Disease relevance of ADA

• ADA deficiency causes severe combined immunodeficiency disease (SCID) in humans [1].
• We have constructed retroviruses containing human ADA cDNA and a dominant selectable marker, a mutated dihydrofolate reductase gene (DHFR*) encoding methotrexate resistance [2].
• Human ADA cDNA was inserted alone (DHFR*-ADA) or with a simian virus 40 (SV40) promoter (DHFR*-SVADA) [2].
• Cells from "null"-ALL patients had an ADA/PNP ratio that was intermediate between that of normal T cells and that of T-ALL cells or thymocytes, but their 5'NT activity and LDH isoenzyme pattern were thymocyte-like [3].
• The PNP and ADA staining was observed in lymphoid cells of patients with lymphoproliferative disorders [4].
• The high rate of neurologic abnormalities observed in long-term surviving patients with ADA deficiency indicates that HSCT commonly fails to control CNS complications in this metabolic disease [5].

Psychiatry related information on ADA

• Nitric oxide, adenosine deaminase, xanthine oxidase and superoxide dismutase in patients with panic disorder: alterations by antidepressant treatment [6].
• Direct assessments of ADA catalytic activity in autistic individuals and unaffected siblings carrying ADA1/ADA1 vs ADA1/ADA2 genotypes may provide stronger evidence of ADA2 contributions to autistic disorder [7].
• A specific correlation to drug addition and its duration was observed: LAS subjects who discontinued drug abuse (median addiction time: 3 years) presented ADA values (median = 13 U) that are lower than for addicts (median = 27.2 U; median addiction time = 7 years) and are close to those observed for asymptomatic HIV-I serum-positive group [8].
• Association of adenosine deaminase polymorphism with mild mental retardation [9].
• DESIGN AND METHODS: Serum neopterin concentration, and the chitotriosidase (ChT), angiotensin-converting enzyme (ACE) and adenosine deaminase (ADA) activities were determined in 30 patients with AD, in 19 patients with other types of dementia, and in 24 nonaffected controls [10].

High impact information on ADA

• Adenosine deaminase deficiency results in toxic accumulations of metabolites that cause T cell apoptosis [11].
• The initial protocols were aimed at the correction of peripheral blood T lymphocytes, but recent strategies are attempting ADA gene transfer into peripheral blood or bone marrow stem cells [12].
• Adenosine deaminase (ADA) deficiency causes a form of severe combined immunodeficiency [12].
• Stable gene transfer and expression of human ADA has now been obtained in hematopoietic stem cells of mice and, more recently, in large animals [12].
• Mosaicism due to reversion was evidenced by absence of a maternally transmitted deleterious mutation in 13/15 authenticated B cell lines and in 17% of single alleles cloned from blood DNA, despite retention of a maternal 'private' ADA polymorphism linked to the mutation [13].

Chemical compound and disease context of ADA

• Adenosine deaminase (ADA), a protein whose deficit leads to severe combined immunodeficiency, binds to the cell surface by means of either CD26, A(1) adenosine receptors, or A(2B) adenosine receptors [14].
• Variation in the distribution of these enzymes in T cell subsets may explain their different sensitivities to deoxyadenosine and deoxyguanosine toxicity and the different effects on T cell development of ADA or PNP deficiency [15].
• HIV-1 external envelope glycoprotein gp120 inhibits adenosine deaminase (ADA) binding to its cell surface receptor in lymphocytes, CD26, by a mechanism that does not require the gp120-CD4 interaction [16].
• Adenosine deaminase (ADA) is a purine enzyme which is essential for the proliferation, maturation and function of lymphoid cells, and congenital deficiency of this enzyme is associated with severe combined immunodeficiency disease [17].
• Adenosine deaminase, 5'-nucleotidase, xanthine oxidase, superoxide dismutase, and catalase activities in gastric juices from patients with gastric cancer, ulcer, and atrophic gastritis [18].

Biological context of ADA

• Amino acid sequence analysis and immunoprecipitation studies demonstrated that this 43-kilodalton protein was adenosine deaminase (ADA) [1].
• We have now mutagenized conserved alpha2-helix residues in human and mouse ADA and used surface plasmon resonance to evaluate binding kinetics to immobilized rabbit CD26 [19].
• The 125I-labeled ADA-specific binding to human CD26 was not affected by Tat, even at concentrations which induced cell death [20].
• We performed a study in 83 children with untreated ALL to establish the relationships of ADA and PNP to clinical outcome, in vitro drug resistance and differentiation stage of B-cell lineage ALL [21].
• The observation suggests that, in a diabetic environment, intrauterine selection may act against double heterozygotes for the ACP1 and ADA systems [22].

Anatomical context of ADA

• ADA was coexpressed with CD26 on the Jurkat T cell lines, and an in vitro binding assay showed that the binding was through the extracellular domain of CD26 [1].
• From colocalization studies, it is deduced that ADA colocalizing with adenosine receptors on dendritic cells interact with CD26 expressed on lymphocytes [14].
• ADA activity was also increased after infection of a human ADA-deficient B-cell line [2].
• Although NIH 3T3 cells infected with either construct produced human ADA activity, substantially greater levels were attained with DHFR*-SVADA [2].
• In erythrocytes from healthy individuals, mean (SD) ADA activity was 5619 (2584) nmol/s per liter of packed cells [23].

Associations of ADA with chemical compounds

• The deoxynucleoside kinases (deoxyguanosine, deoxyadenosine, and deoxycytidine kinases) paralleled the changes in ADA and TdT activity among the different T subsets [15].
• On epithelia and lymphoid cells of humans, but not mice, ADA also occurs bound to the membrane glycoprotein CD26/dipeptidyl peptidase IV [19].
• Mutating these residues to alanine increased dissociation rates 6-11-fold and the apparent dissociation constant K(D) for wild type human ADA from 17 to 112-160 nm, changing binding free energy by 1.1-1.3 kcal/mol [19].
• It is associated with molecules of immunological importance such as the protein tyrosine phosphatase CD45 and adenosine deaminase (ADA) on the cell surface [24].
• Among the 5 non-conserved residues within this segment, Arg-142 in human and Gln-142 in mouse ADA largely determined the capacity for stable binding to CD26 (Richard, E., Arredondo-Vega, F. X., Santisteban, I., Kelly, S. J., Patel, D. D., and Hershfield, M. S. (2000) J. Exp. Med. 192, 1223-1235) [19].

Physical interactions of ADA

• Human ADA binds to CD26 on the surface 1-LN cells and immobilized CD26 isolated from the same cells with similar affinity [25].
• Reporter assays and chromatin immunoprecipitation experiments indicate a physical interaction of p63 with the two putative p53 binding sites we identified in the ADA gene [26].
• We have examined the effects of equivalent site-directed mutations in each of the three R-motif copies of dsRAD on RNA-binding activity and adenosine deaminase enzyme activity [27].
• We measured urinary levels of total protein, N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase, and adenosine deaminase-binding protein in ten children with osteogenic sarcoma who were receiving combination chemotherapy that included 12 doses of methotrexate (12 g/m2) [28].

Co-localisations of ADA

• Introduction of the nucleotide substitution into an ADA 1 cDNA and transfection into monkey kidney (Cos) cells confirmed that the mutation resulted in expression of an enzyme that comigrated with the naturally occurring ADA 2 allozyme [29].
• SDF-1alpha and gp120 induce the appearance of pseudopodia in which CD26 and CXCR4 colocalize and in which ADA is not present [30].

Regulatory relationships of ADA

• Cell surface adenosine deaminase binds and stimulates plasminogen activation on 1-LN human prostate cancer cells [25].
• We have tried to determine whether inactivation of AdoHcyase might also contribute to dAdo toxicity to adenosine deaminase-inhibited cells. dAdo rapidly inactivates intracellular AdoHcyase and causes the accumulation of AdoHcy in WI-L2 human B lymphoblastoid cells [31].
• The presence of ADA may promote the signaling through the adenosine A1 receptor in HEK293 cells [32].
• More importantly, adenosine in the absence of cell surface ADA inhibited T cell proliferation and IL-2 production induced by various stimuli [33].
• We investigated the metabolism of some adenosine analogues in adenosine deaminase inhibited normal and adenine phosphoribosyltransferase (APRT) deficient human erythrocytes [34].

Other interactions of ADA

• Direct association of adenosine deaminase with a T cell activation antigen, CD26 [1].
• A suspension of living lymphocytes is mixed with agarose sol containing the reagents for the detection of PNP or ADA activity on a glass slide [4].
• Proinflammatory cytokines did not affect ADA1 activity or ADA mRNA expression in RA FLS [35].
• Since ADA and Pg bind to CD26 at distinct but nearby sites, we investigated a possible interaction between these two proteins on the surface of 1-LN cells [25].
• Increased ADA and decreased XO, SOD, and CAT activities were found in cancerous bladder tissues compared with those of cancer-free adjacent tissues and of control bladder tissues [36].

Analytical, diagnostic and therapeutic context of ADA

• Our results show that by a 3-fold reduction in the EC(50) for the antigen, ADA potentiated T cell proliferation in autologous cocultures with antigen-pulsed immature or mature dendritic cells [14].
• Three of the ADA-deficient patients and one of the PNP-deficient patients were given transplants of haploidentical parental bone marrow stem cells without pretransplant immunosuppression [37].
• Transfection of cultured mouse L-cells with this plasmid resulted in the acute expression of human ADA enzymatic activity, as assayed by isoelectric focusing [38].
• Even though the sequence of porcine DP IV, amplified by RT-PCR, revealed 88% identity between both enzymes, the species-specific variations between amino acids 328 to 341 are likely to be responsible for the differences in ADA-binding [39].
• On the other hand, ADA, 5NT activities and protein concentrations in the gastric juice were lower in the gastritis group than control group [18].

References