Disease relevance of ADA

• Derivatized bovine adenosine deaminase is used in enzyme replacement therapy and as an adjunct to gene therapy against severe combined immunodeficiency syndrome [1].
• We employed intracoronary infusions of calf intestine adenosine deaminase (ADA) to test the hypothesis that adenosine regulates coronary blood flow during myocardial reactive hyperemia (RH) [2].
• Infusions of 4.5 U ADA/min per kg body weight into the left circumflex coronary artery of 10 open-chest dogs reversibly reduced repayment of flow debt by 30-39% (P less than 0.05) following 5-, 10-, 15-, 20-, and 30-second coronary occlusions, the percentage reduction being independent of occlusion length [2].
• We concluded that serum ADA activity may be of value in bovine liver disease diagnosis [3].
• In the present study, ADA seric activity was evaluated comparatively to the comparative tuberculin test in the diagnosis of bovine tuberculosis [4].

High impact information on ADA

• In comparison, ATP and the stable analogue of AMP, adenosine monophosphorothioate (AMPS), were significantly less potent and efficacious than adenosine and AMP, and adenosine receptor antagonist 8-(p-sulfophenyl)theophylline and abolished in the presence of adenosine deaminase and alpha, beta-methylene-ADP (APCP, an inhibitor of AMP degradation) [5].
• Binding of the A1-adenosine antagonist [3H]8-cyclopentyl-1,3-dipropylxanthine (DPCPX) to guinea pig atrial membranes treated with adenosine deaminase and APCP was reduced up to 60% by 100 microM concentrations of AMP, AMPS, and adenosine [5].
• In six other dogs, ADA plus theophylline did not reduce RH flow debt repayment below that produced by ADA alone [2].
• Intracoronary infusions of [131]ADA in seven dogs produced interstitial ADA concentrations between 1.2 and 13.1 U/ml in perfused myocardium and, in five of these dogs, 131I activity in the cardiac node was 1.8-35 times that of contiguous mediastinal tissue [2].
• The purified enzyme was not inhibited by 2'-deoxycoformycin, a transition state analog inhibitor of adenosine deaminase and AMP deaminase, suggesting that the catalytic mechanism of DRADA might be different from that of other deaminases [6].

Chemical compound and disease context of ADA

• Purine 2'-deoxyriboside was shown to behave as a competitive inhibitor of adenosine deaminase from calf intestinal mucosa and Bacillus cereus, with apparent Ki values of 4.5 and 8.5 microM, respectively [7].

Biological context of ADA

• Docking simulations of aminopyrazolopyrimidines into the ADA binding site were also performed, to rationalize the structure-activity relationships of this class of inhibitors [8].
• To define more specific structural details of substrate preferences for binding and catalysis, we have studied the ADA binding efficiencies and deamination kinetics of several synthetic adenosine analogues in which the furanosyl ring is biased toward a particular conformation [9].
• In addition, the substrate specificities (Km and Vmax) of purified calf spleen PNP for inosine and 2',3'-dideoxyinosine (ddI) and of purified calf intestinal ADA for 2',3'-dideoxyadenosine (ddA), 6-chloro-2',3'-dideoxypurine (6-Cl-ddP), and 2'-beta-fluoro-2', 3'-dideoxyadenosine (F-ddA) have been explored [10].
• The aqueous extraction of dried garlic powder showed also an inhibition if ADA activity, but the IC50 value was in the range of 2.5 mg per ml indicating that parts of the active principle were lost during the preparation of the garlic powder [11].
• The experimental evidence allows us to hypothesise some similarity in the three dimensional structures of the binding site of the two proteins, ADA and A1 adenosine receptor, in spite of lacking any homologies in the amino acid sequences [12].

Anatomical context of ADA

• RESULTS: The activities of ADA and PNP were 42-fold and 247-fold higher in the cerebral microvessels than in the cerebral cortex, respectively, while there was no detectable CDA activity in the microvessel fraction and very little overall activity in the cortex [10].
• CONCLUSIONS: ADA and PNP may serve as an enzymatic blood-brain barrier for some of the anti-HIV dideoxynucleosides [10].
• Activities of alkaline phosphatase, gamma-glutamyl transpeptidase, ADA, PNP and CDA were determined in various tissue homogenates (cerebral cortex, BBMECs and erythrocytes) [10].
• Aqueous extracts of fresh garlic (Allium sativum L.) inhibited efficiently the activity of adenosine deaminase (ADA) of cultivated endothelial cells [11].
• Nucleoside dialdehydes 1, 4, and 5 were weak substrates for adenosine aminohydrolase from calf intestinal mucosa [13].

Associations of ADA with chemical compounds

• Theophylline, a specific adenosine antagonist, reduced repayment of flow debt by 27-36% (P less than 0.02) in eight dogs, an effect similar to that of ADA [2].
• The latter value was confirmed (22 s-1) by spectrofluorometrically monitoring the trapping of ADA by excess erythro-9-(2-hydroxy-3-nonyl) adenine as aMDAP.ADA dissociated [14].
• Similarly, purine riboside inhibitors of ADA that prefer the N hemisphere were more potent inhibitors than S analogues [9].
• A series of erythro-1-(2-hydroxy-3-nonyl)imidazole derivatives have been synthesized and evaluated for adenosine deaminase (ADA) inhibitory activity, in order to introduce simplifications in the ADA inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 1a) and 3-deaza-EHNA (1c) [15].
• Opening the pyrimidine or pyridine ring of EHNA or 3-deaza-EHNA respectively led to compounds which are still ADA inhibitors [15].

Physical interactions of ADA

• ADA activity was found to be modulated by the membrane-bound adenosine deaminase complexing protein (CP=DPPIV=CD26) [16].

Other interactions of ADA

• A2R antagonist CSC and adenosine degradation by adenosine deaminase reduced hypoxic stimulation of VEGF mRNA 68% +/- 18% (P = 0.038) and 37% +/- 6% (P = 0.025), respectively, in a dose-dependent manner [17].
• For detection of this site in membranes, it was necessary to remove metabolites with high affinities for this site enzymatically, e.g., adenosine by addition of adenosine deaminase and inosine by addition of nucleoside phosphorylase [18].
• We investigated the subcellular location of adenosine deaminase-complexing protein in the proximal renal tubules of rabbit kidney and its interaction with intravenously infused monomeric calf adenosine deaminase [19].

Analytical, diagnostic and therapeutic context of ADA

• Furthermore, ADA incubated in the absence of an inhibitor (ADA native) did not form any crystals using conventional crystallization methods [20].
• There was no agreement in the diagnosis of bovine TB between comparative tuberculin test and determination of ADA seric values, using two different cutoff points, being 6.12 U/L and 15.0 U/L, (kappa = -0.086 and kappa = -0.082, respectively) [4].
• The possibility of determining the Michaelis constant of the irreversible deamination of adenosine to inosine by adenosine deaminase, using capillary electrophoresis, was investigated [21].
• Kinetic and thermodynamic studies have been made on the effect of the inosine product on the activity of adenosine deaminase in a 50 mM sodium phosphate buffer, pH 7.5, at 27 degrees C using UV spectrophotometry and isothermal titration calorimetry (ITC) [22].
• Immobilization of adenosine deaminase onto agarose and casein [23].

References