoxyadenosine, phenylisopropyladenosine, or adenylylimidodiphosphate. The growth inhibition is not relieved by addition of uridine or deoxycytidine, nor is it potentiated by homocysteine thiolactone. Inhibition of adenosine uptake does not inhibit adenosine-dependent growth arrest. PC12 variants that are deficient in adenosine kinase are as sensitive as wild-type cells to the growth-inhibitory effects of adenosine. These experiments suggest that adenosine prevents cell division at an adenosine receptor rather than acting after being metabolically altered. The adenosine receptor that inhibits cell division does not appear to be the adenosine receptor that stimulates adenylate cyclase for these reasons: (1) phenylisopropyladenosine, which is a potent agonist of this receptor, does not inhibit cell division; (2) 3',5' dideoxyadenosine does not antagonize the effect of adenosine on cell division; and (3) theophylline does not affect growth inhibition by adenosine. Thus, these experiments suggest the existence of a second adenosine receptor that can inhibit cell division. Adenosine also promotes the morphological differentiation of PC12 cells. In the presence of the adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenosine (EHNA), adenosine causes the formation of short neurites (one-half to one and one-half cell diameters in length). Adenosine also increases the rate of neurite formation of both long and short neurites in response to NGF.
...
PMID:Adenosine inhibits cell division and promotes neurite extension in PC12 cells. 608 75

Inhibitors of adenosylmethionine (AdoMet)-dependent methyltransferases reduce histamine release from enzymatically dispersed human lung mast cells activated with either anti-human IgE or calcium ionophore A23187. The IC25 values for adenosine and 3-deazaadenosine (DZA) inhibiting anti-IgE-induced histamine release were 395 microM and 301 microM respectively. The addition of homocysteine thiolactone (Hcy) potentiated the effects of adenosine and DZA, reducing their IC25 values to 32 microM and 10.5 microM respectively. The adenosine deaminase (adenosine aminohydrolase EC 3.5.4.4) inhibitors erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) inhibited anti-IgE-induced histamine release with an IC50 of 162 microM. This inhibition was not potentiated by Hcy. The combination of DZA and Hcy effectively inhibited histamine release induced by concentrations of A23187 which released a similar amount of histamine to anti-IgE. However the combination was 17 times less potent against A23187-compared with anti-IgE-induced release. These observations suggest that AdoMet-dependent methyltransferases play an important role in IgE-dependent histamine release from human lung mast cells but their role in A23187-induced release is less clear.
...
PMID:The effect of methyltransferase inhibitors on histamine release from human dispersed lung mast cells activated with anti-human IgE and calcium ionophore A23187. 620 73

Previous work in our laboratory led us to postulate that N2a cells release adenosine into growth medium, where it acts at the extracellular adenosine receptors to modulate the sensitivity of the cells to the cyclic AMP-elevating effect of adenosine [Green, RD, J Pharmacol Exp Ther 201:610, 1977]. We have now devised a high-performance liquid chromatographic (HPLC) procedure capable of quantitating the concentrations of adenosine in cells and tissue culture media. Growth media of N2a cells and a variant of N2a cells deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRT-) contain 10-20 nM adenosine, while that of a variant deficient in adenosine kinase (AK-) is elevated severalfold. It appears that the concentration of adenosine in growth media is determined by both the rate at which it is released by cells into the medium and the rate at which it is metabolized by adenosine deaminase present in the serum in the growth medium. Both N2a and AK- cells release considerable amounts of adenosine into serum-free medium (SFM) over a short period. Adenosine release is greater from AK- cells and is accelerated by erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), a potent adenosine deaminase inhibitor. This accelerated release is retarded by dipyridamole and homocysteine. Surprisingly, dipyridamole and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20 1724), a potent phosphodiesterase inhibitor, stimulate basal adenosine release from N2a but not from AK- cells. It remains to be determined if this is due to an effect of these compounds on adenosine kinase. These results give further support for the hypothesis that adenosine in growth medium modulates the sensitivity of the cells to the cyclic AMP-elevating affect of adenosine, and furthermore they suggest that adenosine in growth media may tonically stimulate adenylate cyclase and affect processes controlled by the cyclic AMP:cyclic AMP-dependent protein kinase system.
...
PMID:Release of adenosine by C1300 neuroblastoma cells in tissue culture. 626 30

9-Deazaadenosine (c9Ado), a novel C-nucleoside, has been found to inhibit lymphocyte-mediated cytolysis (LMC) in a time-dependent manner. c9Ado inhibited LMC by 50% at concentrations of 10 and 0.07 microM after drug-pretreatment periods of 3 and 22 hr, respectively, although a 1-hr pretreatment of cytolytic lymphocytes with 100 microM c9Ado had no effect upon this lymphocyte function. c9Ado was metabolized rapidly and extensively to 9-deazaadenosine 5'-triphosphate (c9ATP) both by mouse cytolytic lymphocytes and by human erythrocytes. Adenosine kinase purified from rabbit liver phosphorylated c9Ado with a Km of 200 microM and a Vmax of 8% that for adenosine. The metabolic buildup of c9ATP in lymphocytes was accompanied by a large, time-dependent decrease in cellular ATP and by smaller percentage decreases in CTP, UTP and GTP. Among other biochemical effects examined, c9Ado was found to cause a decrease in lymphocyte cAMP content and appeared to be neither an inhibitor nor a substrate for S-adenosylhomocysteine hydrolase. Consistent with this latter result, L-homocysteine thiolactone had no effect on the inhibition of LMC by c9Ado. Neither the inhibition of LMC by c9Ado nor the metabolic formation of c9ATP in lymphocytes was affected by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), indicating that c9Ado is not a substrate for adenosine deaminase. 5-Iodotubercidin, a non-competitive inhibitor (Kis = 9 nM, Ku = 20 nM) of adenosine kinase, prevented the above effects of c9Ado on lymphocyte function, c9ATP formation, and ATP levels. Either complete preservation (with coformycin) or partial replenishment (with adenosine plus EHNA) of ATP levels in c9Ado-treated lymphocytes resulted in partial restoration of cytolytic function to cells containing large amounts of c9ATP. These results suggest that c9Ado is inhibitory to LMC both because it causes a decrease in the absolute concentration of ATP within the cytolytic lymphocytes and because it permits the establishment within these cells of an unfavorable c9ATP:ATP ratio which impedes the utilization of ATP in a reaction essential to the execution of this lymphocyte function.
...
PMID:Inhibition of lymphocyte function by 9-deazaadenosine. 630 53

Purine nucleosides, which accumulate in adenosine deaminase and purine nucleoside phosphorylase deficiency, are toxic to lymphoid cells. Since adenine nucleosides inhibit S-adenosylhomocysteine hydrolase, they could potentially decrease intracellular methionine synthesis. To test this hypothesis, we measured methionine synthesis by the use of [14C]formate as a radioactive precursor in cultured human T and B lymphoblasts treated with varying concentrations of purine nucleosides; 2'-deoxycoformycin and 8-aminoguanosine were added to inhibit adenosine deaminase and purine nucleoside phosphorylase, respectively. In the T lymphoblasts methionine synthesis was inhibited approximately 50% by 10 microM of 2'-deoxyadenosine, adenine arabinoside, or 2'-deoxyguanosine. By contrast, in the B lymphoblasts methionine synthesis was considerably less affected by these nucleosides, with 50% inhibition occurring at 100 microM of 2'-deoxyadenosine and adenine arabinoside; 100 microM of 2'-deoxyguanosine yielded less than 10% inhibition. Adenosine and guanosine were considerably less potent inhibitors of methionine synthesis in both the T and B lymphoblasts. An adenosine deaminase-deficient and a purine nucleoside phosphorylase-deficient cell line, both of B cell origin, exhibited sensitivities to the nucleosides similar to those of the normal B cell lines. In both the T and B cell lines homocysteine reversed the methionine synthesis inhibition induced by the adenine nucleosides and guanosine and largely reversed that induced by 2'-deoxyguanosine. Methionine synthesis from homocysteine generates free tetrahydrofolate from 5-methyltetrahydrofolate, the main intracellular storage form of folate. We conclude that purine nucleoside toxicity may be partly mediated through (a) decreased intracellular methionine synthesis, and (b) altered folate metabolism.
...
PMID:Decreased methionine synthesis in purine nucleoside-treated T and B lymphoblasts and reversal by homocysteine. 633 27

Serial-flow cytometric analysis of DNA content of T lymphoblasts (MOLT-4) and B lymphoblasts (MGL-8) was performed to correlate the cytotoxic properties of adenosine deaminase inhibition with alterations of DNA synthesis and disruptions of the cell cycle. The addition of deoxyadenosine up to 50 mumol/L potently decreased the growth of T lymphoblasts, and these changes were enhanced with the addition of 100 mumol/L homocysteine thiolactone. These conditions caused a virtual absence of cells from S and G2M phases after 24 hours. The DNA distribution was similar in cells cultured for 24 hours in 50 mumol/L deoxyguanosine or 2.5 mumol/L hydroxyurea. These observations suggested accumulation of cells in the G1 phase. T lymphoblasts cultured with up to 50 mumol/L adenosine had a substantial decrease in growth, which was not modified by the addition of homocysteine thiolactone. Cell cycle distributions of T lymphoblasts cultured for 24 to 48 hours under these conditions showed mild decreases in the G2M population. The addition of adenosine up to 50 mumol/L decreased the growth of B lymphoblasts, and these changes were enhanced by the addition of 100 mumol/L homocysteine thiolactone. These conditions induced mild decreases in the S-phase population in B lymphoblasts. The addition of deoxyadenosine, even with homocysteine thiolactone, did not modify growth in B lymphoblasts and the cell-cycle distributions were indistinguishable from distributions of control populations after 24 and 48 hours. The observations provide independent support for a reduction of DNA synthesis associated with cytotoxicity during adenosine-deaminase inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Altered cell cycle distributions of cultured human lymphoblasts during cytotoxicity related to adenosine deaminase inhibition. 660 57

An inherited deficiency of adenosine deaminase (Ado deaminase; adenosine aminohydrolase, EC 3.5.4.4) causes severe combined immunodeficiency disease in humans. A similar deficiency in purine nucleoside phosphorylase (Puo phosphorylase; purine-nucleoside:orthophosphate ribosyltransferase, EC 2.4.2.1) engenders a selective cellular immune deficit. To elucidate the possible metabolic basis for the contrasting immunologic phenotypes, we compared the toxicity toward mature resting human lymphocytes of the Ado deaminase substrates deoxyadenosine and adenosine and the Puo phosphorylase substrate deoxyguanosine. When Ado deaminase was inhibited, micromolar concentrations of deoxyadenosine progressively killed nondividing helper and suppressor-cytotoxic T cells, but not B cells. The toxicity required phosphorylation, with subsequent dATP formation. The deoxyadenosine analogs 2-chlorodeoxyadenosine, 2-fluorodeoxyadenosine, and adenine arabinonucleoside also killed resting T cells. Cell death was unrelated to inhibition of adenosylhomocysteinase (EC 3.3.1.1) but was preceded by a gradual decline in ATP levels. As much as 1 mM deoxyguanosine did not impair resting lymphocyte viability, despite the synthesis of dGTP. The combination of 200 microM adenosine plus 500 microM homocysteine thiolactone killed dividing lymphocytes but had no discernible toxic effect toward resting T cells, which accumulated adenosylhomocysteine over a 4-hr period but thereafter excreted the nucleoside into the culture medium. The different clinical syndromes associated with genetic deficiencies of Ado deaminase and Puo phosphorylase may be explained by the ability of dATP to kill mature resting T lymphocytes by depleting ATP levels.
...
PMID:Possible metabolic basis for the different immunodeficient states associated with genetic deficiencies of adenosine deaminase and purine nucleoside phosphorylase. 680 16

Binding of adenosine to S-adenosyl-L-homocysteine (AdoHcy) hydrolase (EC 3.3.1.1.) and partial conversion of bound adenosine to a substance liberating adenine has been demonstrated under conditions of enzymatic synthesis and hydrolysis of ADoHcy (Ueland, P. M., and Helland, S. (1980) J. Biol. Chem. 255, 7722-7727). Gel filtration of cytosol from isolated rat hepatocytes treated with [14C]adenosine on a high performance liquid chromatography protein column showed that labeled adenine/adenosine eluted as a peak which co-chromatographed exactly with AdoHcy hydrolase. Formation of this peak was inhibited by exposure of the cells to compounds (ara-A, 3-deazaadenosine, and homocysteine) interacting with the catalytic site of the enzyme. Furthermore, the adenine/adenosine-protein complex and AdoHcy hydrolase focused at exactly the same pH (pI = 5.76) in a granulated bed. On this basis it was concluded that labeled adenosine formed a stable complex with AdoHcy hydrolase. A substantial portion (about 50%) of endogenous adenosine in rat hepatocytes seemed to be associated with AdoHcy hydrolase, and this portion equaled the amount of cellular adenosine which was not readily mobilized by high level of extracellular adenosine deaminase. Exposure of the hepatocytes to compounds which block the formation of the adenosine-AdoHcy hydrolase complex (ara-A, 3-deazaadenosine, and homocysteine) for 1 to 2.5 h only slightly reduced the amount of adenosine associated with the enzyme, indicating a slow turnover of the complex under the conditions of the experiment. It was concluded that adenosine is sequestered in rat hepatocytes through the interaction with AdoHcy hydrolase. The physiological implication of this process may be related to the metabolism and biological effects of adenosine as well as the regulation of AdoHcy hydrolase activity.
...
PMID:Binding of adenosine to intracellular S-adenosylhomocysteine hydrolase in isolated rat hepatocytes. 682 9


<< Previous 1 2 3 4 5 Next >>

---