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Biochemical Pharmacology Oct 2003Adenosine deaminase (ADA) catalyzes the conversion of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. ADA-deficient individuals suffer from... (Review)
Review
Adenosine deaminase (ADA) catalyzes the conversion of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. ADA-deficient individuals suffer from severe combined immunodeficiency and are unable to produce significant numbers of mature T or B lymphocytes. This occurs as a consequence of the accumulation of ADA substrates or their metabolites. dATP is a candidate toxic metabolite because its concentration in RBCs of ADA-deficient patients correlates with the severity of disease. Murine fetal thymic organ culture (FTOC) under ADA-deficient conditions can be used as a model system to investigate the biochemical mechanism responsible for the inhibition of thymopoiesis. In ADA-deficient FTOCs initiated at day 15 of gestation, thymocyte development was arrested at the CD4(-)CD8(-)CD44(lo)CD25(+) to CD4(-)CD8(-)CD44(lo)CD25(-) transition. Apoptosis appeared to be involved because the cultures could be rescued by the pan-caspase inhibitor zVADfmk, a Bcl-2 transgene, or deletion of apoptotic protease activating factor-1. As in ADA-deficient patients, dATP was also elevated in ADA-deficient FTOCs. dATP levels were normalized and thymocyte development was rescued in cultures treated with an inhibitor of adenosine kinase, the enzyme that phosphorylates deoxyadenosine to dAMP. zVADfmk also prevented the accumulation of dATP in ADA-deficient FTOCs, suggesting that deoxyadenosine was derived from thymocytes undergoing apoptosis as a consequence of failing the beta selection checkpoint. In contrast, dATP levels remained elevated in ADA-deficient FTOCs with fetal thymuses from Bcl-2 transgenic mice. These data suggest that thymocyte apoptosis as a consequence of failing developmental checkpoints involves one or more caspases that are not regulated by Bcl-2.
Topics: Adenosine Deaminase; Animals; Apoptosis; Fetus; Humans; Thymus Gland
PubMed: 14555239
DOI: 10.1016/s0006-2952(03)00530-6 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Jun 2020
Topics: Adenosine Deaminase; Biomedical Research; Humans; Immunologic Deficiency Syndromes; Intercellular Signaling Peptides and Proteins
PubMed: 32521969
DOI: 10.3760/cma.j.cn112140-20191016-00651 -
Ryoikibetsu Shokogun Shirizu 1998
Review
Topics: Adenosine Deaminase; Bone Marrow Transplantation; Humans; Mutation; Prognosis; Purine-Pyrimidine Metabolism, Inborn Errors
PubMed: 9590099
DOI: No ID Found -
Molecular Cell Nov 2023Effective immunity requires the innate immune system to distinguish foreign nucleic acids from cellular ones. Cellular double-stranded RNAs (dsRNAs) are edited by the...
Effective immunity requires the innate immune system to distinguish foreign nucleic acids from cellular ones. Cellular double-stranded RNAs (dsRNAs) are edited by the RNA-editing enzyme ADAR1 to evade being recognized as viral dsRNA by cytoplasmic dsRNA sensors, including MDA5 and PKR. The loss of ADAR1-mediated RNA editing of cellular dsRNA activates MDA5. Additional RNA-editing-independent functions of ADAR1 have been proposed, but a specific mechanism has not been delineated. We now demonstrate that the loss of ADAR1-mediated RNA editing specifically activates MDA5, whereas loss of the cytoplasmic ADAR1p150 isoform or its dsRNA-binding activity enabled PKR activation. Deleting both MDA5 and PKR resulted in complete rescue of the embryonic lethality of Adar1p150 mice to adulthood, contrasting with the limited or no rescue by removing MDA5 or PKR alone. Our findings demonstrate that MDA5 and PKR are the primary in vivo effectors of fatal autoinflammation following the loss of ADAR1p150.
Topics: Animals; Mice; Adenosine Deaminase; Cytoplasm; Immunity, Innate; RNA, Double-Stranded
PubMed: 37797622
DOI: 10.1016/j.molcel.2023.09.018 -
Comparative Biochemistry and... Jun 1995Extracts of liver and spleen were used to isolate opossum adenosine deaminase isoenzymes (ADA1 and ADA2) and to determine their activities with adenosine and... (Comparative Study)
Comparative Study
Extracts of liver and spleen were used to isolate opossum adenosine deaminase isoenzymes (ADA1 and ADA2) and to determine their activities with adenosine and 2'-deoxyadenosine as substrates. Km values (microM) for adenosine and 2'-deoxyadenosine, respectively, as substrates for partially purified opossum liver adenosine deaminase isoenzymes were ADA1: 57 +/- 7 vs. 26 +/- 4 and ADA2: 285 +/- 25 vs. 580 +/- 92. In crude spleen extract, ADA2 activity was stable at 56 degrees C during 40 min of incubation. ADA1 activity declined in a linear fashion under the above conditions with an apparent T1/2 of 80 min. Sephadex G-150 column chromatography of crude spleen extract showed the apparent molecular weight of the ADA activity not inhibited by (+/-)-EHNA (i.e. ADA2) to be 170 kDa; ADA activity fully inhibited by (+/-)-EHNA (i.e. ADA1) eluted in the fractions corresponding to a molecular weight of 35 kDa.
Topics: Adenosine Deaminase; Animals; Enzyme Stability; Humans; Isoenzymes; Kinetics; Liver; Opossums; Spleen
PubMed: 7599990
DOI: 10.1016/0305-0491(94)00249-t -
In Vivo (Athens, Greece) 2024Adenosine deaminase family acting on RNA 1 (ADAR1) expression was examined to determine its correlation with endometriosis. The biological functions and inhibitory...
BACKGROUND/AIM
Adenosine deaminase family acting on RNA 1 (ADAR1) expression was examined to determine its correlation with endometriosis. The biological functions and inhibitory effects of ADAR1 knockdown were investigated in a human endometriotic cell line.
MATERIALS AND METHODS
ADAR1 was examined in patients with and without endometriosis using reverse transcription polymerase chain reaction (RT-PCR), and the apoptotic expression of ADAR1 small interfering RNA (siRNA) was confirmed using flow cytometry. The biological functions and inhibitory effects of ADAR1 knockdown were investigated using RT-PCR in a 12Z immortalized human endometriotic cell line.
RESULTS
ADAR1 expression was significantly higher in patients with endometriosis than in those without (p<0.001). ADAR1 siRNA increased early and late apoptosis, compared to the mock (24.83%) and control (19.96%) cells. ADAR1 knockdown led to apoptosis through MDA5, RIG-I, IRF3, IRF7, caspase 3, caspase 7, and caspase 8 expression in the cell lines.
CONCLUSION
ADAR1 is a potential novel therapeutic target in endometriosis.
Topics: Female; Humans; Adenosine Deaminase; Endometriosis; Cell Line; RNA, Small Interfering; Caspase 3
PubMed: 38418109
DOI: 10.21873/invivo.13489 -
Lancet (London, England) Mar 2021
Topics: Adenosine Deaminase; Aged; Female; Humans; Inflammation; Infliximab; Intercellular Signaling Peptides and Proteins; Vasculitis
PubMed: 33676630
DOI: 10.1016/S0140-6736(20)32660-X -
Biochimica Et Biophysica Acta Aug 1992Several adenosine analogs, such as coformycin, 2'-deoxycoformycin and erythro-9-(3-nonyl-p-aminobenzyl)adenine (EHNA), which are strong inhibitors of mammalian adenosine...
Several adenosine analogs, such as coformycin, 2'-deoxycoformycin and erythro-9-(3-nonyl-p-aminobenzyl)adenine (EHNA), which are strong inhibitors of mammalian adenosine deaminase, are much weaker inhibitors of the Saccharomyces cerevisiae enzyme. The specificity of the yeast enzyme is more restricted than that of mammalian adenosine deaminase, particularly towards the ribose moiety and around position 6 and 1 of the substrate. The sulphydryl group appears to be more masked in the yeast than in the mammalian enzyme. The kinetic effects of pH with adenosine substrate and with the inhibitor purine riboside are reported. The findings on specificity and pH kinetic effects can be interpreted in a model involving proton transfer from the -SH group of the enzyme to the N-1 atom of the substrate.
Topics: Adenine; Adenosine Deaminase; Adenosine Deaminase Inhibitors; Binding Sites; Hydrogen-Ion Concentration; Kinetics; Saccharomyces cerevisiae; Temperature
PubMed: 1504093
DOI: 10.1016/0167-4838(92)90410-f -
Journal of Biomolecular Structure &... Feb 2023Adenosine deaminase is a zinc dependent key enzyme of purine metabolism which irreversibly converts adenosine to inosine and form ammonia. Overexpression of adenosine...
Adenosine deaminase is a zinc dependent key enzyme of purine metabolism which irreversibly converts adenosine to inosine and form ammonia. Overexpression of adenosine deaminase has been linked to a variety of pathophysiological conditions such as atherosclerosis, hypertension, and diabetes. In the case of a cell-mediated immune response, ADA is thought to be a marker, particularly in type II diabetes. Deoxycoformycin is the most potent ADA inhibitor that has been discovered so far, but it has several drawbacks, including being toxic and having poor pharmacokinetics. Taxifolin, a flavonoid derived from plants, was discovered to be a potent inhibitor of the human ADA (hADA) enzyme in the current study. Taxifolin bound at the active site of human ADA and showed fifty percent inhibition at a concentration of 400 µM against the enzyme. To better understand the interactions between taxifolin and human ADA, docking and molecular dynamic simulations were performed. In-silico studies using autodock revealed that taxifolin bound in the active site of human ADA with a binding energy of -7.4 kcal mol and a theoretical Ki of 3.7 uM. Comparative analysis indicated that taxifolin and deoxycoformycin share a common binding space in the active site of human ADA and inhibit its catalytic activity similarly. The work emphasises the need of employing taxifolin as a lead chemical in order to produce a more precise and effective inhibitor of the human ADA enzyme with therapeutic potential.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Adenosine Deaminase; Pentostatin; Diabetes Mellitus, Type 2; Adenosine Deaminase Inhibitors
PubMed: 34851227
DOI: 10.1080/07391102.2021.2006087 -
Journal of Inherited Metabolic Disease Jun 1997Adenosine deaminase (ADA) deficiency was the first known cause of primary immunodeficiency. Over the past 25 years the basis for immune deficiency has largely been... (Review)
Review
Adenosine deaminase (ADA) deficiency was the first known cause of primary immunodeficiency. Over the past 25 years the basis for immune deficiency has largely been established. Now it appears that ADA deficiency may also cause hepatic toxicity, raising new questions about its pathogenesis. The ADA gene has been sequenced and the ADA three-dimensional structure solved. The relationship between genotype and phenotype is being analysed, and ADA deficiency has become a focus for novel approaches to enzyme replacement and gene therapy.
Topics: Adenosine Deaminase; Animals; Humans; Purine-Pyrimidine Metabolism, Inborn Errors
PubMed: 9211190
DOI: 10.1023/a:1005300621350