Disease relevance of deoxyadenosine

• Deoxyadenosine metabolism and cytotoxicity in cultured mouse T lymphoma cells: a model for immunodeficiency disease [1].
• It is proposed that dATP can mediate both 2'-deoxyguanosine and 2'-deoxyadenosine toxicity in T lymphoblasts [2].
• Adenosine deaminase (ADA) deficiency causes severe combined immune deficiency (SCID) by interfering with the metabolism of deoxyadenosine, which is toxic to T lymphocytes at all stages of differentiation [3].
• Administration of adenosine or 2'-deoxyadenosine without dCF did not cause hemolysis, and use of these two agents with dCF did not potentiate the observed hemolysis [4].
• Deoxycytidine kinase-mediated toxicity of deoxyadenosine analogs toward malignant human lymphoblasts in vitro and toward murine L1210 leukemia in vivo [5].

Psychiatry related information on deoxyadenosine

• With longer reaction times, the formation of a minor amount of dialkylated 2'-deoxyadenosine was observed [6].
• Five patients had nausea/vomiting, and/or lethargy following DCF, but there was no correlation between the plasma levels of deoxyadenosine and adenosine and the incidence or severity of these side effects [7].

High impact information on deoxyadenosine

• The ADA substrates, adenosine and deoxyadenosine, are increased in ADA-deficient mice [8].
• The activity of S-adenosylhomocysteine hydrolase, which is inactivated by deoxyadenosine, increased to normal in red cells and nucleated marrow cells [9].
• Each BcPh diol epoxide isomer exhibits a remarkable preference for covalent binding to DNA over hydrolysis, each yields a unique distribution of products with the nucleosides of DNA and each reacts extensively with deoxyadenosine residues in DNA [10].
• This enzyme, although constitutively expressed in most tissues, is expressed at high level in immature T cells, and study of the pathophysiology of the disorder indicates that increased deoxyadenosine or altered methylation capacity have toxic effects on T-cell maturation [11].
• 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 [12].

Chemical compound and disease context of deoxyadenosine

• The repair of DNA single strand breaks in chronic lymphocytic leukemia cells was as rapid as for proliferating L5178Y cells, but repair was significantly inhibited by 2'-deoxycoformycin/deoxyadenosine [13].
• Incubation of deoxycoformycin-treated L1210 leukemia cells with dipyridamole or nitrobenzylthioinosine, inhibitors of nucleoside transport, enhanced the long-term incorporation of 2'-deoxyadenosine and adenosine into the nucleotide pool and the toxicity of 2'-deoxyadenosine for the cells [14].
• 5-Hexyl-2'-deoxyuridine blocks the cytotoxic effects of 5-fluorodeoxyuridine or deoxyadenosine in leukemia L1210 cells in culture [15].
• Leukemia L1210 cell lines, ED1 and ED2, were generated which were resistant to the cytotoxic effects of deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine and deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine plus 2,3-dihydro-1H-pyrazole[2,3a]imidazole/Desferal, respectively [16].
• Supplementation of cells cultured under hypoxia with a combination of deoxynucleosides (100 microM deoxycytidine, 10 microM deoxyadenosine, 10 microM deoxyguanosine) was found to stimulate reprogression through the cycle, provided the residual oxygen tension in the protective atmosphere exceeded 40 ppm [17].

Biological context of deoxyadenosine

• 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 [12].
• The lymphotoxic effect of deoxyadenosine and CdA required their phosphorylation, and was inhibited by deoxycytidine [18].
• Deoxyguanosine or deoxyadenosine combined with HAG-IQ inhibited cell growth in an additive manner; three-drug combinations, HAG-IQ plus either deoxyguanosine/8-aminoguanosine or deoxyadenosine/deoxycoformycin, were strongly synergistic [19].
• Duplex DNA oligomer constructs (32 base pairs) were prepared that contained a single benzo[a]pyrene (BP) adduct at a specific deoxyadenosine or deoxyguanosine site in either one or both strands [20].
• In summary, we describe a previously undescribed human DNA repair activity, possibly a glycosylase, that excises from DNA pbqC and pbqA, exocyclic adducts resulting from reaction of deoxycytidine and deoxyadenosine with the benzene metabolite, p-BQ [21].

Anatomical context of deoxyadenosine

• The high lipophilicity of the new agents permits the transport of adenosine and deoxyadenosine across organic liquid membranes [22].
• Elevated dATP levels in lymphocytes and bone marrow, and increased urinary excretion of deoxyadenosine, persisted despite hypertransfusion of the child with irradiated erythrocytes from a donor with normal adenosine deaminase [23].
• We have determined concentrations of adenosine, deoxyadenosine, and deoxyATP (dATP) in cord blood from an infant prenatally diagnosed as ADA deficient [24].
• These cell lines have normal deoxyadenosine kinase (ATP:deoxyadenosine 5'-phosphotransferase, EC 2.7.1.76) activity [25].
• Furthermore, phagocytosis of nucleated erythrocytes augmented the excretion of deoxyadenosine [26].

Associations of deoxyadenosine with other chemical compounds

• Adenosine deaminase (ADA) is a purine catabolic enzyme that manages levels of the biologically active purines adenosine and 2'-deoxyadenosine in tissues and cells [27].
• These results suggest that NAD depletion, probably triggered by poly(ADP-ribose) formation, is the principle cause of death in normal resting human lymphocytes exposed to deoxyadenosine plus deoxycoformycin, or to CdA [18].
• ADA-deficient cultures were also rescued by the adenosine kinase inhibitor 5'-amino-5'-deoxyadenosine (5'A5'dAdo), indicating that the metabolite responsible for the inhibition of thymocyte development is not adenosine or deoxyadenosine, but a phosphorylated derivative of an ADA substrate [28].
• The deoxyadenosine analogs 2-chlorodeoxyadenosine, 2-fluorodeoxyadenosine, and adenine arabinonucleoside also killed resting T cells [29].
• In the presence of deoxyadenosine or deoxyguanosine, elevation of the corresponding deoxyribonucleoside triphosphate (dATP or dGTP) occurs in T cell, but not in B cell, lines [30].

Gene context of deoxyadenosine

• Exposure of the transfected cells to 2'-deoxyadenosine and an ADA inhibitor increased the dATP pool and resulted in a marked increase in A-T insertions at recombination junctions, with an overall decreased frequency of V(D)J recombination [31].
• Resistance of an adenosine kinase-deficient human lymphoblastoid cell line to effects of deoxyadenosine on growth, S-adenosylhomocysteine hydrolase inactivation, and dATP accumulation [32].
• In human T cells, we investigated the effect of dCF and deoxyadenosine (AdR) on cell activation, interleukin 2 (IL 2) production, and IL 2 receptor induction after allogeneic and lectin-induced stimulation [33].
• 2'Deoxycoformycin and deoxyadenosine affect IL 2 production and IL 2 receptor expression of human T cells [33].
• The above data are consistent with the metabolism of SAM to ATP by a route recently identified by us whereby ATP is formed from deoxyadenosine: namely binding to the enzyme S-adenosylhomocysteine hydrolase with subsequent release of adenine and further conversion to ATP via APRT [34].

Analytical, diagnostic and therapeutic context of deoxyadenosine

• When administered by continuous intravenous infusion, the deoxyadenosine analog was well tolerated [35].
• We have used flow cytometry to investigate the mechanism of deoxyadenosine toxicity in cultured T-leukemic cells [36].
• Primary mouse embryo cell cultures were grown in the presence of [14C]guanine, labeling primarily deoxyguanosine residues in the cellular DNA, or in the presence of [14C]adenine, labeling both deoxyguanosine and deoxyadenosine residues in the cellular DNA [37].
• Four peaks of deoxyadenosine phosphorylating activity were resolved by affinity chromatography with AMP-Sepharose 4B [38].
• This is based on stereospecific two-step conversion of the mono-thionucleotide into the corresponding deoxyadenosine 5'-O-alpha-[(18)O]thiotriphosphate, followed by the use of terminal deoxyribonucleotidyl transferase and MALDI TOF mass spectrometry of the resulting elongated primer [39].

References