Disease relevance of Ada

• BACKGROUND: CD26 is a T-cell co-stimulator, and interacts with adenosine deaminase, human immunodeficiency virus (HIV) Tat-1 protein and extracellular matrix [1].
• Thus, the examination of ADA deficiency has identified the importance of purinergic signaling during lymphoid development and in the regulation of aspects of chronic lung disease [2].
• Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation [2].
• Genetic deficiencies in the purine catabolic enzyme adenosine deaminase (ADA) in humans results primarily in a severe lymphopenia and immunodeficiency that can lead to the death of affected individuals early in life [2].
• Inhibition of adenosine deaminase during ischemia results in a injury similar to that seen after a shorter period of insult [3].

Psychiatry related information on Ada

• We examined, in rats, the activity of the major metabolic enzymes for adenosine - adenosine deaminase, adenosine kinase, ecto- and cytosolic 5'-nucleotidase - in sleep/wake regulatory regions as well as cerebral cortex, and how the activity varies across the day and with sleep deprivation [4].
• The inhibition of cortical ADA activity measured ex vivo parallels the decrease in spontaneous motor activity in a time-dependent manner [5].
• PURPOSE: 6-Cl-2',3'-dideoxypurine (6-Cl-ddP), an adenosine deaminase (ADA) activated prodrug of ddI, may be an effective antiretroviral agent for the treatment of AIDS dementia due to its ability to deliver increased concentrations of ddI to brain tissue [6].

High impact information on Ada

• The metabolic basis of the immunodeficiency is likely related to the sensitivity of lymphocytes to the accumulation of the ADA substrates adenosine and 2'-deoxyadenosine [2].
• ADA-deficient mice develop similar abnormalities that are dependent on the accumulation of adenosine and 2'-deoxyadenosine [2].
• Investigations using ADA-deficient mice have provided compelling evidence to support the hypothesis that T and B cells are sensitive to increased concentrations of 2'-deoxyadenosine that kill cells through mechanisms that involve the accumulation of dATP and the induction of apoptosis [2].
• In addition to effects on the developing immune system, ADA-deficient humans exhibit phenotypes in other physiological systems including the renal, neural, skeletal, and pulmonary systems [2].
• A high level of human ADA expression was observed in infected endothelial cell populations both before and after selection in G418 [7].

Chemical compound and disease context of Ada

• Detailed analysis of the pulmonary insufficiency seen in ADA-deficient mice suggests that the accumulation of adenosine in the lung can directly access cellular signaling pathways that lead to the development and exacerbation of chronic lung disease [2].
• Double-stranded (ds) RNA-specific adenosine deaminase converts adenosine residues into inosines in dsRNA and edits transcripts of certain cellular and viral genes such as glutamate receptor (GluR) subunits and hepatitis delta antigen [8].
• Adenosine deaminase from deoxycoformycin-sensitive and -resistant rat hepatoma cells. Purification and characterization [9].
• The adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) (1.0-100 micrograms/kg) and deoxycoformycin (0.1-1 micrograms/kg) potentiated the reactive hyperemia elicited by a brief (24-s) anoxic challenge [10].
• Effect of adenosine deaminase, N6-phenylisopropyladenosine and hypothyroidism on the responsiveness of rat brown adipocytes to noradrenaline [11].

Biological context of Ada

• Enhanced oral bioavailability of 2'- beta-fluoro-2',3'-dideoxyadenosine (F-ddA) through local inhibition of intestinal adenosine deaminase [12].
• Enzymes adenosine deaminase (ADA) and 5-nucleotidase (5-'NT) are known to play active role in tissue/cell proliferation and differentiation [13].
• Those Ado analogues subject to deamination by adenosine deaminase (ADA) were also studied in the intact Sprague-Dawley rat after pretreatment with the ADA inhibitor 2'-deoxycoformycin [14].
• In this study the kinetics of ADA expression was assessed by immunomorphologic and enzymatic methods in tissues of ACI rats given injections of DCF [15].
• The hematocrit and hemoglobin levels of control animals receiving human adenosine deaminase (ADA)-expressing cells were not significantly different from baseline (P > .05; n = 5) [16].

Anatomical context of Ada

• We found that ADA exhibits a characteristic spatial pattern of activity in the rat CNS with the lowest activity in the parietal cortex and highest in the region of the tuberomammillary nucleus (15.0+/-4.8 and 63.4+/-28.0 nmoles/mg protein/15 min, mean+/-S.D., respectively) [17].
• 2-Beta-fluoro-2',3'-dideoxyadenosine (F-ddA) is an adenosine deaminase (ADA) activated prodrug of 2-beta-fluoro-2',3'-dideoxyinosine (F-ddI) with enhanced delivery to the central nervous system (CNS) that has been tested clinically for the treatment of AIDS [12].
• Expression of adenosine deaminase and 5'-nucleotidase in artificially induced deciduoma in rat and hamster [13].
• Immunohistochemical analysis of adenosine deaminase in rat brain revealed an extensive plexus of adenosine deaminase-containing neurons in the basal hypothalamus [18].
• Adenosine deaminase was added to media containing the adipocytes from older rats to remove endogenous adenosine [19].

Associations of Ada with chemical compounds

• We postulate that adenosine deaminase plays an important role in the mechanism that controls regional concentration of adenosine in the brain and thus, it is a part of the sleep-wake regulatory mechanism [17].
• RESULTS: High concentrations of EHNA in coperfusions with F-ddA completely inhibited intestinal ADA, increasing the permeability coefficient of F-ddA by nearly threefold but producing high systemic inhibition of ADA [12].
• Ze 911 concentration dependently (0.1 - 15 mg/mL) inhibited PSPs in the presence of the adenosine A2A receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC, 0.2 microM) and adenosine deaminase (1 U/mL) [20].
• Morphologic changes and immunohistochemical localization of adenosine deaminase in tissues of rats given injections of 2'-deoxycoformycin [15].
• Inhibition of adenosine deaminase by 80% with the tight-binding inhibitor 2'-deoxycoformycin led to a 20% increase in the residual adenine nucleotide pool [3].

Physical interactions of Ada

• Its inotropic action was almost completely abolished by pretreatment of atria with adenosine deaminase and correlated well with its binding ability to the cardiac adenosine A1 receptor [21].

Regulatory relationships of Ada

• Glucagon inhibition of insulin-stimulated 2-deoxyglucose uptake by rat adipocytes in the presence of adenosine deaminase [22].
• The beta3-adrenoceptor agonist CL316243 (CL) suppressed all the insulin actions in adenosine deaminase (ADA)-treated cells, but was without effect in non-ADA-treated cells [23].
• The addition to the medium of adenosine deaminase (0.4 U/ml) stimulated calcitonin secretion [24].
• This enhanced proliferative response was not blocked by adenosine per se or inhibition of adenosine kinase but was blocked by inhibition of adenosine deaminase and by 2-chloroadenosine (adenosine deaminase-resistant adenosine analogue) [25].
• The effect of adenosine deaminase on terbutaline-stimulated secretion was antagonized by selective adenosine A1 receptor agonists, N6-cyclopentyladenosine (CPA) and 1-deaza-2-chloro-N6-cyclopentyladenosine (DCCA) [26].

Other interactions of Ada

• Both isoproterenol (10(-6) M) and adenosine deaminase reduced insulin sensitivity and also rapidly (t1/2 approximately 1.5 min) decreased the effect of a maximal insulin concentration on the number of cell surface IGF-II receptors by 35-50%, and by 70% when added together [27].
• 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 [28].
• The post-ATP facilitation could be prevented by the adenosine A1 receptor antagonists 8-phenyltheophylline or 1,3-dipropyl-8-cyclopentyltheophylline (50 nM), or superfusion of adenosine deaminase [29].
• Sucrase and maltase activities were fully expressed nearest the crypt, alkaline phosphatase in cells higher on the villus, and adenosine deaminase higher still, whereas thymidine kinase activity was limited to the crypts [30].
• Maximal initial rates of the AMP catabolic enzymes 5'-nucleotidase, adenosine deaminase, and AMP deaminase were elevated in the hearts of BB/Wistar and streptozocin-induced diabetic rats [31].

Analytical, diagnostic and therapeutic context of Ada

• Immunohistochemistry of adenosine deaminase: implications for adenosine neurotransmission [18].
• This finding was corroborated by the observations that CTF behaves identically to adenosine when subjected to liquid chromatography, is inactivated and converted to inosine by adenosine deaminase, and is qualitatively and quantitatively indistinguishable from adenosine in its biological activity [32].
• The activity of adenosine deaminase (ADA) was measured in 62 discrete regions of the CNS, and in some autonomic and sensory ganglia, peripheral nerves, and peripheral tissues of the rat using an automated high-pressure liquid chromatography (HPLC) method [33].
• Electron paramagnetic resonance spin trapping measurements of free radical generation showed that inhibition of adenosine deaminase with EHNA blocked free radical generation and that it also increased the recovery of contractile function by more than 2-fold [34].
• Enrichment or depletion of cortical thymocytes by density gradient centrifugation, cortisone treatment, or selective lysis with anti-Thy-1 plus complement resulted in parallel increases or decreases in ADA levles [35].

References