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Nature Reviews. Immunology Apr 2024Recent progress in human and mouse genetics has transformed our understanding of the molecular mechanisms by which recognition of self double-stranded RNA (self-dsRNA)... (Review)
Review
Recent progress in human and mouse genetics has transformed our understanding of the molecular mechanisms by which recognition of self double-stranded RNA (self-dsRNA) causes immunopathology. Novel mouse models recapitulate loss-of-function mutations in the RNA editing enzyme ADAR1 that are found in patients with Aicardi-Goutières syndrome (AGS) - a monogenic inflammatory disease associated with increased levels of type I interferon. Extensive analyses of the genotype-phenotype relationships in these mice have now firmly established a causal relationship between increased intracellular concentrations of endogenous immunostimulatory dsRNA and type I interferon-driven immunopathology. Activation of the dsRNA-specific immune sensor MDA5 perpetuates the overproduction of type I interferons, and chronic engagement of the interferon-inducible innate immune receptors PKR and ZBP1 by dsRNA drives immunopathology by activating an integrated stress response or by inducing excessive cell death. Biochemical and genetic data support a role for the p150 isoform of ADAR1 in the cytosol in suppressing the spontaneous, pathological response to self-dsRNA.
Topics: Humans; Mice; Animals; RNA, Double-Stranded; Interferon Type I; Adenosine Deaminase
PubMed: 37752355
DOI: 10.1038/s41577-023-00940-3 -
Expert Opinion on Biological Therapy Sep 2007Numerous parallels exist between limited oxygen availability (hypoxia) and acute inflammation. The lungs in particular are prone to acute inflammation during hypoxia,... (Review)
Review
Numerous parallels exist between limited oxygen availability (hypoxia) and acute inflammation. The lungs in particular are prone to acute inflammation during hypoxia, resulting in pulmonary edema, vascular leakage and neutrophil infiltration. The innate response elicited by hypoxia is associated with increased extracellular adenosine effects. Although studies on acute pulmonary hypoxia show a protective role of extracellular adenosine by attenuating pulmonary edema and excessive inflammation, chronic elevation of pulmonary adenosine may be detrimental. Adenosine deaminase (ADA)-deficient mice, for example, develop signs of chronic pulmonary injury in association with highly elevated levels of adenosine. Thus, the authors hypothesized the existence of hypoxia-elicited clearance mechanisms to offset deleterious influences of chronically elevated adenosine. Such studies indicated a second response to hypoxia characterized by pulmonary induction of ADA and CD26. In fact, hypoxia-inducible ADA is enzymatically active and tethered on the outside of the membrane via CD26 to form a complex capable of degrading extracellular adenosine to inosine. This paper reviews metabolic and transcriptional changes of extracellular adenosine generation, signaling and degradation during acute and prolonged pulmonary hypoxia.
Topics: Adenosine; Adenosine Deaminase; Animals; Cell Hypoxia; Dipeptidyl Peptidase 4; Endothelium, Vascular; Humans; Lung Diseases; Signal Transduction
PubMed: 17727332
DOI: 10.1517/14712598.7.9.1437 -
Indian Journal of Pediatrics Aug 2016
Topics: Adenosine Deaminase; Agammaglobulinemia; Humans; Immunologic Deficiency Syndromes; Mutation; Severe Combined Immunodeficiency
PubMed: 27086606
DOI: 10.1007/s12098-016-2098-y -
Protein Expression and Purification Aug 2011The sequencing of the genome of Streptomyces coelicolor A3(2) identified seven putative adenine/adenosine deaminases and adenosine deaminase-like proteins, none of which...
The sequencing of the genome of Streptomyces coelicolor A3(2) identified seven putative adenine/adenosine deaminases and adenosine deaminase-like proteins, none of which have been biochemically characterized. This report describes recombinant expression, purification and characterization of SCO4901 which had been annotated in data bases as a putative adenosine deaminase. The purified putative adenosine deaminase gives a subunit Mr=48,400 on denaturing gel electrophoresis and an oligomer molecular weight of approximately 182,000 by comparative gel filtration. These values are consistent with the active enzyme being composed of four subunits with identical molecular weights. The turnover rate of adenosine is 11.5 s⁻¹ at 30 °C. Since adenine is deaminated ∼10³ slower by the enzyme when compared to that of adenosine, these data strongly show that the purified enzyme is an adenosine deaminase (ADA) and not an adenine deaminase (ADE). Other adenine nucleosides/nucleotides, including 9-β-D-arabinofuranosyl-adenine (ara-A), 5'-AMP, 5'-ADP and 5'-ATP, are not substrates for the enzyme. Coformycin and 2'-deoxycoformycin are potent competitive inhibitors of the enzyme with inhibition constants of 0.25 and 3.4 nM, respectively. Amino acid sequence alignment of ScADA with ADAs from other organisms reveals that eight of the nine highly conserved catalytic site residues in other ADAs are also conserved in ScADA. The only non-conserved residue is Asn317, which replaces Asp296 in the murine enzyme. Based on these data, it is suggested here that ADA and ADE proteins are divergently related enzymes that have evolved from a common α/β barrel scaffold to catalyze the deamination of different substrates, using a similar catalytic mechanism.
Topics: Adenosine; Adenosine Deaminase; Amino Acid Sequence; Animals; Bacterial Proteins; Cloning, Molecular; Electrophoresis, Polyacrylamide Gel; Escherichia coli; Humans; Inosine; Models, Molecular; Molecular Sequence Data; Recombinant Proteins; Sequence Alignment; Streptomyces coelicolor
PubMed: 21511036
DOI: 10.1016/j.pep.2011.04.003 -
Clinical and Experimental Hypertension... 2019Adenosine modulates cardiovascular functions reducing blood pressure and heart rate. Adenosine deaminase (ADA) by the irreversible deamination of adenosine to inosine...
Adenosine modulates cardiovascular functions reducing blood pressure and heart rate. Adenosine deaminase (ADA) by the irreversible deamination of adenosine to inosine contributes to the regulation of adenosine concentration in body fluids. We have studied the interaction between smoking and ADA genetic variability concerning their effects on blood pressure. We have studied 344 subjects admitted to the hospital for cardiovascular diseases. The genotypes of two polymorphic loci within the ADA gene were determined: ADA and ADA. Both loci show two alleles: ADA*1 and ADA*2 in ADA locus and ADA*1 and ADA*2 in ADA locus. In the absence of smoking, the proportion of subjects with hypertension tends to be lower in carriers of the ADA*2 allele. In smoking subjects, the pattern is reversed and the proportion of those with hypertension tends to be higher in carriers of the ADA*2 allele. A similar pattern is observed for ADA locus. Smoking increases the proportion of subjects showing hypertension: such effect is more marked in those carrying the ADA*2 allele as compared to subjects with ADA*1/*1 genotype. The same pattern of association is observed for ADA locus. The two loci show an additive effect. The odds ratio for hypertension in smokers vs nonsmokers is 1.450 in subjects carrying ADA*1/*1 and ADA*1/*1 genotypes, while it is 11.200 in subjects carrying the *2 alleles in both loci. From a practical point, a view of our results suggest that smokers carrying both ADA*2 and ADA*2 alleles have a higher risk of hypertension.
Topics: Adenosine Deaminase; Adult; Alleles; Female; Genotype; Humans; Hypertension; Polymorphism, Genetic; Smoking
PubMed: 30192643
DOI: 10.1080/10641963.2018.1516776 -
The Journal of Antimicrobial... Oct 2003
Review
Topics: Adenosine Deaminase; Animals; Catalysis; Drug Design; Humans; Nucleosides; Prodrugs; Ribavirin
PubMed: 12951339
DOI: 10.1093/jac/dkg405 -
JAMA Network Open May 2023
Topics: Humans; Adenosine Deaminase; Intercellular Signaling Peptides and Proteins; Erythrocytes
PubMed: 37256627
DOI: 10.1001/jamanetworkopen.2023.15828 -
Trends in Pharmacological Sciences Feb 2003Chronic lung diseases are associated with persistent lung inflammation and damage. The mechanisms that govern the chronic nature of these disorders are not known.... (Review)
Review
Chronic lung diseases are associated with persistent lung inflammation and damage. The mechanisms that govern the chronic nature of these disorders are not known. Adenosine is a signaling nucleoside that is generated in hypoxic environments such as that found in the inflamed lung, which suggests that it might serve a regulatory role in chronic lung diseases. Support for this hypothesis comes from studies in adenosine-deaminase-deficient mice where lung adenosine levels accumulate in association with increased lung inflammation and damage. Furthermore, lowering adenosine levels or antagonizing adenosine receptors can reverse pulmonary phenotypes in this model, suggesting that chronic adenosine elevations can affect signaling pathways that mediate aspects of chronic lung disease.
Topics: Adenosine; Adenosine Deaminase; Animals; Humans; Lung Diseases; Mice; Receptors, Purinergic P1
PubMed: 12559769
DOI: 10.1016/S0165-6147(02)00045-7 -
Veterinary Research Communications Sep 2023Enzyme adenosine deaminase (ADA) is a marker of inflammation in domestic animals, but it is unclear whether it is a reliable marker of oxidative stress, especially in...
Enzyme adenosine deaminase (ADA) is a marker of inflammation in domestic animals, but it is unclear whether it is a reliable marker of oxidative stress, especially in the transition period in dairy cows. This study aims to assess if ADA and redox status measurements in saliva provide the same utility to detect disease condition as that obtained from serum. Sixty-eight multiparous Holstein cows, between 2 and 3 weeks postpartum were selected. Five study groups were established: control (healthy), and cows with ketosis, mastitis, laminitis, and metritis. The parameters measured were ADA activity, total oxidants (TOS), antioxidants (TAC), and OSi ratio.Regarding redox status, no significant differences arise in both saliva and serum being the correlations negative and not significant. In saliva, ADA activity in healthy cows differs from those with pathological processes, having the lowest activities. In serum, ADA activity is similar in the healthy and ketosis cows, showing the lowest activities meanwhile animals with mastitis, laminitis, or metritis have significantly higher activities. In conclusion, the measurement of ADA activities and redox status in saliva does not give consistent results, being preferable to measure them in serum during the transition period.
Topics: Animals; Cattle; Female; Adenosine Deaminase; Cattle Diseases; Ketosis; Lactation; Mastitis; Milk; Oxidation-Reduction; Postpartum Period; Saliva
PubMed: 36607499
DOI: 10.1007/s11259-023-10069-2 -
Journal of Veterinary Diagnostic... Jan 2018We validated 2 assays for the measurement of adenosine deaminase (ADA) activity in the saliva of pigs: the Giusti-Galanti manual method (ADA-GG) and a commercial...
We validated 2 assays for the measurement of adenosine deaminase (ADA) activity in the saliva of pigs: the Giusti-Galanti manual method (ADA-GG) and a commercial automated assay (Diazyme Laboratories; ADA-D). Intra-assay coefficients of variation (CVs) were <7 and 9%, and interassay CVs were <12 and 5%, for ADA-GG and ADA-D, respectively. Accuracy was measured by 2 methods: recovery and linearity-under-dilution. Recovery was 82.4-106.8% for ADA-GG, and 92.8-107.9% for ADA-D. Serial dilutions showed R > 0.95 and 0.99 for ADA-GG and ADA-D, respectively. Linear regression between the methods gave R = 0.997 ( p < 0.0001), and a Bland-Altman plot showed a proportional bias of 112 IU/L (95% confidence interval of -99 to 322 IU/L) for ADA-D. No significant differences were observed between the results obtained by either method in saliva or serum. ADA activity was much higher in porcine saliva than in serum. Salivary ADA activity was significantly higher in lame pigs compared to healthy animals. However, serum ADA activity was significantly lower in lame pigs.
Topics: Adenosine Deaminase; Animals; Humans; Linear Models; Saliva; Spectrophotometry; Swine
PubMed: 29145785
DOI: 10.1177/1040638717742947