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)

Epidermal growth factor (EGF) and insulin induced similar effects in isolated rat adipocytes. To determine whether EGF and insulin produced similar effects through the same mechanisms, we focused on lipolysis. Insulin inhibited the lipolysis stimulated by isoproterenol, glucagon (either alone or in combination with adenosine deaminase), adenosine deaminase itself, or forskolin. In contrast, EGF did not inhibit the lipolysis stimulated by forskolin or by hormones when the cells were also incubated with adenosine deaminase. The effect of insulin, but not that of EGF, on isoproterenol-stimulated lipolysis disappeared when adipocytes were incubated with 1 microM wortmannin. These results indicate that EGF and insulin affected lipolysis through different mechanisms. We observed that EGF, but not insulin, increased cytosolic Ca2+. The effect of EGF, but not that of insulin, disappeared when the cells were incubated in a Ca2+-free medium. We suggest that EGF, but not insulin, mediate its antilipolytic effect through a Ca2+-dependent mechanism which, however, do not involve Ca2+-activated protein kinase C isoforms. This is based on the following: 1) phorbol 12-myristate 13-acetate affected lipolysis in an opposite way to that of EGF; and 2) the protein kinase C inhibitor bisindolylmaleimide GF 109203X did not affect the antilipolytic action of EGF. Our results indicate that the antilipolytic effect of EGF resembles more that of vasopressin than that of insulin.
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PMID:The antilipolytic effects of insulin and epidermal growth factor in rat adipocytes are mediated by different mechanisms. 882 75

In 33 children, 23 with acute lymphoblastic leukemia (ALL) and 10 with solid tumors, the phenotype of the enzyme adenosine deaminase (ADA) was detected in the erythrocytes by electrophoresis in cellulose acetate. In all children the ADA enzyme activity was also determined in the plasma by spectrophotometry at the onset of the disease, during remission, at the end of the therapy, and during relapse. The phenotype in all children was ADA1-1. There was a difference in enzyme activity between the mean values of children with ALI and those with solid tumors. There were also differences among the subtypes of ALL and also among the stages of ALL and the stages of solid tumors. In 23 children with ALL the mean value (MV) and the corresponding standard error (SEM) of enzyme activity at the onset of the disease were MV +/- SEM = 60.2 +/- 6.2 IU/L. This was higher than that of the control group (control group: MV +/- SEM = 27.8 +/- 3.3 IU/L). During remission the enzyme activity was lower than that of the control group (MV +/- SEM = 19.6 +/- 1.7 IU/L); at the end of the therapy it was MV +/- SEM = 24.0 +/- 1.3 IU/L, which is close to that of the control group; and during relapse it was much higher compared with the control group (MV +/- SEM = 73.1 +/- 4.6 IU/L). These values are discussed in connection to the leukaemic subtypes. In 10 children with solid tumors the mean value of enzyme activity at the onset of the disease was MV +/- SEM = 48.8 +/- 2.4 IU/L. During therapy it was MV +/- SEM = 32.4 +/- 1.9 IU/L and at the end of therapy MV +/- SEM = 22.1 +/- 2.5 IU/L. The aim of this work is to study the qualitative isoenzyme abnormalities to better understand the biological nature of the malignancies, to distinguish main groups and subsets of ALL and solid tumors on an enzymatic basis, and to identify possible sensitive key enzymes as targets for chemotherapy.
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PMID:Prognostic significance of adenosine deaminase in children with malignancies. 883 33

The aim of the present study was to investigate the mechanisms regulating endothelin-1 (ET-1) secretion in rat thyroid FRTL-5 cells. ET-1 was found to be secreted after stimulation with adenosine and ATP. The release of ET-1 was sensitive to pertussis toxin, indicating a role of G-proteins in the stimulus-secretion coupling. The stimulation evoked by ATP or adenosine was inhibited by the P1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and in the presence of adenosine deaminase the adenosine- and ATP-mediated ET-1 secretion was abolished. These evidences suggest a role of a P1-adenosine receptor in the secretion of ET-1. Increasing cyclic AMP with forskolin decreased the adenosine-mediated secretion. In addition, the intracellular calcium chelator BAPTA or inhibition of calcium entry with Ni2+ prevented the response. Protein kinase C (PKC) is also partly involved in ET-1 secretion in FRTL-5 cells. Activation of PKC with the phorbol ester phorbol 12-myristate 13-acetate (PMA) stimulated the secretion of ET-1 in a time- and dose-dependent manner. Furthermore, downregulation of PKC decreased the secretion of ET-1 stimulated by adenosine. In conclusion, ET-1 secretion in FRTL-5 cells is stimulated via a pertussis toxin-sensitive P1-receptor pathway which is modulated by several signal transduction mechanisms including cAMP, Ca2+, and PKC.
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PMID:Purinergic agonists stimulate the secretion of endothelin-1 in rat thyroid FRTL-5 cells. 895 3

Adenosine has been shown to modulate cell proliferation in FRTL-5 thyroid cells, although the mechanisms by which this interaction occurs is still unclear. In the present study we investigated the effects of adenosine on the 3H-thymidine incorporation, cell cycle kinetics, and expression of the transcription factor c-Fos in cells stimulated via three different mitogenic pathways, i.e., by thyroid stimulating hormone (TSH) [adenosine 3',5'-cyclic monophosphate(cAMP)], insulin (tyrosine kinase), or phorbol 12-myristate 13-acetate (protein kinase C). Addition of adenosine to cells grown in medium containing hormones and serum did not inhibit the incorporation of 3H-thymidine. If adenosine was added to hormone-deprived cells together with any of the tested mitogens, the stimulation of the 3H-thymidine incorporation was inhibited in a dose-dependent manner. The inhibition was significantly lower when the cells were preincubated with TSH or insulin for 48 h. Flow cytometric studies showed that adenosine evoked an inhibition of the cells in the G0/G1 phase. Submaximal doses of adenosine (10 nM-10 microM) were able to induce c-Fos expression in FRTL-5 cells. However, the mitogen-induced expression of c-Fos was not reduced by maximal dose of adenosine (100 microM). The effect of adenosine on DNA synthesis was not dependent on pertussis toxin-sensitive G-proteins. In addition, adenosine A1- or A2- receptor antagonists did not block the effect of adenosine. The effect of adenosine was abolished by treatment of the cells with adenosine deaminase, suggesting that the observed effect was not mediated by a metabolite of adenosine. The results suggest that adenosine is an effective blocker of mitogen-evoked DNA synthesis of FRTL-5 cells, provided that adenosine is administered simultaneously with the mitogen.
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PMID:Adenosine inhibits DNA synthesis stimulated with TSH, insulin, and phorbol 12-myristate 13-acetate in rat thyroid FRTL-5 cells. 918 Sep 3

Twelve control (C) and 12 prenatally androgenized (PA) lactating (L) first-calf heifers and five (two C and three PA) similar, nonlactating (NL) heifers were used to assess the effects of PA and L on the metabolic activity of s.c. adipose tissue (AT). Heifers were fed an 85% concentrate diet, and their calves were weaned at 112 +/- 1 d of age. Adipose tissue was biopsied at approximately 77 d (period 1, during lactation for L heifers) and 126 d (period 2, after L heifers had calves weaned) postpartum. The NL heifers gained .22 kg/d faster (P = .20) and had greater fat deposition than L heifers during period 1. The PA heifers were fatter and gained 14.6% faster than C heifers during lactation. Epinephrine (E) and norepinephrine (NE) increased in vitro fatty acid (FA) release 25 (P < .01) and 15% (P < .06), respectively, above basal rates. Near-maximal release of FA, as estimated by stimulation with E plus theophylline plus adenosine deaminase (ETAD), was 73% (4,110 vs 2,379 +/- 161 nEq/[2 h.100 mg of tissue]; P < .01) above basal rates. Basal FA release was unaffected, but ETAD-stimulated rates were decreased (P < .04; 4,430 +/- 246 vs 3,789 +/- 209 nEq/[2 h.100 mg of tissue]) by PA. Stimulation of FA release by E (P = .22) or NE (P = .31) did not differ between C and PA. For NL heifers, PA decreased (P < .02) FA release, which corresponded with their greater fat deposition, but PA did not affect L heifers (PA x L interaction, P = .14). The content of NEFA in s.c. AT (pool size) was 34% greater (P < .01) during period 2 than during period 1. Pool size was not affected (P = .72) by NE but was increased by E (1,628 vs 1,777 +/- 92 nEq/100 mg of tissue; P < .05) and ETAD (1,628 vs 2,176 +/- 93 nEq/100 mg of tissue; P < .01). For L heifers, PA tended (P < .07) to increase incorporation of acetate into FA during period 1. Thus, PA resulted in subtle increases in lipogenesis and decreases in lipolysis during the first lactation-weaning cycle that were consistent with greater rates of gain and fat deposition.
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PMID:Effects of prenatal androgenization and lactation on adipose tissue metabolism in finishing single-calf heifers. 925 May 10

Synthesis of (R)-(-)- and (S)-(+)-synadenol (1a and 2a, 95-96% ee) is described. Racemic synadenol (1a + 2a) was deaminated with adenosine deaminase to give (R)-(-)-synadenol (1a) and (S)-(+)-hypoxanthine derivative 5. Acetylation of the latter compound gave acetate 6. Reaction with N, N-dimethylchloromethyleneammonium chloride led to 6-chloropurine derivative 7. Ammonolysis furnished (S)-(+)-synadenol (2a). Absolute configuration of 1a was established by two methods: (i) synthesis from (R)-methylenecyclopropanecarboxylic acid (8) and (ii) X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. Racemic methylenecyclopropanecarboxylic acid (10) was resolved by a modification of the described procedure. The R-enantiomer 8 was converted to ethyl ester 13 which was brominated to give vicinal dibromides 14. Reduction with diisobutylaluminum hydride then furnished alcohol 15 which was acetylated to the corresponding acetate 16. Alkylation-elimination procedure of adenine with 16 yielded acetates 17 and 18. Deprotection with ammonia afforded a mixture of Z- and E-isomers 1a and 19 of the R-configuration. Comparison with products 1a and 2a by chiral HPLC established the R-configuration of (-)-synadenol (1a). These results were confirmed by X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. The latter forms a pseudosymmetric dimer with adenine-adenine base pairing in the lattice with the nucleobase in an anti-like conformation. Enantiomers 1a and 2a exhibit varied enantioselectivity toward different viruses. Both enantiomers are equipotent against human cytomegalovirus (HCMV) and varicella zoster virus (VZV). The S-enantiomer 2a is somewhat more effective than R-enantiomer 1a in herpes simplex virus 1 and 2 (HSV-1 and HSV-2) assays. By contrast, enantioselectivity of antiviral effect is reversed in Epstein-Barr virus (EBV) and human immunodeficiency virus type 1 (HIV-1) assays where the R-enantiomer 1a is preferred. In these assays, the S-enantiomer 2a is less effective (EBV) or devoid of activity (HIV-1).
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PMID:(R)-(-)- and (S)-(+)-Synadenol: synthesis, absolute configuration, and enantioselectivity of antiviral effect. 985 93

1. We investigated the effects of pH elevation or depression on adenosine output from buffer-perfused rat gracilis muscle, and kinetic properties of adenosine-forming enzymes, 5'-nucleotidase (5'N) and non-specific phosphatase (PT), and adenosine-removing enzymes, adenosine kinase (AK) and adenosine deaminase (AD), in homogenates of muscle. 2. Depression of the perfusion buffer pH from 7.4 to 6.8, by addition of sodium acetate, reduced arterial perfusion pressure from 8.44 +/- 1.44 to 7.33 +/- 0.58 kPa, and increased adenosine output from 35 +/- 5 to 56 +/- 6 pmol min-1 (g wet wt muscle)-1 and AMP output from 1.8 +/- 0.3 to 9.1 +/- 3.9 pmol min-1 (g wet wt muscle)-1. 3. Elevation of the buffer pH to 7.8, by addition of ammonium chloride, reduced arterial perfusion pressure from 8.74 +/- 0.57 to 6.96 +/- 1.37 kPa, and increased adenosine output from 25 +/- 5 to 47 +/- 8 pmol min-1 (g wet wt muscle)-1 and AMP output from 3.7 +/- 1.1 to 24.6 +/- 6.8 pmol min-1 (g wet wt muscle)-1. 4. Activity of membrane-bound 5'N was an order of magnitude higher than that of either cytosolic 5'N or PT: pH depression reduced the K(m) of 5'N, which increased its capacity to form adenosine by 10-20% for every 0.5 unit decrease inpH within the physiological range. PT was only found in the membrane fraction: its contribution to extracellular adenosine formation increased from about 5% at pH 7.0 to about 15% at pH 8.0. 5. Cytosolic 5'N had a low activity, which was unaffected by pH; the rate of intracellular adenosine formation was an order of magnitude lower than the rate of adenosine removal by adenosine kinase or adenosine deaminase, which were both exclusively intracellular enzymes. 6. We conclude that (i) adenosine is formed in the extracellular compartment of rat skeletal muscle, principally by membrane-bound 5'N, where it is protected from enzymatic breakdown; (ii) adenosine is formed intracellularly at a very low rate, and is unlikely to leave the cell; (iii) enhanced adenosine formation at low pH is driven by an increased extracellular AMP concentration and an increased affinity of membrane-bound 5'N for AMP; (iv) enhanced adenosine formation at high pH is driven solely by the elevated extracellular AMP concentration, since the catalytic capacity of membrane 5'N is reduced at high pH.
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PMID:Evidence for control of adenosine metabolism in rat oxidative skeletal muscle by changes in pH. 1071 70

In this study, the phenotype and allele frequencies of five enzyme systems were determined in a total of 611 unrelated Turkish individuals and analyzed by using the exact and the chi 2 test. The following five red cell enzymes were identified by cellulose acetate electrophoresis: phosphoglucomutase (PGM), adenosine deaminase (ADA), phosphoglucose isomerase (PGI), adenylate kinase (AK), and 6-phosphogluconate dehydrogenase (6-PGD). The ADA, PGM and AK enzymes were found to be polymorphic in the Turkish population. The results of the statistical analysis showed, that the phenotype frequencies of the five enzyme under study are in Hardy-Weinberg equilibrium. Statistical analysis was performed in order to examine whether there are significant differences in the phenotype frequencies between the Turkish population and four American population groups. This analysis showed, that there are some statistically significant differences between the Turkish and the other groups. Moreover, the observed phenotype and allele frequencies were compared with those obtained in other population groups of Turkey.
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PMID:Population data of five genetic markers in the Turkish population: comparison with four American population groups. 1237 92

The inhibition of formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide anion (O2(.-)) generation by 2-benzyloxybenzaldehyde (CCY1a) was investigated in rat neutrophils, and the underlying mechanism of this inhibition was assessed. CCY1a concentration-dependently inhibited O2(.-) generation (IC(50)=18.5+/-4.3 microM). In cell-free systems, CCY1a failed to alter O2(.-) generation during dihydroxyfumaric acid autoxidation, in phorbol 12-myristate 13-acetate (PMA)-activated neutrophil particulate NADPH oxidase preparations, or during arachidonic acid-induced NADPH oxidase activation. CCY1a increased cellular cyclic AMP (cAMP) levels in a time- and concentration-dependent manner, and this cAMP-elevating effect was inhibited by the adenylyl cyclase inhibitor 9-(tetrahydro-2'-furyl)adenine (SQ22536), adenosine deaminase (ADA), and the adenosine receptor antagonist 8-(p-sulfophenyl)theophylline. In neutrophils, inhibition of O2(.-) generation by CCY1a was partially reversed by the protein kinase A inhibitor (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-l][1,6]benzodiazocine-10-carboxylic acid, hexyl ester (KT5720). CCY1a did not affect fMLP-induced p38 mitogen-activated protein kinase phosphorylation, but concentration-dependently attenuated the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt (IC(50) about 31.3 and 19.4 microM, respectively). The plateau phase, but not the initial spike, of fMLP-induced [Ca2+](i) changes was inhibited by CCY1a in a concentration-dependent manner. CCY1a inhibition of Ca2+ entry, ERK, and Akt phosphorylation was not prevented by SQ22536 or ADA. fMLP-induced phospholipase D (PLD) activation was inhibited by CCY1a (IC(50)=13.9+/-2.0 microM). ADA and KT5720 did not prevent the inhibition of PLD activation by CCY1a. Collectively, these results indicate that the inhibition by CCY1a of fMLP-induced O2(.-) generation in rat neutrophils can probably be attributed to the increase in cAMP levels, and to the blockade of Ca2+ entry, suppression of Akt, and PLD activation via cAMP-independent mechanisms.
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PMID:Investigation of the cellular mechanism of inhibition of formyl-methionyl-leucyl-phenylalanine-induced superoxide anion generation in rat neutrophils by 2-benzyloxybenzaldehyde. 1266 40

The second generation of methylenecyclopropane analogues of nucleosides 5a-5i and 6a-6i was synthesized and evaluated for antiviral activity. The 2,2-bis(hydroxymethyl)methylenecyclopropane (11) was converted to dibromo derivative 7 via acetate 12. Alkylation-elimination of adenine (16) with 7 afforded the Z/E mixture of acetates 17 + 18, which was deacetylated to give analogues 5a and 6a separated by chromatography. A similar reaction with 2-amino-6-chloropurine (19) afforded acetates 20 + 21 and, after deprotection and separation, isomers 5f and 6f. The latter served as starting materials for synthesis of analogues 5b, 5e, 5g-5i and 6b, 6e, 6g-6i. Alkylation-elimination of N(4)-acetylcytosine (22) with 7 afforded a mixture of isomers 5c + 6c which were separated via N(4)-benzoyl derivatives 23 and 24. Deprotection furnished analogues 5c and 6c. Alkylation of 2,4-bis(trimethylsilyloxy)-5-methylpyrimidine (25) with 7 led to bromo derivative 26. Elimination of HBr followed by deacetylation and separation gave thymine analogues 5d and 6d. The guanine Z-isomer 5b was the most effective against human and murine cytomegalovirus (HCMV and MCMV) with EC(50) = 0.27-0.49 microM and no cytotoxicity. The 6-methoxy analogue 5g was also active (EC(50) = 2.0-3.5 microM) whereas adenine Z-isomer 5a was less potent (EC(50) = 3.6-11.7 microM). Cytosine analogue 5c was moderately effective, but 2-amino-6-cyclopropylamino derivative 5e was inactive. All E-isomers were devoid of anti-CMV activity, and none of the analogues was significantly active against herpes simplex viruses (HSV-1 or HSV-2). The potency against Epstein-Barr virus (EBV) was assay-dependent. In Daudi cells, the E-isomers of 2-amino-6-cyclopropylamino- and 2,6-diaminopurine derivatives 6e and 6h were the most potent (EC(50) approximately 0.3 microM), whereas only the thymine Z-isomer 5d was active (EC(50) = 4.6 microM). Guanine Z-derivative 5b was the most effective compound in H-1 cells (EC(50) = 7 microM). In the Z-series, the 2-amino-6-methoxypurine analogue 5g was the most effective against varicella zoster virus (VZV, EC(50) = 3.3 microM) and 2,6-diaminopurine 5h against hepatitis B virus (HBV, EC(50) = 4 microM). Adenine analogues 5a and 6a were moderately active as substrates for adenosine deaminase.
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PMID:Synthesis and antiviral activity of (Z)- and (E)-2,2-[bis(hydroxymethyl)cyclopropylidene]methylpurines and -pyrimidines: second-generation methylenecyclopropane analogues of nucleosides. 1473 38


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