Role Of Adenosine Deaminase Research Articles

Role of adenosine deaminase and dATP levels in thymocyte apoptosis.

While ADA is a ubiquitous enzyme in the purine degradation pathway. Surprisingly, inherited deficiency in ADA in human, results in a specific severe combined immunodeficiency decease, where the tissue damage is restricted to the lymphoid lineage.1 Previous studies have demonstrated that during T lymphocyte development ADA activity peaks at immature cortical CD4+CD8+ double positive (DP) thymocytes.2,3

Possible role of adenosine deaminase in vaso-occlusive diseases

To describe several emerging concepts regarding the biosynthesis, metabolism and biological roles of adenosine and to illustrate the possible significance of these ideas to vascular biology by proposing a hypothesis pertaining to the role of erythrocyte-derived adenosine deaminase in vaso-occlusive diseases associated with damaged erythrocytes. Three pathways of adenosine biosynthesis have been well established: the intracellular ATP pathway, the extracellular ATP pathway and the transmethylation pathway. A fourth pathway that has received relatively little attention, but could be particularly important in vascular smooth muscle, is the cyclic AMP-adenosine pathway. This pathway involves the extracellular or intracellular metabolism, or both, of cyclic AMP to AMP and hence to adenosine. Our recent experiments in cultured vascular smooth muscle cells, isolated vascular beds and intact animals support the existence of the cyclic AMP-adenosine pathway. Together these four pathways of adenosine formation should assure pharmacologically active levels of vascular adenosine. ANTIVASO-OCCLUSIVE ACTIONS OF ADENOSINE: The overall pharmacologic profile of adenosine suggests that this nucleoside functions to protect vascular beds from vaso-occlusive events. In this regard, some well known effects of adenosine include vasodilation, release of nitric oxide from vascular endothelial cells and inhibition of platelet aggregation, platelet adhesion, neutrophil-endothelial interactions, renin release and noradrenergic neurotransmission. Moreover, studies indicate that adenosine also releases nitric oxide from cultured vascular smooth muscle cells and inhibits vascular smooth muscle cell growth. Thus, any condition that reduces the levels of adenosine in the blood vessel wall or blood vessel-blood interface might predispose toward vaso-occlusive events. Adenosine deaminase rapidly metabolizes adenosine to inosine, which lacks antivaso-occlusive properties. Because erythrocytes are generously endowed with adenosine deaminase, any condition that damages erythrocytes will cause leakage of adenosine deaminase from erythrocytes directly onto the blood vessel wall, thus diminishing local vascular levels of adenosine. Experiments using dimethyl sulfoxide-induced hemolysis have confirmed the hypothesis that erythrocyte-derived adenosine deaminase can reduce adenosine levels in vivo. THE ROLE OF ERYTHROCYTE-DERIVED ADENOSINE DEAMINASE IN VASO-OCCLUSIVE DISEASES: Because multiple biosynthetic pathways maintain pharmacologically active levels of adenosine within the blood vessel wall and adenosine exerts a number of antivaso-occlusive effects, release of adenosine deaminase from erythrocytes may increase the risk for vaso-occlusive events.

Expression of ecto-adenosine deaminase and CD26 in human T cells triggered by the TCR-CD3 complex. Possible role of adenosine deaminase as costimulatory molecule.

The expression of surface adenosine deaminase (ADA) and CD26 in activated human T cells was studied by flow cytometry. PBLs and CD3+ or CD4+ cells, when subjected to a variety of stimuli (anti-CD3 Abs plus IL-2 or phorbol esters), presented two structurally different cell populations, which differed in size and cellular complexity (populations B1 and B2). In PBLs triggered by an anti-CD3 mAb there was no significant increase of expression of either surface ADA or CD26 in cells of population B1, whose structure is similar to that of nonstimulated cells. In contrast, there was a significant increase in the percentage of expression of ADA and CD26 in the population B2, which corresponds to structurally more complex and larger cells. In the case of activation via TCR-CD3 but in the presence of IL-2 or via phorbol esters, the increase was found in cells from both populations, but B2 cells always showed a higher percentage of expression than B1 cells. The results of increased expression of surface ADA and CD26 were similar in whole T cells or in purer preparations such as CD3+ or CD4+ lymphocytes. Polyclonal Abs against ADA were not able to induce an activation response in T cells even when cross-linked by a secondary Ab. Interestingly, these Abs produced anergy in CD4+ cells subjected to an anti-CD3 stimulus. In contrast, addition of ADA produced an enzyme-independent synergism in the response through the TCR-CD3 complex. In T cells, ADA and CD26 colocalized on the surface of T cells; thus, the effect of exogenous ADA seems to be mediated by CD26 molecules that are not interacting with endogenous ADA (spare CD26 molecules). The presence of spare CD26 molecules on the surface of CD4+ cells was demonstrated by flow cytometry in the presence of exogenous ADA and also by confocal microscopy. The set of results strongly indicates that ADA binding to CD26 produces a costimulatory response in T cell activation events.

Enzyme variability and neonatal jaundice. The role of adenosine deaminase and acid phosphatase.

A sample of children treated by phototherapy during the neonatal period has been studied in the population of Penne (South Eastern Italy) in order to confirm the association previously reported in newborns from the population of Rome between neonatal jaundice and phenotypes of adenosine deaminase (ADA) and acid phosphatase (ACP1). The present data confirm that the incidence of clinically relevant jaundice is much greater in newborns of phenotype ACP1 BA carrying ADA2 allele than in other infants. Since ACP1 probably acts as flavin mononucleotide phosphatase and is modulated by purine nucleotides, it is likely that enzymes of purine nucleotide metabolism (including ADA), ACP1 and flavoenzymes (including gluthatione reductase and enzymes of Krebs cycle), may represent a polygenic complex influencing bilirubin levels in the first few days of life.

Serum adenosine deaminase activity in the differentiation of respiratory diseases in children

Adenosine deaminase (ADA) catalyzes the conversion of adenosine to inosine. Since it was reported that two children with severe combined immunodeficiency lacked any detectable ADA activity in their red blood cells, a renewed interest has been focused on the role of ADA in the immunological system [1,2]. Furthermore, determination of ADA activity in serum and pleural fluid has found a wider clinical application in establishing the diagnosis of patients with pleural effusion stemming from many different disorders [3-51. A well-known example of these observations is that of the high ADA activity of tuberculosis in adults [3,6]. ADA activity of tuberculosis in children, however, has not been investigated, and there has been no longitudinal study of ADA activity vis-a-vis advancing age. The purpose of this paper is to establish the normal serum ADA activity value in children and to evaluate the usefulness of ADA value in diagnosing respiratory diseases.

Lack of adenosine deaminase deficiency in the mutant mouse wasted

The possibility that the mutant mouse wasted (wst/wst) may serve as an animal model for studies of severe combined immunodeficiency disease (SCID) and the role of adenosine deaminase (ADA, EC 3.5.4.4) in adenosine metabolism were investigated. The specific activity of ADA in wst/wst compared with control mice was significantly lower by 26% in thymus, but significantly higher by 18% in spleen and 32% in cerebellum. V max values of ADA in spleens were 4356 higher in wst/wst mice and no changes were observed in K m values. In contrast, the V max of ADA was unchanged in erythrocytes from wst/wst mice, but the K m for adenosine was significantly elevated. Thus, based on ADA measurements alone, it may be premature to consider wst/wst mice as a model for ADA deficiency and SCID in humans.

Role of adenosine deaminase in human monocyte differentiation and tumor cell cytotoxicity.

Role of adenosine deaminase in human monocyte differentiation and tumor cell cytotoxicity.

Immunohistochemical localization of adenosine deaminase in rat and calf tissues.

Adenosine deaminase (ADA) is an enzyme of a salvage pathway of purine metabolism. Its deficiency is associated with one of the hereditary forms of severe combined immunodeficiency (Giblett et al.,1972). The enzyme is likely involved in the differentiation of T lymphocytes (Ballet et al., 1976; Barton et al., 1979; Chechik et al., 1981), monocytes (Fischer et al., 1976), and epithelial cells(Trotta and Balis, 1977). In view of a possible role of ADA in cellular differentiation, it is important to identify which cells contain this enzyme and to establish their distribution in various tissues of intact organisms. Recently, we have shown that antibody to calf ADA can be used for the immunochemical and immunomorphologic detection of human, rat and mouse enzyme (Chechik and SenGupta, 1981). In the present study, we have employed the anti-calf ADA antibody for the immunohistochemical localization of ADA in the rat and calf.KeywordsStrong StainingAdenosine DeaminaseImmunohistochemical LocalizationSevere Combine ImmunodeficiencyPurine MetabolismThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Role of adenosine deaminase in activation of macrophages.

The intracellular adenosine deaminase activity of induced macrophages was twice that of resident cells. Coformycin, a specific inhibitor of adenosine deaminase, inhibited the activation of macrophages, as measured by superoxide generation.

Role of adenosine deaminase, ecto-(5'-nucleotidase) and ecto-(non-specific phosphatase) in cyanide-induced adenosine monophosphate catabolism in rat polymorphonuclear leucocytes.

1. The role of adenosine deaminase (EC 3.5.4.4), ecto-(5'-nucleotidase) (EC 3.1.3.5) and ecto-(non-specific phosphatase) in the CN-induced catabolism of adenine nucleotides in intact rat polymorphonuclear leucocytes was investigated by inhibiting the enzymes in situ. 2. KCN (10mM for 90 min) induced a 20-30% fall in ATP concentration accompanied by an approximately equimolar increase in hypoxanthine, ADP, AMP and adenosine concentrations were unchanged, and IMP and inosine remained undetectable ( less than 0.05 nmol/10(7) cells). 3. Cells remained 98% intact, as judged by loss of the cytoplasmic enzyme lactate dehydrogenase (EC 1.1.1.27). 4. Pentostatin (30 microM), a specific inhibitor of adenosine deaminase, completely inhibited hypoxanthine production from exogenous adenosine (55 microM), but did not black CN-induced hypoxanthine production or cause adenosine accumulation in intact cells. This implied that IMP rather than adenosine was an intermediate in AMP breakdown in response to cyanide. 5. Antibodies raised against purified plasma-membrane 5'-nucleotidase inhibited the ecto-(5'-nucleotidase) by 95-98%. Non-specific phosphatases were blocked by 10 mM-sodium beta-glycerophosphate. 6. These two agents together blocked hypoxanthine production from exogenous AMP and IMP (200 microM) by more than 90%, but had no effect on production from endogenous substrates. 7. These data suggest that ectophosphatases do not participate in CN-induced catabolism of intracellular AMP in rat polymorphonuclear leucocytes. 8. A minor IMPase, not inhibited by antiserum, was detected in the soluble fraction of disrupted cells.

A role for adenosine deaminase in human monocyte maturation.

The occurrence of a deficiency of adenosine deaminase (ADA) activity in some patients with severe combined immunodeficiency suggests a possible relationship between the activity of ADA and the aberration of the immune system. To help delineate the function of ADA in the immune response we have examined its role in monocyte maturation. When incubated in vitro, peripheral blood monocytes transformed, within 3 days, to macrophagea as assessed by phase-contrast microscopy and an increase in the specific activity of the lysosomal enzyme acid phosphatase. The specific activity of ADA increased as much as ninefold, reaching a peak after the 1st day in culture, while the activities of other enzymes involved in the purine salvage pathway were not altered. Sucrose density ultracentrifugation of extracts prepared immediately after the isolation of monocytes revealed the presence of two forms of ADA with molecular weights of approximately 30,000 and 110,000. The increase in ADA specific activity during monocyte cultivation correlated with an increase in the activity of the smaller molecular species. A specific inhibitor ADA, erythro-9-(2-hydroxy-3-nonyl) adenine, prevented the increase in acid phosphatase activity, as well as the morphological changes associated with the monocyte maturation. These data suggest a role for ADA in monocyte to macrophage maturation. In view of the central role of macrophages in immune function, this observation may relate to the association of combined immunodeficiency and a deficiency of this enzyme.

Pyrimidine starvation induced by adenosine in fibroblasts and lymphoid cells: role of adenosine deaminase.

In the presence of 10(-4) to 10(-5) molar adenosine, established cell lines of fibroblastic or lymphoid origin die of pyrimidine starvation. Less than lethal concentrations inhibit cell growth. Over a broad concentration range, the effects of adenosine are prevented by providing a suitable pyrimidine source. We suggest that the recently described immune deficiency disease associated with absence of adenosine deaminase may be the result of pyrimidine starvation induced by adenosine nucleotides in cells of the lymphoid system.