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

The mechanism of action of the adenosine analog, neplanocin A (NPC), was investigated in human colon carcinoma cell line HT-29. Cell viability was reduced to 38 and 17% of control by 24-h exposure to 10(-5) and 10(-4) M NPC, respectively. Cytocidal activity was not affected by inhibition of adenosine deaminase with 2'-deoxycoformycin. Concomitant with decreased cell viability was the reduced incorporation of [14C]dThd and [3H]Leu, and to a lesser extent [3H]Urd, into acid-precipitable material. Labeling of rRNA and tRNA during drug treatment for 24 h with [methyl-3H]Met and [14C]Urd revealed that NPC primarily inhibited RNA methylation, and to a lesser extent, RNA synthesis. RNase T2 digests of total RNA indicated that base and 2'-O-methylation were inhibited to approximately the same degree. Metabolites of NPC were measured by reverse-phase high-performance liquid chromatography and it was found that the major drug metabolite was the drug analog of S-adenosylmethionine with little formation of the respective, S-adenosylhomocysteine metabolite. NPC was utilized to a very small degree for RNA synthesis where only 2 and 30 pmol of NPC/A260 were incorporated into rRNA and tRNA after 24-h exposure to 10(-5) and 10(-4) M NPC, respectively. These results indicate that NPC is metabolized to a metabolite of S-adenosylmethionine which is a poor methyl donor for RNA methyltransferases, and that the accompanying decrease in RNA methylation and protein synthesis appears to be related to its cytocidal activity.
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PMID:Neplanocin A. A cyclopentenyl analog of adenosine with specificity for inhibiting RNA methylation. 633 23

A patient with refractory T-cell acute lymphoblastic leukemia was treated with eight courses of the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), over a 5-month period. After developing resistance to dCF, he responded to treatment with the combination of dCF and 9-beta-D-arabinofuranosyladenine (ara-A). We monitored the levels in plasma and urine of adenosine, 2'-deoxyadenosine, and ara-A as well as the accumulation of their nucleotide derivatives in erythrocytes and circulating lymphoblasts. We also monitored the activities of adenosine deaminase and S-adenosylhomocysteine (AdoHcy) hydrolase and the concentrations of AdoHcy and S-adenosylmethionine in lymphoblasts. Production of 2'-deoxyadenosine was related to both the duration of dCF infusion and the magnitude of cytolysis that occurred during treatment: much more 2'-deoxyadenosine was produced by dCF infusion when disease was active than by the same infusion given during remission. Resistance to dCF was associated with a decrease of greater than 90% in the amount of deoxyadenosine 5'-triphosphate accumulated by circulating lymphoblasts. Infusion of dCF resulted in increases of up to 20-fold in the concentration of AdoHcy in circulating lymphoblasts, causing a decrease in the S-adenosylmethionine:AdoHcy ratio (the "methylation index") from a pretreatment value of greater than 40:1 to less than 4:1. This ratio decreased to 2.5:1 during combined treatment with dCF and ara-A, which caused nearly complete inactivation of lymphoblast AdoHcy hydrolase. Decline in the methylation index was accompanied by inhibition of the methylation of newly synthesized lymphoblast RNA. Impaired ability to catabolize AdoHcy may have contributed to the cytolytic responses to dCF and ara-A, as well as to hepatic and central nervous system toxicity associated with their combined use.
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PMID:S-adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2'-deoxycoformycin alone and in combination with 9-beta-D-arabinofuranosyladenine. 660 86

Mice were given constant infusions of the adenosine deaminase inhibitor, 2'-deoxycoformycin, by i.p. implantation of microosmotic pumps, delivering the compound at a rate of 0.16 mg hr-1 kg-1. In accordance with published data, we observed that adenosine deaminase in most tissues was nearly completely inhibited. In addition, the S-adenosylhomocysteine hydrolase activity decreased slowly and showed a half-life in liver of about 4 hr. The rate and extent of the inactivation were highest in spleen. The amounts of adenosine, 2'-deoxyadenosine, S-adenosylhomocysteine, and S-adenosylmethionine were determined in treated animals and control animals. The tissue levels of adenosine and, to a lesser degree, S-adenosylhomocysteine and S-adenosylmethionine were critically dependent on the procedure used for processing the tissues. Lowest concentrations were observed when the organs were frozen in situ by liquid nitrogen. Treatment with 2'-deoxycoformycin induced no or a moderate increase in tissue content of adenosine and S-adenosylhomocysteine, whereas the amount of 2'-deoxyadenosine increased markedly, especially in spleen and thymus. 2'-Deoxycoformycin treatment caused an increase in adenosine and 2'-deoxyadenosine, but not S-adenosylhomocysteine, in serum of mice.
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PMID:Effect of 2'-deoxycoformycin infusion on S-adenosylhomocysteine hydrolase and the amount of S-adenosylhomocysteine and related compounds in tissues of mice. 660 64

Selective failure of lymphoid development occurs in genetic deficiency of adenosine deaminase (ADA). We examined the in vivo effects of a potent inhibitor of ADA, 2'-deoxycoformycin, which was used to treat a patient with refractory acute leukemia. Unexpectedly, within 7 days of starting treatment, the leukemic phenotype underwent complete conversion from T lymphoblastic to promyelocytic, with kinetics that suggested a precursor-product relationship between the two cell populations. Pretreatment T lymphoblasts and posttreatment promyelocytes had the same abnormal karyotype. Upon culture in vitro, the former transformed spontaneously over several weeks into mature myeloid cells. We conclude that the leukemia arose from a multipotent stem cell capable of both lymphoid and myeloid differentiation. Effects of ADA inhibition on leukemia cells during treatment included expansion of the deoxyadenosine nucleotide pool and accumulation of S-adenosylhomocysteine, a potent inhibitor of S-adenosylmethionine-dependent methylation. The influence of these changes on the leukemic phenotype is discussed in terms of (i) selective cytotoxicity to T lymphoblasts, which accumulated deoxyadenosine nucleotides more efficiently than did the patient's promyelocytes during in vitro incubation with deoxycoformycin plus deoxyadenosine, and (ii) induction of an altered program of differentiation.
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PMID:Conversion of a stem cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2'-deoxycoformycin. 660 71

Alteration of membrane fluidity during enzymatic methylation of membrane phosphatidyl-ethanolamine (PE) and neutralization of negative charges of membrane proteins due to methylation of carboxyl groups may contribute to sperm motility. Therefore, enzymatic phospholipid methylation and carboxymethylation, and the consequences of their inhibition on motility, were studied using human sperm. These studies gave the following results. Human sperm homoganates contained two phospholipid N-methyltransferases (PMT) which converted PE to phosphatidylcholine (PC) in the presence of S-adenosylmethionine (SAM). The first PMT converted PE to phosphatidyl-N-methylethanolamine (PME). In had a Km of 4.0 microM and a pH optimum of 8.0. The second PMT converted PME to phosphatidyl-N,N-dimethylethanolamine and PC. It had a Km of 71 microM and a pH optimum of 10.0. Spermatozoa also contained protein carboxymethylase (PCM) and methyl aceptor protein (MAP). The intracellular levels of S-adenosylhomocysteine (SAH), an inhibitor of SAM-mediated methylations, were increased by adding adenosine (100 microM), L-homocysteine thiolactone (L-HCT, 10 microM), and erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA, 10 microM), an inhibitor of adenosine deaminase, to human sperm ejaculates that had been diluted with sodium phosphate buffer at pH 7.4 and 25 degrees. The motility index of each sperm suspension was determined every hour for 4 hr. In the presence of the mixture of adenosine, L-HCT and EHNA, the motility index was depressed by 57%. Under similar conditions, phospholipid methylation was depressed by 48%. Similar experiments were also conducted in the presence of 3-deazaadenosine (Deaza, 80 microM), a selective inhibitor of SAH hydrolase. In the presence of adenosine and L-HCT, Deaza depressed the motility index by 60% and phospholipid methylation by 86%. The potencies of SAH in the inhibition of phospholipid methylation and protein carboxymethylation in sperm homogenates had the following order: PMT I greater than PCM greater than PMT II. These observations indicate that the PMT system and/or the PCM-MAP system play a significant role in the regulation of human sperm motility.
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PMID:Depression of human sperm motility by inhibition of enzymatic methylation. 686 Mar 62

The inactivation of S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1) in isolated rat hepatocytes by 9-beta-D-arabinofuranosyladenine (ara-A) was associated with tight binding of ara-A to the enzyme and showed an initial phase obeying first-order kinetics characterized by Ki (concentration of half-maximal rate of inactivation) of 12 microM for ara-A and a maximal rate of inactivation of 0.7 min-1. Two to 3% of the enzyme in rat hepatocytes was not available for inactivation. Similar results were obtained with some cultured cells, including mouse plasmacytoma cells (MPC-11), mouse fibroblasts (L-929), and human chronic myelogenic leukemia cells (K-562). In a cellular medium devoid of adenosine deaminase, inhibitors of this enzyme did not affect the inactivation process in rat hepatocytes and only slightly enhanced this process in the cultured cells (at low concentrations of ara-A). Inactivation of AdoHcy hydrolase in rat hepatocytes was associated with a massive build-up of AdoHcy (from 75 to 5200 pmol/10(6) cells after 3 hr of incubation) and a moderate increase in cellular S-adenosylmethionine. The accumulation of AdoHcy in the cultured cells exposed to ara-A was less pronounced and no increase in cellular S-adenosylmethionine was observed. There was a quantitatively important export of AdoHcy from the rat hepatocytes and the cultured cells into the extracellular medium, whereas no leakage of S-adenosylmethionine was detected. The inactivation of AdoHcy hydrolase by ara-A in rat hepatocytes was inhibited in the presence of adenosine or homocysteine in the cellular medium. This effect of homocysteine correlated with increased cellular level of AdoHcy induced by this agent but was also associated with reduction in cellular uptake of ara-A.
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PMID:Inactivation of S-adenosylhomocysteine hydrolase by 9-beta-D-arabinofuranosyladenine in intact cells. 705 72

The effects of arabinosyladenine, an antiviral and antitumor agent used therapeutically, on the metabolism of adenosylhomocysteine were studied in rat liver. A rapid but transient accumulation of adenosylhomocysteine and adenosylmethionine was observed after a single i.p. injection of the adenosine analogue. The extent and duration of the accumulation was increased by multiple doses of arabinosyladenine and by giving the nucleoside in combination with erythro-9-(2-hydroxy-3-nonyl)-adenine, a potent inhibitor of adenosine deaminase, which significantly increased its concentration in the liver. Hepatic adenosine concentration was also enhanced by the treatment but less dramatically. Accumulation of adenosylhomocysteine resulted from a rapid but reversible in vivo inactivation of adenosylhomocysteine hydrolase. Approximately 10% of the hydrolase activity persisted despite the inactivation treatment. After four injections with arabinosyladenine (200 mumol/kg body wt.) in combination with the adenosine deaminase inhibitor (50 mumol/kg body wt.), given at 1 h intervals, the concentration of adenosylhomocysteine was increased 30-fold and that of adenosylmethionine 5-fold as compared with the control values. The concentrations remained at that level for at least 2 h and then gradually declined to the control level. The activity of adenosylhomocysteine hydrolase stayed at the 10% level for several hours but returned to the control level within 24 h of the last injection. The results show that prolonged treatment with arabinosyladenine, especially in combination with an adenosine deaminase inhibitor, causes marked but reversible changes in methionine metabolism, resulting in the hepatic accumulation of adenosylhomocysteine to a level that is likely to interfere with biological methylation reactions. This offers an additional mechanism by which arabinosyladenine may evoke toxic effects in animal cells.
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PMID:Effect of 9-beta-D-arabinofuranosyladenine and erythro-9-(2-hydroxy-3-nonyl) adenine on the metabolism of S-adenosylhomocysteine, S-adenosylmethionine, and adenosine in rat liver. 715 18

The adenosine analog xylosyladenine is a potent inducer of hemoglobin synthesis in Friend virus-infected murine erythroleukemia (MEL) cells. In cultures treated with 0.1 microM xylosyladenine and an inhibitor of adenosine deaminase, 80% of the cells accumulated hemoglobin. Under these conditions, cell growth was inhibited by 50%. No effect was observed in the absence of adenosine deaminase inhibition. An adenosine kinase-deficient MEL subline was isolated and was found to be resistant to induction by xylosyladenine. Treated cells accumulated substantial amounts of the xylofuranosyl analogs of ATP, S-adenosylmethionine, and S-adenosylhomocysteine, indicating that metabolites of xylosyladenine participate in S-adenosylmethionine-mediated transmethylation reactions. Measurements of in vivo nucleic acid methylation showed that xylosyladenine causes a marked inhibition of 2'-O-methyluridine, 2'-O-methylcytidine, 5-methyluridine, and 5-methylcytidine formation in the RNA of treated cells. DNA methylation was not inhibited. These data suggest that the xylofuranosyl analogs of S-adenosylmethionine and/or S-adenosylhomocysteine can inhibit intracellular RNA methylation in MEL cells while having little or no such effect on DNA methylation.
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PMID:Induction of hemoglobin synthesis by xylosyladenine in murine erythroleukemia cells. Metabolism of xylosyladenine and effects on transmethylation. 730 32

Previous work has shown that extracellular adenosine inhibits the incorporation of radiolabelled leucine into proteins in isolated rat hepatocytes [Tinton, Lefebvre, Cousin and Buc Calderon (1993) Biochim. Biophys. Acta 1176, 1-6]. In this study, we investigated whether its metabolism into adenine nucleotides, inosine or S-adenosylhomocysteine (AdoHcy) is required to induce such an impairment. Incubation of isolated hepatocytes in the presence of adenosine at 0.5 or 1 mM reduces the synthesis of proteins by about 45% after 120 min of incubation. Such an inhibition occurred without cell lysis and was not modified by adding the adenosine kinase inhibitor 5-iodotubercidin (15 microM) or the adenosine deaminase inhibitor coformycin (0.1 microM). It is therefore unlikely that the anabolic and catabolic pathways of adenosine are involved in the inhibition of protein synthesis. Adenosine (1 mM) increased the level of AdoHcy and S-adenosylmethionine by 20- and 5-fold respectively after 60 min of incubation and reduced the methylation index. These events as well as the inhibition of protein synthesis were strongly enhanced in the presence of L-homocysteine (2 mM). It is therefore concluded that the metabolism of adenosine into AdoHcy, which is known to be a potent inhibitor of cellular methylation reactions, may play an important role in the control of translation.
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PMID:Homocysteine enhances the inhibitory effect of extracellular adenosine on the synthesis of proteins in isolated rat hepatocytes. 757 24

We report the generation and characterization of mice lacking adenosine deaminase (ADA). In humans, absence of ADA causes severe combined immunodeficiency. In contrast, ADA-deficient mice die perinatally with marked liver-cell degeneration, but lack abnormalities in the thymus. The ADA substrates, adenosine and deoxyadenosine, are increased in ADA-deficient mice. Adenine deoxyribonucleotides are only modestly elevated, whereas S-adenosylhomocysteine hydrolase activity is reduced more than 85%. Consequently, the ratio of S-adenosylhomocysteine (AdoMet) to S-adenosyl homocysteine (AdoHcy) is reduced threefold in liver. We conclude that ADA plays a more critical role in murine than human fetal development. The murine liver pathology may be due to AdoHcy-mediated inhibition of AdoMet-dependent transmethylation reactions.
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PMID:Adenosine-deaminase-deficient mice die perinatally and exhibit liver-cell degeneration, atelectasis and small intestinal cell death. 767 Apr 65


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