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)

Adenine nucleotide breakdown to nucleosides and purine bases was measured in cultures of human lymphoblastoid cells following: 1) the inhibition of oxidative phosphorylation in the absence of glucose or 2) the addition of 2-deoxyglucose. A mutant cell line, deficient in adenosine kinase, in the presence of an adenosine deaminase inhibitor was used to measure utilization of the two pathways of AMP catabolism involving initial action of either purine 5'-nucleotidase or AMP deaminase. In such a system the appearance of adenosine induced by the oxidative phosphorylation inhibitor, rotenone, implies that approximately 70% of AMP breakdown occurs via dephosphorylation. By the same method, deamination accounts for 82% of AMP breakdown when 2-deoxyglucose is added. The occurrence of AMP dephosphorylation is not correlated with elevated concentrations of substrate or with decreased concentrations of the inhibitors of 5'-nucleotidase, ATP and ADP. Dephosphorylation occurs if, and only if, the adenylate energy charge decreases to about 0.6 in these experiments. In cultures deprived of glucose and oxygen, adenine nucleotide degradation via dephosphorylation results in recovery of normal energy charge values.
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PMID:Adenine nucleotide degradation during energy depletion in human lymphoblasts. Adenosine accumulation and adenylate energy charge correlation. 47 72

A case of red cell adenosine deaminase (ADA) overproduction associated with hereditary hemolytic anemia is reported here. This appears to be the second report. Proband is a 38-year-old Japanese male who had hemoglobin, 15.8 g/100 ml; reticulocyte count, 4.5%; serum indirect bilirubin, 4.9 mg/100 ml; 51Cr-labeled red cell half-life, 12 days; red cells showed moderate stomatocytosis. His red cell ADA activity showed 40-fold increase while that of the mother showed 4-fold increase. The mother was hematologically normal. The father had a normal enzyme activity. The proband and the mother showed slightly high serum uric acid levels. The proband's red cell showed: ATP, 628 nmoles/ml (normal, 1,010--1,550); adenine nucleotide pool, 46% of the normal mean; 2,3-diphosphoglycerate content, 3,782 nmoles/ml (normal 4,170--5,300); increased oxygen affinity of hemoglobin, P50 of intact erythrocytes being 21.8 mmHg (normal, 24.1--26.1). Red cell glycolytic intermediates in the proband were low in general, and the rate of lactate production was low. Kinetic studies using crude hemolysate revealed a normal Km for adenosine, normal electrophoretic mobility but slightly abnormal pH curve and slightly low utilization of 2-deoxyadenosine. The ADA activity of lymphocytes was nearly normal.
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PMID:A case of red-cell adenosine deaminase overproduction associated with hereditary hemolytic anemia found in Japan. 73 30

Intact beating fetal mouse hearts in organ culture were deprived of oxygen and glucose for up to 4 h, resulting in loss of beating, an 80% fall in ATP, reduction of energy charge from 0.85 to 0.48, and doubling of total nucleoside concentration. Radiolabeled adenine nucleotides were degraded to hypoxanthine and inosine, which were lost from the hearts into the medium during the deprivation period. Adenosine and adenine also appeared in the medium when adenosine deaminase was inhibited. After 24 h of O2 and glucose resupply, ATP returned to 60% of control, and energy charge rose to 0.76. Labeled nucleosides and bases remaining in the heart or exogenous labeled adenine were utilized to resynthesize ATP. [14C]glycine was rapidly taken up by recovering hearts but was not used for de novo adenine nucleotide synthesis. Ability to recover ATP and spontaneous contraction appear related to residual nucleotide and nucleoside content rather than to energy charge.
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PMID:Metabolism of adenine nucleotides in the cultured fetal mouse heart. 88 70

The role of adenosine in postprandial jejunal hyperemia was investigated by determining the effect of placement of predigested food into the jejunal lumen on blood flow and oxygen consumption before and during intra-arterial infusion of dipyridamole (1.5 microM arterial concn) or adenosine deaminase (9 U/ml arterial concn) in anesthetized dogs. Neither drug significantly altered resting jejunal blood flow and oxygen consumption. Before dipyridamole or deaminase, food placement increased blood flow by 30-36%, 26-42%, and 21-46%, and oxygen consumption by 13-22%, 21-22%, and 26-29%, during 0- to 3-, 4- to 7-, and 8- to 11-min placement periods, respectively. Adenosine deaminase abolished the entire 11-min hyperemia, whereas dipyridamole significantly enhanced the initial 7-min hyperemia (45-49%). Both drugs abolished the initial 7-min food-induced increase in oxygen consumption. Dipyridamole attenuated (14%), whereas deaminase did not alter (28%), the increased oxygen consumption that occurred at 8-11 min. Adenosine deaminase also prevented the food-induced increase in venoarterial adenosine concentration difference. In separate series of experiments, luminal placement of food significantly increased jejunal lymphatic adenosine concentration and release. Also, reactive hyperemia was accompanied by an increase in venous adenosine concentration and release. This study provides further evidence to support the thesis that adenosine plays a role in postprandial and reactive hyperemia in the canine jejunum.
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PMID:Role of adenosine in postprandial and reactive hyperemia in canine jejunum. 141 8

The ability of brown fat cells isolated from control and cold-acclimated hamsters to respond to adenosine was investigated. In measurements of the rate of oxygen consumption, it was observed that cells from control hamsters responded as expected to addition of adenosine deaminase, 3-isobutyl-1-methylxanthine (IBMX), or 2-chloroadenosine (i.e., norepinephrine dose-response curves were shifted to left in presence of adenosine deaminase or IBMX and to right with 2-chloroadenosine). However, brown fat cells isolated from cold-acclimated hamsters, under identical conditions, showed almost complete absence of adenosine control. Thus acclimation to cold induced a desensitization to adenosine by physiological means. To evaluate the molecular mechanism underlying desensitization to adenosine, [3H]phenylisopropyladenosine ([3H]PIA) binding to brown fat membranes from control and cold-acclimated hamsters was investigated. [3H]PIA bound with similar high affinity (KD approximately 5 nM) and saturability (Bmax approximately 15 fmol/mg protein) in both membrane preparations, demonstrating that desensitization to adenosine was not due to changes in adenosine receptor number or receptor affinity for adenosine. Furthermore, GTP induced a reduction in [3H]PIA affinity in brown fat membranes from both control and cold-acclimated hamsters, indicating that desensitization was probably not due to an uncoupling between the receptor and Gi protein. It was therefore concluded that the adenosine desensitization process may be located at the Gi protein-adenylate cyclase interaction.
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PMID:Cold acclimation induces desensitization to adenosine in brown fat cells without changing receptor binding. 169 90

This study was designed to test the hypothesis that endogenous adenosine participates in the global coronary functional hyperemia accompanying intracoronary infusions of norepinephrine (NE) and isoproterenol (ISO). Intracoronary adenosine deaminase (ADA) was employed to test the hypothesis in isolated, perfused guinea pig hearts. We measured coronary perfusate flow (CPF) at a constant coronary perfusion pressure. Heart rate (HR), left ventricular pressure, and its rate of development were also measured. Global myocardial oxygen consumption (MVO2) and oxygen extraction were calculated, and blood gases and pH were measured routinely in inflow and outflow perfusate samples. In the absence of ADA, NE and ISO increased HR 67 +/- 6 and 106 +/- 11 beats.min-1, left ventricular pressure development 519 +/- 46 and 375 +/- 35 mm Hg.s-1, MVO2 22 +/- 2 and 28 +/- 3 microliters.min-1.g-1, and CPF 1.6 +/- 0.2 and 2.2 +/- 0.2 ml.min-1.g-1, respectively. With constant infusion of ADA (4.5 U.min-1.g-1, a dose which produces no direct effects on cardiac function) for 4 min, similar increments in HR and left ventricular pressure development were achieved with both catecholamines. Corresponding changes in MVO2 (9 +/- 2 and 6 +/- 3 microliters.min-1.g-1) were significantly less than those seen in the absence of ADA. Moreover, CPF did not increase in response to NE and ISO in the presence of ADA. These findings support an important role for adenosine in catecholamine-induced global coronary functional hyperemia in isolated, perfused guinea pig hearts.
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PMID:Role of adenosine in catecholamine-induced global coronary functional hyperemia in isolated guinea pig hearts. 169 17

We have used directly combined high-performance liquid chromatography-mass spectrometry (LC/MS) to examine the mechanism of the reaction catalyzed by the double-stranded RNA unwinding/modifying activity [Bass & Weintraub (1988) Cell 55, 1089-1098]. A double-stranded RNA substrate in which all adenosines were uniformly labeled with 13C was synthesized. An LC/MS analysis of the nucleoside products from the modified, labeled substrate confirmed that adenosine is modified to inosine during the unwinding/modifying reaction. Most importantly, we found that no carbons are exchanged during the reaction. By including H2(18)O in the reaction, we showed that water serves efficiently as the oxygen donor in vitro. These results are consistent with a hydrolytic deamination mechanism and rule out a base replacement mechanism. Although the double-stranded RNA unwinding/modifying activity appears to utilize a catalytic mechanism similar to that of adenosine deaminase, coformycin, a transition-state analogue, will not inhibit the unwinding/modifying activity.
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PMID:The mechanism of adenosine to inosine conversion by the double-stranded RNA unwinding/modifying activity: a high-performance liquid chromatography-mass spectrometry analysis. 174 69

The peripheral mechanisms by which ephedrine and caffeine influence thermogenesis were investigated in innervated rat interscapular brown adipose tissue (IBAT) by assessing its rate of oxygen consumption (MO2) in vitro. Dose-response measurements with tissues from intact or sympathectomized (6-OHDA) animals indicate that the thermogenic effects of low concentrations of ephedrine and also of caffeine are entirely dependent upon the presence of intact sympathetic nerve endings, and thus depend on presynaptic mechanisms. Direct postsynaptic stimulation of thermogenesis is only apparent at much higher concentrations, namely greater than 1 microM for ephedrine and greater than 2mM for caffeine. At subminimal concentrations that neither ephedrine nor caffeine influenced basal tissue respiration, they induced a 4-5-fold increase in basal MO2 when administered in combination, a synergistic response prevented by pre-treatment of the rat with 6-OHDA. Synergistic increases in IBAT respiration were also obtained when subminimal concentration of ephedrine was added to 3-propylxanthine (a specific inhibitor of phosphodiesterase), to 8-phenyltheophylline (a potent adenosine receptor antagonist) or to adenosine deaminase (for enzymatic inactivation of endogenous adenosine). Conversely, the marked synergism in thermogenic response with ephedrine + caffeine was reduced in the presence of 2-chloroadenosine (an adenosine analogue). In tissues from fasted rats, the ephedrine + caffeine synergism in thermogenic response, although attenuated, was nevertheless present. These studies therefore demonstrate that ephedrine, at doses comparable with therapeutic use, stimulates thermogenesis in BAT via sympathetically released NA. In addition, a synergistic interaction between caffeine and ephedrine on BAT thermogenesis is explained by ephedrine's enhancement of sympathetic neuronal release of NA, together with caffeine's dual ability to antagonize adenosine and to inhibit cellular phosphodiesterase activity.
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PMID:Peripheral mechanisms of thermogenesis induced by ephedrine and caffeine in brown adipose tissue. 188 57

We evaluated various biochemical parameters in influenza virus-infected mice and focused on adenosine catabolism in the supernatant of bronchoalveolar lavage fluid (s-BALF), lung tissue, and serum (plasma). The activities of adenosine deaminase (ADA) and xanthine oxidase (XO), which generates O2-, were elevated in the s-BALF, lung tissue homogenate, and serum (plasma). The elevations were most remarkable in s-BALF and in lung tissue: We found a 170-fold increase in ADA activity and a 400-fold increase in XO activity as measured per volume of alveolar lavage fluid. The ratio of activity of XO to activity of xanthine dehydrogenase in s-BALF increased from 0.15 +/- 0.05 (control; no infection) to 1.06 +/- 0.13 on day 6 after viral infection. Increased levels of various adenosine catabolites (i.e., inosine, hypoxanthine, xanthine, and uric acid) in serum and s-BALF were confirmed. We also identified O2- generation from XO in s-BALF obtained on days 6 and 8 after infection, and the generation of O2- was enhanced remarkably in the presence of adenosine. Lastly, treatment with allopurinol (an inhibitor of XO) and with chemically modified superoxide dismutase (a scavenger of O2-) improved the survival rate of influenza virus-infected mice. These results indicate that generation of oxygen-free radicals by XO, coupled with catabolic supply of hypoxanthine from adenosine catabolism, is a pathogenic principle in influenza virus infection in mice and that a therapeutic approach by elimination of oxygen radicals thus seems possible.
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PMID:Dependence on O2- generation by xanthine oxidase of pathogenesis of influenza virus infection in mice. 215 24

Exercise-induced increases in tissue adenosine level vary in muscles having different oxidative capacities. These studies were designed to further evaluate the role of this potent vasodilator as a modulator of active hyperemia in muscles having different intrinsic metabolic profiles. Soleus (slow-twitch oxidative) and gracilis (fast-twitch glycolytic) muscles of anesthetized cats were stimulated to contract isometrically in the presence of adenosine deaminase (ADA) or ADA that had been deactivated by boiling (BADA). Stimulation parameters were chosen to provide similar high and low blood flow responses in the two muscle types. ADA did not affect resting blood flow or vascular resistance. In the soleus muscle, ADA attenuated both the increase in blood flow and oxygen consumption and the decrease in vascular resistance at the high level of muscle stimulation. In addition, muscle performance decreased to 60% of its initial level in the presence of ADA, although the same initial performance level was maintained over the stimulation period during BADA infusion. Temporal studies in the soleus muscle demonstrated an ADA-induced decrease in oxygen consumption, which was the product of an attenuated blood flow, followed by reductions in muscle performance. ADA had no effect on active hyperemia in either muscle at the low stimulation level. Additionally, ADA did not attenuate active hyperemia in the gracilis when stimulated at a level that normally produced muscle fatigue. Therefore these data support a role for adenosine in mediating vasodilation in skeletal muscle composed of high-oxidative fibers at high levels of muscle performance but do not support a role for adenosine in skeletal muscle having low-oxidative fibers, even at levels of exercise which produce fatigue.
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PMID:Adenosine and active hyperemia in soleus and gracilis muscle of cats. 222 Nov 33


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