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Annals of the Rheumatic Diseases Feb 2022
Topics: Adenosine Deaminase; Biomarkers; Humans
PubMed: 32054602
DOI: 10.1136/annrheumdis-2020-217055 -
British Medical Bulletin Jan 1995In the last decade, gene transfer into hematopoietic cells has evolved from an experimental procedure which resulted in successfully transduced in vitro hematopoietic... (Review)
Review
In the last decade, gene transfer into hematopoietic cells has evolved from an experimental procedure which resulted in successfully transduced in vitro hematopoietic colonies to the first clinical trials in patients suffering from severe combined immunodeficiency disease caused by the absence of functional adenosine deaminase. Significant in vivo expression of the newly introduced gene encoding human adenosine deaminase has been observed in descendents of murine and rhesus monkey hematopoietic stem cells following retrovirus mediated gene transfer. So far, 10 patients have received genetically repaired T-cells, hematopoietic stem cells or both without the appearance of any side effect. The clinical bone marrow gene transfer studies differ largely from the monkey studies with respect to myeloablation, which was applied in the monkey studies, but not in the patient studies. Ongoing studies in patients show that the introduced gene is present in circulating blood cells. In the initial phase of the trial, the frequency of transduced circulating blood cells is lower than in rhesus monkey studies. This difference may be contributed to the fact that conditioning was not performed in the patients.
Topics: Adenosine Deaminase; Animals; Clinical Trials as Topic; Disease Models, Animal; Gene Transfer Techniques; Genetic Therapy; Hematopoietic Stem Cells; Humans; Infant; Macaca mulatta; Severe Combined Immunodeficiency
PubMed: 7767649
DOI: 10.1093/oxfordjournals.bmb.a072954 -
Experimental & Applied Acarology 2006Adenosine deaminase is involved in purine metabolism and is a key enzyme for the control of the cellular levels of adenosine. Adenosine deaminase activity showed...
Adenosine deaminase is involved in purine metabolism and is a key enzyme for the control of the cellular levels of adenosine. Adenosine deaminase activity showed significant changes during embryogenesis of the camel tick Hyalomma dromedarii. From the elution profile of chromatography on DEAE-sepharose, three forms of enzyme (ADAI, ADAII and ADAIII) were separated. ADAII was purified to homogeneity after chromatography on Sephacryl S-200. The molecular mass of adenosine deaminase ADAII was 42 kDa for the native enzyme and represented a monomer of 42 kDa by SDS-PAGE. The enzyme had a pH optimum at 7.5 and temperature optimum at 40 degrees C with heat stability up to 40 degrees C. ADAII had a K (m) of 0.5 mM adenosine with higher affinity toward deoxyadenosine and adenosine than other purines. Ni(2+), Ba(2+), Zn(2+), Li(2+), Hg(2+) and Mg(2+) partially inhibited the ADAII. Mg(2+) was the strongest inhibitor by 91% of the enzyme's activity.
Topics: Adenosine Deaminase; Animals; Arachnid Vectors; Camelus; Cations, Divalent; Female; Hydrogen-Ion Concentration; Ixodidae; Molecular Weight; Substrate Specificity; Temperature; Time Factors
PubMed: 17089216
DOI: 10.1007/s10493-006-9023-4 -
Molecular and Cellular Biochemistry Feb 1980A deficiency of the enzyme adenosine deaminase is associated with an autosomal recessive form of severe combined immunodeficiency disease in man. The molecular forms of... (Review)
Review
A deficiency of the enzyme adenosine deaminase is associated with an autosomal recessive form of severe combined immunodeficiency disease in man. The molecular forms of the normal human enzyme have now been well characterized in an effort to better understand the nature of the enzyme defect in affected patients. In some human tissues adenosine deaminase exists predominantly as a small molecular form while in other tissues a large form composed of adenosine deaminase (small form) and an adenosine deaminase-binding protein predominates. The small form of the enzyme purified to homogeneity by antibody affinity chromatography is a monomer of native molecular weight of 37,600. The adenosine deaminase-binding protein, purified by adenosine deaminase affinity chromatography, appears to be a dimer of native molecular weight 213,000 and contains carbohydrate. Based on direct binding measurements, chemical cross-linking studies and sedimentation equilibrium analyses, small form adenosine deaminase has been shown to combine with purified binding protein in a molar ratio of 2:1 respectively to produce the large form adenosine deaminase. Reduced, but widely ranging levels of adenosine deaminating activity, have been reported in various tissues of adenosine deaminase deficient patients. Further, the characteristics of this residual enzyme activity have been analyzed immunochemically to substantiate genetic heterogeneity in this disorder. While many types of immunodeficiency are currently recognized in man, in most cases the molecular defect is unknown. The discovery of a deficiency of the enzyme, adenosine deaminase, ADA, (EC 3.5.4.4), in some patients with severe combined immunodeficiency disease represented an early clue to the pathogenesis of immune dysfunction at the molecular level 1-4. Affected patients with markedly reduced levels of ADA exhibit a defect of both cellular and humoral immunity characterized clinically by severe recurrent infections with a fatal outcome if untreated. Attempts to elucidate the nature of the genetic mutation(s) leading to the reduction of ADA activity in these immunodeficient patients have been complicated in part by an incomplete understanding of the nature of ADA in normal tissues. In this review we will consider the structural characteristics of the normal and mutant forms of ADA as they are currently understood.
Topics: Adenosine Deaminase; Erythrocytes; Genetic Variation; Humans; Immunologic Deficiency Syndromes; Isoenzymes; Kinetics; Macromolecular Substances; Molecular Weight; Mutation; Nucleoside Deaminases
PubMed: 6988697
DOI: 10.1007/BF00220303 -
Nucleic Acids Research Aug 2020Adenosine deaminases acting on RNA (ADARs) are enzymes that convert adenosine to inosine in duplex RNA, a modification that exhibits a multitude of effects on RNA...
Adenosine deaminases acting on RNA (ADARs) are enzymes that convert adenosine to inosine in duplex RNA, a modification that exhibits a multitude of effects on RNA structure and function. Recent studies have identified ADAR1 as a potential cancer therapeutic target. ADARs are also important in the development of directed RNA editing therapeutics. A comprehensive understanding of the molecular mechanism of the ADAR reaction will advance efforts to develop ADAR inhibitors and new tools for directed RNA editing. Here we report the X-ray crystal structure of a fragment of human ADAR2 comprising its deaminase domain and double stranded RNA binding domain 2 (dsRBD2) bound to an RNA duplex as an asymmetric homodimer. We identified a highly conserved ADAR dimerization interface and validated the importance of these sequence elements on dimer formation via gel mobility shift assays and size exclusion chromatography. We also show that mutation in the dimerization interface inhibits editing in an RNA substrate-dependent manner for both ADAR1 and ADAR2.
Topics: Adenosine Deaminase; Crystallography, X-Ray; Humans; Models, Molecular; Mutation; Protein Binding; Protein Domains; Protein Multimerization; RNA Editing; RNA, Double-Stranded; RNA-Binding Proteins
PubMed: 32597966
DOI: 10.1093/nar/gkaa532 -
Bulletin of Experimental Biology and... Oct 2022The aim of this study was to test the hypothesis that the higher the activity of adenosinedeaminase (ADA) in the brain, the greater should be the motor activity of...
The aim of this study was to test the hypothesis that the higher the activity of adenosinedeaminase (ADA) in the brain, the greater should be the motor activity of animals, and possibly the stronger the psychostimulant effect of caffeine. We studied the effect of caffeine (10 and 20 mg/kg) on the motor activity and ADA activity in the frontal cortex of the brain in 2- and 5-month-old rats with different levels of spontaneous motor activity. Total motor activity significantly decreased with age, which was accompanied by a decrease in ADA activity. Administration of caffeine in a dose of 10 mg/kg stimulated motor activity in both 2- and 5-month-old animals, while ADA activity decreased in 2-month-old rats and increased in 5-month-old animals. Administration of caffeine in a dose of 20 mg/kg did not change the motor activity, however, in 5-month-old animals it led to an even greater increase in ADA activity. Thus, the age-related decrease in motor activity can be due to a decrease in ADA activity. However, the effect of caffeine on motor activity is not directly related to ADA activity in the cerebral cortex.
Topics: Animals; Rats; Caffeine; Rats, Wistar; Adenosine Deaminase; Cerebral Cortex; Brain
PubMed: 36322309
DOI: 10.1007/s10517-022-05616-x -
[Hokkaido Igaku Zasshi] the Hokkaido... Jan 1996Severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency is a fatal recessive disorder caused by mutations in the gene encoding ADA. Based on... (Review)
Review
Severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency is a fatal recessive disorder caused by mutations in the gene encoding ADA. Based on the first clinical trial of two young girls with ADA-deficient SCID by recombinant retrovirus-mediated gene transfer at the National Institute of Health of USA, we prepared to treat a four-year-old boy with ADA-deficient SCID who had been treated with PEG-ADA for 3 years. Approval to perform the clinical trial of gene therapy by using his peripheral blood T lymphocytes as the target and recombinant retroviral vector (LASN) as the vector for ADA gene transfer was obtained from both of the Ministry of Health and Welfare and the Ministry of Education, Science, Sports and Culture on 13 February, 1995. The first clinical trial of gene therapy for the patient was initiated on 1 August 1995. He received 8 x 10(8) LASN-transduced lymphocytes in an injection administered intravenously on 8 August and 2.5 x 10(9) transduced lymphocytes on 4 September without any side reactions. The procedure, safety and efficacy of clinical trial of gene therapy were discussed.
Topics: Adenosine Deaminase; Child; Child, Preschool; Clinical Trials as Topic; Female; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Male; Mutation; Retroviridae; Severe Combined Immunodeficiency
PubMed: 8727372
DOI: No ID Found -
Current Pharmaceutical Design 2004Peptide and protein growth factors play critical roles in the control of proliferation, differentiation and survival of most, if not all, cell types. In this review, we... (Comparative Study)
Comparative Study Review
Peptide and protein growth factors play critical roles in the control of proliferation, differentiation and survival of most, if not all, cell types. In this review, we describe a newly isolated growth factor from Aplysia californica, mollusk derived growth factor (MDGF), that is a member of the adenosine deaminase-related growth factor (ADGF) subfamily. Other known subfamily members from a range of invertebrate and vertebrate species include: insect-derived growth factor, Drosophila ADGFs, tsetse salivary growth factors, insect adenosine deaminases (ADAs; Lutzomyia, Culex, Aedes, Anopheles), and cat eye syndrome critical region gene 1 (CECR1) in humans, pigs, and zebrafish. ADGFs from vertebrates and invertebrates contain both an ADA domain and a novel N-terminal region of about 100 amino acids. Catalytic residues involved in ADA activity are conserved in ADGFs, and inhibitors of ADA can block ADGF activity. ADA enzymatic activity has been shown, by inhibitor and site-directed mutagenesis studies, to be related to the ability of ADGFs from many species to stimulate cell proliferation. The available evidence suggests that the conversion of adenosine to inosine (or their analogs) is important for the mitogenic actions of ADGFs. Future investigations of this novel subfamily should lead to the identification of their receptors.
Topics: Adenosine Deaminase; Animals; Aplysia; Growth Substances; Humans
PubMed: 15579078
DOI: 10.2174/1381612043382594 -
Molecular Medicine Reports Feb 2020Adenosine deaminase 2 (ADA2) belongs to the novel family of adenosine deaminase growth factors (ADGFs), which play an important role in tissue development. The...
Adenosine deaminase 2 (ADA2) belongs to the novel family of adenosine deaminase growth factors (ADGFs), which play an important role in tissue development. The deficiency of adenosine deaminase 2 (DADA2) is a recently recognized autosomal recessive autoinflammatory disease, characterized by various systemic vascular and inflammatory manifestations, which is associated with ADA2 mutations. Considering that a recent screening of an international registry of children with systemic primary vasculitis revealed novel and already known variants in ADA2, this study aimed to further investigate the functional significance of the rare variants detected, namely p.Gly47Arg, p.Gly47Ala, p.Arg8Trp, p.Leu351Gln and p.Ala357Thr, by using a structural biological approach. Three‑dimensional models of the mutants were developed and their three‑dimensional (3D) structures were subjected to detailed interaction and conformational analyses. This led to suggestions that the novel mutations found may affect the formation/stability of the homodimer or may influence the activity of the enzyme. It was thus concluded that the Arg8Trp and Gly47Arg mutations affect the position and interaction of the dimer‑associated HN1 helical structure and therefore, dimer formation and stabilization, while Leu351Gln and Ala357Thr influence the metal coordination in the active site. These findings shed further light onto the structural consequences of the mutations under investigation.
Topics: Adenosine Deaminase; Amino Acid Sequence; Child; Humans; Intercellular Signaling Peptides and Proteins; Mutation; Polyarteritis Nodosa
PubMed: 31974608
DOI: 10.3892/mmr.2019.10862 -
Polski Merkuriusz Lekarski : Organ... Dec 1997The isoenzymes ADA1 and ADA2 of the enzyme adenosine deaminase (ADA 3.5.4.4) deaminate mainly two nucleotides: adenosine and 2'-deoxyadenosine, molecules with many... (Review)
Review
The isoenzymes ADA1 and ADA2 of the enzyme adenosine deaminase (ADA 3.5.4.4) deaminate mainly two nucleotides: adenosine and 2'-deoxyadenosine, molecules with many effects on human cells. Thus, the ADA1 and ADA2 in human cells are of extreme importance. Biochemical and biological properties of the isoenzymes ADA1 and ADA2 as well as their usefulness in diagnostic of many diseases were described.
Topics: Adenosine Deaminase; Cells, Cultured; Humans; Isoenzymes
PubMed: 9523470
DOI: No ID Found