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)

Myocardial ischemia is characterized by the liberation of adenosine and by complement-mediated inflammation. We have reported that amidated C3, formed when ammonia (NH3) disrupts the thiolester bond of C3, serves as an alternative pathway convertase, generates C5b-9, and stimulates phagocytic oxidative metabolism. We investigated whether the deamination of adenosine by adenosine deaminase in hematopoietic cells might liberate sufficient ammonia to form amidated C3 and thereby trigger complement-mediated inflammation at ischemic sites. In the presence of 4 mM adenosine, NH3 production per erythrocyte (RBC) was equal to that per neutrophil (PMN) (3.3 X 10(-15) mol/cell per h). Because RBC outnumber PMN in normal blood by a thousandfold, RBC are the major source of NH3 production in the presence of adenosine. NH3 production derived only from the deamination of adenosine by the enzyme adenosine deaminase and was abolished by 0.4 microM 2'-deoxycoformycin, a specific inhibitor of adenosine deaminase. When purified human C3 was incubated with 5 X 10(8) human RBC in the presence of adenosine, disruption of the C3 thiolester increased more than twofold over that measured in C3 incubated with buffer, or in C3 incubated with RBC (P less than 0.05). The formation of amidated C3 was abolished by the preincubation of RBC with 2'-deoxycoformycin (P less than 0.001). Amidated C3 elicited statistically significant release of superoxide, myeloperoxidase, and lactoferrin from PMN. Thus, the formation of amidated C3 by RBC deamination of adenosine triggers a cascade of complement-mediated inflammatory reactions.
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PMID:The erythrocyte as instigator of inflammation. Generation of amidated C3 by erythrocyte adenosine deaminase. 278 75

A 6-year-old boy with T-cell acute lymphoblastic leukaemia (ALL) in relapse was treated with the adenosine deaminase inhibitor, 2'-deoxycoformycin (DCF). Remarkably, his residual leukaemia underwent an abrupt phenotypic shift, coincident with a massive anti-leukaemic effect of DCF. Both at diagnosis and prior to therapy with DCF, blast cells had typical lymphoblastic morphology and T-cell characteristics (terminal transferase +, T-antigen +, Ia -, cALLa -, myeloperoxidase -, and high in adenosine deaminase content). After four courses of DCF by constant infusion, the blast cells were myeloid in appearance and reactivity to a variety of tests (terminal transferase -, myeloperoxidase +, Sudan black B +, esterase +, My-1 +). We hypothesize that DCF therapy created a selection pressure, blocking pathways of T-cell differentiation and proliferation, permitting the emergence of a newly dominant myeloid subclone of a multipotential leukaemic cell progenitor with the innate capacity for both T-lymphocytic and myeloid differentiation.
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PMID:Phenotypic conversion of acute leukaemia from T-lymphoblastic to myeloblastic induced by therapy with 2'-deoxycoformycin. 660 43

Peripheral blood or bone marrow of 24 patients with chronic myeloid leukemia (CML) were characterized for their surface membrane marker profiles using flow cytometry and fluorescence microscopy. Purine metabolism enzyme activities were compared with membrane immunophenotype and cytochemical stains. CML subtypes were correlated with the expression of surface membrane antigens detected by the monoclonal antibodies. On the basis of immunophenotyping we found the following characteristic marker profiles: In stable phase of CML (CML-SP)-CD15, CD11b, CDw65, CD13, in accelerated phase of CML (CML-AP)-CD15, CDw65, CD11b, CD13 and CD33, in myeloid blastic phase of CML(CML-BP-M)-CD13, CD33, HLA-DR, CD11b, CD15, CDw65, in myeloid and lymphoid (mixed) blastic phase of CML (CML-BP-M+L)-CD13, CD33, CD34, HLA-DR, CD11b, CD10 and in chronic myelomonocytic leukemia (CMML)-CD14, CDw65, CD11b, CD33 and HLA-DR. Analysis of purine metabolism enzyme activities showed that there was a correlation between the values of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) and various types of CML. ADA levels in CML-SP, CML-AP and CMML were comparable with those in normal cells. In CML-BP-M, which represents proliferation of less mature myeloid cells (similar to less mature AML subtypes), ADA activity increased and PNP activity decreased. ADA activity was significantly different between control group and CML-BP-M (p < 0.01), between CML-SP and CML-BP-M (p < 0.05). The values of PNP activity were the highest in stable phase of CML (125 pkat. 10(-6) cells) and the lowest (23 pkat.10(-6) cells) in CML-BP-M+L. PNP activity in the other groups corresponded to control values. High ADA/PNP ratio was found in CML-BP-M and CML-BP-M+L (0.7 and 2.0, respectively) in comparison to CML-SP (0.2). It follows from our results that ADA/PNP ratio enables to discriminate between stable and blast phases of CML (p < 0.01). The level of the cytochemical enzymes (CHAE, MPO, SBB, ANAE and 5' NT) varied and reflected the degree of cell differentiation and maturation. CHAE and MPO were characteristic enzymes for CML, ANBE for CMML and 5' NT for CML-BP-lymphoid.
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PMID:Chronic myeloid leukemia: correlation between purine metabolism enzyme activities and membrane immunophenotype. 761 76

We hypothesized that adenosine, known to be release from inflammatory sites, could lessen the potentially damaging activity of neutrophils (PMN) primed by tumor necrosis factor-alpha (TNF alpha) at sites of infection. We investigated the effect of adenosine on PMN primed with cell-free medium from mononuclear leukocytes (MNL) that had been treated with lipopolysaccharide (LPS) yielding a conditioned medium rich in TNF alpha and on PMN primed with recombinant human TNF alpha (rhTNF alpha). LPS (10 ng/mL) minimally primed PMN, but LPS-MNL-conditioned medium increased PMN chemiluminescence in response to f-Met-Leu-Phe (fMLP) 1242% compared with unprimed PMN. LPS-MNL-conditioned medium contained adenosine (approximately 30 nM). Converting the adenosine in the LPS-MNL-conditioned medium to inosine with adenosine deaminase (ADA) or blocking adenosine binding to PMN with the adenosine receptor antagonist 1,3-dipropyl-8-(phenyl-p-acrylate)-xanthine (BW A1433U) resulted in a near doubling of chemiluminescence. The LPS-MNL-conditioned medium contained TNF alpha (836 pg/mL; approximately 1 U/mL). Recombinant human TNF alpha (1 U/mL) primed PMN for a 1033% increase in chemiluminescence. Added adenosine decreased rhTNF alpha-primed PMN chemiluminescence (IC50 approximately 100 nM), and adenosine (100 nM) decreased both superoxide and myeloperoxidase release from rhTNF alpha-primed fMLP-stimulated PMN. The activity of adenosine was counteracted by ADA and BW A1433U, and the modulating effect of adenosine was on the primed response rather than on priming per se. Thus, physiological concentrations of adenosine reduce the effects of recombinant human TNF alpha and native human TNF alpha (released from LPS-treated MNL) on PMN activity. Endogenous adenosine may preclude or minimize damage to infected tissue by damping the TNF alpha-primed PMN oxidative response.
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PMID:Adenosine modulation of tumor necrosis factor-alpha-induced neutrophil activation. 861 64

Methylxanthines are best known as phosphodiesterase inhibitors that cause a rise in intracellular cAMP. One would expect the two methylxanthines, caffeine and pentoxifylline, to have similar actions on neutrophils (PMN). However, caffeine stimulated and pentoxifylline inhibited PMN oxidative activity. Micromolar concentrations of pentoxifylline decreased native and recombinant tumor necrosis factor-alpha (TNF alpha)-primed formyl met-leu-phe (fMLP)-stimulated PMN chemiluminescence, superoxide production and myeloperoxidase (MPO) release. In contrast, equal concentrations of caffeine increased chemiluminescence and MPO release with no effect on superoxide production. These activities of the methylxanthines were only observed in the presence of physiological concentrations of adenosine, and were abolished by the treatment of the PMN with adenosine deaminase. The activities of adenosine, pentoxifylline and caffeine on PMN activity could not be readily explained by changes in PMN [cAMP]. Thus for TNF alpha-primed PMN, pentoxifylline decreases PMN activity by enhancing the effect of adenosine on degranulation and superoxide production; whereas caffeine increases PMN activity by counteracting the effect of adenosine on degranulation.
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PMID:Methylxanthines with adenosine alter TNF alpha-primed PMN activation. 865 88

The interaction of platelets with neutrophil granulocytes is considered to play an important role in the inflammatory process, and the present study was focused on platelet-induced modulation of Fcgamma receptor-mediated functions in neutrophils. We found that phagocytosis and the respiratory burst (measured as luminol-enhanced chemiluminescence), triggered in neutrophils by immunoglobulin G (IgG)-opsonized yeast particles, were potentiated by platelets and that maximal enhancement was achieved at a physiological neutrophil/platelet ratio of about 1:50 to 1:100. Platelets both increased the intra- and extracellular generation of oxygen radicals as well as the release of myeloperoxidase from stimulated neutrophils. The presence of platelets also induced a cortical actin polymerization in neutrophils, which might explain the increased phagocytic capacity. Platelets appear to affect neutrophil function in a contact-independent manner that most likely involves ATP, indicated by the following: (1) platelet supernatants, but not fixed platelets, affected neutrophil function in the same way as viable platelets; (2) platelets raised the extracellular ATP level four- to fivefold; (3) exogenous ATP mimicked the effects of platelets on actin polymerization, phagocytosis, and the respiratory burst in neutrophils; (4) hydrolysis of extracellular ATP with apyrase or blocking of ATP receptors with suramin reversed the platelet-induced enhancement of neutrophil function. An increased accumulation of extracellular adenosine, induced by inhibiting endogenous adenosine deaminase or adding exogenous adenosine, reversed the effects of platelets. The platelet-induced potentiation of the respiratory burst was inhibited by the tyrosine kinase inhibitor genistein, suggesting that tyrosine phosphorylation is involved. However, platelets did not significantly affect the Fcgamma receptor-triggered calcium response in neutrophils. In conclusion, we show that platelets, through an ATP-dependent mechanism, potentiate IgG-mediated ingestion and production of oxygen metabolites in neutrophils.
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PMID:Platelets enhance Fc(gamma) receptor-mediated phagocytosis and respiratory burst in neutrophils: the role of purinergic modulation and actin polymerization. 869 24

Monophosphoryl lipid A (MLA), a derivative of the minimal substructure of lipopolysaccharide (lipid A) possesses immunomodulatory activity of the parent lipid A yet enjoys reduced toxicity. It has previously been reported that pretreatment with MLA reduces myocardial infarct size and stunning in dogs following ischemia and reperfusion. The aim of this study was to evaluate the ability of monophosphoryl lipid A (MLA) to preserve global cardiac function and peripheral hemodynamics in a rabbit model of prolonged regional ischemia (90 min), and reperfusion (6 h). An evaluation of potential mechanisms by which MLA may preserve cardiac function was also undertaken. Single dose pretreatment with MLA (35 micrograms/kg i.v.) 24 h prior to ischemia resulted in significant improvement in left ventricular developed pressure, dP/dt, rate-pressure product and mean arterial pressure during reperfusion (P < 0.05 v control). Although in this model of prolonged ischemia MLA pretreatment did not reduce infarct size (54.5 +/- 11.4% in control v 63.3 +/- 8.3% in MLA, P = N.S.), evaluation of myocardial adenylate and adenosine catabolite pools at the end of ischemia indicated a preservation of ATP and ADP and a decreased production of downstream adenosine catabolites including inosine, xanthine and uric acid. Adenosine kinase, but not 5'-nucleotidase (5'-NTase) or adenosine deaminase activity determined following reperfusion was 76% and 60% higher (P < 0.05) in non-risk and post-ischemic myocardium of MLA pretreated rabbits compared with controls. Although there was a trend toward lower tissue myeloperoxidase activity in post-ischemic myocardium from treated rabbits, the results were not significantly different from control animals. These results suggest that a 24-h pretreatment with MLA, without further treatment during ischemia or reperfusion was associated with: (1) preservation of global myocardial function during reperfusion; (2) preservation of myocardial high energy adenylates and reduced formation of adenosine catabolites during ischemia; (3) elevated myocardial adenosine kinase activity. Increased recycling of adenosine to phosphorylated nucleotides may result from MLA's affect on adenosine kinase, which could explain the drugs effect on adenylate and adenosine metabolite pools.
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PMID:Preservation of global cardiac function in the rabbit following protracted ischemia/reperfusion using monophosphoryl lipid A (MLA). 874 27

Although the role of adenosine deaminase (ADA), adenylate deaminase (AMP-DA), purine nucleoside phosphorylase (PNP) is well documented in gastric and intestinal carcinoma, their role in inflammatory bowel diseases remains unknown. In the present study, we investigated the profile of these enzymes in blood and intestinal tissues during colitis. Colitis induced in Wistar rats by acetic acid was monitored by a marker enzyme myeloperoxidase (MPO). The tissue levels of MPO increased on 1, 2, 5 and 6 days post-administration (PA) of acetic acid and declined to the control levels by day 7 PA. In parallel the blood levels of ADA and AMP-DA decreased on days 1, 2 and 5 without any significant change on days 6 and 7 PA. Similar observations were recorded for these enzymes in the cytosolic extracts of colonic tissue specimens. In contrast, PNP remained unaltered in both blood and tissue samples. These findings suggest an inverse-relationship between inflammation and purine deaminases in both blood and tissues.
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PMID:Studies on purine enzymes in experimental colitis. 1039 Nov 19

Colitis reduces the blood and tissue levels of adenosine deaminase and adenylate deaminase. Whether this has any effect on blood purines remains to be determined. The aim of this study was to measure the adenylate pool, substrates of the above enzymes, and energy status in blood from rats with colitis. Colitis was induced by intrarectal administration of acetic acid and followed over a period of seven days. The levels of ATP, ADP, AMP, adenosine, inosine, and uric acid were analyzed by HPLC, and energy status was estimated. Myeloperoxidase was used as a marker of colitis. Concentrations of ATP, ADP, AMP and adenosine decreased during days 1-5, whereas energy status decreased on day 2. The concentrations of inosine, uric acid, and hemoglobin remained unaltered, whereas colonic myeloperoxidase activity increased. These, findings demonstrate colitis-induced reduction of the circulating purines, which may be due to their enhanced usage for the repair of the inflamed colon.
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PMID:Blood purine and energy status in rats with colitis. 1128 Nov 97

In a patient with an undiagnosed pleural effusion, the first question to answer is whether the fluid is an exudate or a transudate. This is usually determined by means of Light's criteria, which differentiate transudative effusions from exudative effusions by measuring the levels of total protein and lactate dehydrogenase in the pleural fluid (PF) and serum. In patients under diuretic treatment, Light's criteria misclassify transudates as exudates, but the serum to pleural fluid albumin gradient usually remains above 12 g/L. When tests are done only in PF, protein concentration >30 g/L performs at least as well as the other individual markers. To diagnose tuberculous pleuritis among exudates, PF adenosine deaminase and PF interferon-g exhibit high diagnostic accuracy. When malignancy is suspected the addition of tumour markers to the results of cytologic analysis increases the rate of detection. Other biochemical markers are useful in specific circumstances involving pleural effusion, such as amylase in effusions due to pancreatitis, or oesophageal rupture, and triglycerides in chylothorax. Several PF markers are associated with complicated parapneumonic effusion - e.g. low PF pH and glucose, and high PF LDH activity -- although PF pH appears to be the best biochemical aid in decisions regarding chest tube drainage. Recent reports suggest that neutrophil-derived enzymes (polymorphonuclear elastase and myeloperoxidase) can be useful as early indicators of the need of chest tube insertion; however these findings must be confirmed in large series. This review discusses the clinical usefulness of biochemical markers in the diagnosis and management of pleural effusions. The vast majority of prospective studies in this field have been conducted in adults and, although the mechanisms of pleural effusion production do not differ in children and adults, the prevalence of each etiologic cause does. Therefore it seems advisable to confirm or recalculate the predictive values of each marker in the paediatric population.
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PMID:Useful clinical biological markers in diagnosis of pleural effusions in children. 1498 Feb 72


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