Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using a mixture of synthetic 17-mer oligonucleotides encoding the 64 possible sequences for a peptide of adenosine deaminase as probe, we have isolated a clone for adenosine deaminase mRNA sequences from a collection of T-cell cDNA recombinants. This cDNA clone, phADA-1, contains an insert of 0.8 kilobase. In addition to the peptide chosen for synthesis of the oligonucleotide probe, the complete DNA sequence predicts 16 other experimentally determined peptides. Mapping of total cellular human DNAs with several restriction enzymes revealed relatively simple patterns of hybridization with phADA-1 as probe, including a polymorphism for PvuII cleavage. In agreement with previous studies, the adenosine deaminase gene was localized by blot hybridization to chromosome 20 in a hybrid cell mapping panel. Using the cDNA as probe, an 18-kilobase EcoRI fragment of human cellular DNA was also cloned in bacteriophage Charon 4A. These adenosine deaminase clones will prove valuable in the full characterization of the cellular gene, molecular analysis of inherited enzyme deficiency associated with immunodeficiency, and regional mapping of human chromosome 20.
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PMID:Molecular cloning of human adenosine deaminase gene sequences. 668 8

An in vivo murine model for immunodeficiency of both B and T cells is produced by continuous intraperitoneal infusion of 2'-deoxycoformycin (DCF), a specific tightly binding inhibitor of adenosine deaminase (ADase; adenosine aminohydrolase, EC 3.5.4.4). After DCF infusion, ADase of thymus, spleen, and lymph nodes was inhibited to varying degrees ranging from 57% to 100%. Immunodeficiency under these conditions was indicated by: (i) a striking decrease in lymphocyte response to the T-cell mitogens concanavalin A and phytohemagglutinin; (ii) an impairment of delayed hypersensitivity measured by the footpad reaction; (iii) a decrease in antibody production measured in both in vivo and in vitro plaque-forming cell assay; (iv) a significant prolongation of mouse skin allograft survival after transplantation into the C57BL/6J (H-2b) strain of skin from BALB/c (H-2d) mice; and (v) a marked lymphopenia. Histological examination indicated lymphoid degeneration in the thymus, lymph nodes, and spleen with no alterations in other tissues including bone marrow, kidney, lung, gastrointestinal tract, and liver except for the occurrence of hepatitis. A decrease in the number of Thy-1-positive cells in both spleen and lymph nodes further supported the fact of cytotoxicity of DCF to T cells. Anorexia and weight loss were observed within 5 days of continuous DCF infusion at 0.4 mg/kg body weight per day. These data indicate that this method provides an experimental model for future studies on the biochemical mechanisms responsible for the genetically determined severe combined immunodeficiency disease in man.
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PMID:Animal model for immune dysfunction associated with adenosine deaminase deficiency. 696 8

Hereditary deficiency of the enzyme adenosie deaminase (adenosine aminohydrolase, EC 3.5.4.4) results in an immunodeficiency syndrome characterized by a marked reduction in circulating lymphocytes. We have administered 2'-deoxycoformycin, a potent inhibitor of adenosine deaminase, to a patient with a lymphoproliferative malignancy. The clinical consequences of pharmacologic inhibition of adenosine deaminase activity included an abrupt decrease in the lymphocyte count, abnormalities of renal and hepatic function, and hemolytic anemia. The plasma concentrations of adenosine and deoxyadenosine rose to peak values of 13 microM and 5 microM, respectively, and erythrocyte dATP levels increased to 110 pmol/10(6) cells over 9 days. There was a corresponding decrease in erythrocyte ATP levels from 128 to < 6 pmol/10(6) cells. A similar profound reductin in ATP occurred in the erythrocytes of a second patient. The rapid and unexpected depletion of ATP associated with dATP accumulation may account, at least in part, for the toxicity associated with 2'-deoxycoformycin administration. The inverse relationship of ATP and dATP raises major questions about the control of energy metabolism in erythrocytes.
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PMID:ATP depletion as a consequence of adenosine deaminase inhibition in man. 696 3

Cultured leukemic T-lymphoblasts, incubated in the presence of inhibitors of adenosine deaminase, are exquisitely sensitive to growth inhibition by deoxyadenosine. An analogy between this phenomenon and human combined immunodeficiency disease associated with inborn adenosine deaminase deficiency and the use of inhibitors of adenosine deaminase in the management of T-cell acute lymphoblastic leukemia has been noted. These phenomena are believed to reflect accumulation of high intracellular concentrations of deoxyadenosine triphosphate (dATP) following phosphorylation of deoxyadenosine, inhibiting replicating T-cells. In an attempt to extend these observations to noncultured, nonleukemic T-cells, we studied deoxyadenosine metabolism in human thymocytes. Human thymuses were separated into large replicating and small nondividing cell types by centrifugal elutriation. Both thymocyte subpopulations elevated in their dATP pools on incubation with microM concentrations of deoxyadenosine in the presence of erythro-9-[3-(2-hydroxynonyl)]adenosine, an inhibitor of adenosine deaminase. These dATP pool rises were similar in extent to those found in cultured leukemic T-lymphoblasts. However, the finding that small nonreplicating thymocytes elevate their dATP pool was unexpected. This prompted study of unstimulated peripheral blood lymphocytes. These cells (T and non-T) showed a similar elevation of their dATP pool on incubation with deoxyadenosine. Furthermore, these nondividing peripheral blood lymphocytes were killed by microM concentrations of deoxyadenosine in the presence of an inhibitor of adenosine deaminase. The biochemical mechanism of this G0-phase cell death is not known. These findings provide impetus for the investigation of adenosine deaminase inhibitors as lympholytic immunosuppressants or as agents to noncycling malignant lymphoid cells.
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PMID:Purine deoxynucleoside toxicity in nondividing human lymphoid cells. 697 4

The occurrence of severe immunodeficiency disease in children with inherited adenosine deaminase deficiency, and reports of remission induction in T-cell acute lymphoblastic leukaemia with the adenosine deaminase inhibitor deoxycoformycin, prompted a study of the effects of deoxyadenosine on resting peripheral blood lymphocytes (PBL) and chronic lymphocytic leukaemic (CLL) lymphocytes in short-term culture. In the presence of an inhibitor of adenosine deaminase, micromolar concentrations of dAdo caused elevation of deoxyadenosine-5'-triphosphate (dATP) pools and in vitro lysis of non-dividing PBL and CLL lymphocytes. This death of non-replicating cells indicates a mechanism of deoxyadenosine toxicity independent of DNA replication and ribonucleotide reductase inhibition. Similar changes occurred in vivo in a patient with advanced CLL who responded to treatment with deoxycoformycin, 0.1 mg/kg, days 1-5, with a fall in the WCC from 102.0 x 10(9)/1 to 6.8 x 10(9)/l over 21 d. Therapeutic blockade of deoxyadenosine catabolism deserves further investigation both in the treatment of lymphoproliferative disease and as a method lympholytic immunosuppression.
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PMID:Deoxycoformycin-induced response in chronic lymphocytic leukaemia: deoxyadenosine toxicity in non-replicating lymphocytes. 697 47

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.
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PMID:Analysis of normal and mutant forms of human adenosine deaminase - a review. 698 97

Adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4)-deficient patients recently were found to have abnormally high levels of dATP, a negative allosteric effector of ribonucleotide reductase (ribonucleoside-diphosphate reductase, 2'-deoxyribonucleoside-diphosphate:oxidized thioredoxin 2'-oxidoreductase, EC 1.17.4.1). Therefore it was proposed that the immunodeficiency associated with adenosine deaminase deficiency is mediated through inhibition of ribonucleotide reductase and hence DNA replication. HeLa cells, treated with an adenosine deaminase inhibitor, erythro-9(2-hydroxy-3-nonyl)adenine, and deoxyadenosine to mimic the adenosine deaminase-deficient state, were monitored to determine directly the effects on ribonucleotide reductase activity and levels. A low concentration of erythro-9-(2-hydroxy-3-nonyl)adenine, which did not inhibit cell growth, nevertheless retarded the cells in G2 + M phase of the cell cycle and increased reductase activity. Reductase activity was also elevated in cells treated with a low level of deoxyadenosine which did not affect the cell cycle or cell growth. However, ribonucleotide reductase activity was reduced to one-half of the control value in cells treated with either enough deoxyadenosine to inhibit cell growth or with a combination of erythro-9(2-hydroxy-3-nonyl)adenine and deoxyadenosine, each at concentrations which individually do not inhibit cell growth. Removal of deoxynucleotides, particularly dATP, from these extracts increased ribonucleotide reductase activity to several-fold higher than control values. The reduced activity of ribonucleotide reductase in the simulated adenosine deaminase-deficient HeLa cells provides direct evidence for the thesis that adenosine deaminase deficiency disease is mediated through elevated levels of dATP which inhibit ribonucleotide reductase. In addition, the cell cycle patterns and ribonucleotide reductase levels suggest that the regulatory substance(s) that controls the level of ribonucleotide reductase is not operative until the late S or G2 phase of the cell cycle.
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PMID:Adenosine deaminase impairment and ribonucleotide reductase activity and levels in HeLa cells. 699 99

A new acyclic nucleoside phosphonate (13) containing an adenine moiety was synthesized, which acted as an excellent inhibitor of calf mucosal adenosine deaminase. This inhibitory property allows it to exert great synergistic effect on certain antiviral agents (e.g., ara-A, 37). Phosphonate 13 was not phosphorylated by the bovine brain guanylate kinase nor by 5-phosphoribosyl 1-pyrophosphate synthetase. Syntheses of biologically active nucleotide phosphonate 40 and its phosphonoamidate derivative 42 were accomplished, which showed remarkable activity against herpes viruses and exhibited low host cell toxicity. 3'-Azido-nucleoside phosphonate 20 and 3'-fluoronucleoside phosphonate 32, as well as the corresponding dinucleotide analogs 47 and 48, and their respective phosphonoamidates 53-56 were also synthesized as new compounds, among which phosphonoamidates 53-56 showed potent activity against human immunodeficiency virus. Phosphonoamidates 55 and 56 bearing a methyl D-alaninate moiety exhibited less cellular toxicity than 53 and 54 bearing a methyl L-alaninate moiety. Nucleotide phosphonate 40 as well as dinucleotide phosphonates 47 and 48 were found susceptible to degradation by phosphodiesterases. Their respective phosphonoamidates 42 and 53-56, however, were completely resistant to snake venom and spleen enzymes.
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PMID:Design, synthesis, and structure-activity relationship of novel dinucleotide analogs as agents against herpes and human immunodeficiency viruses. 747 92

Polyethylene glycol-modified adenosine deaminase (PEG-ADA) has now been used for 8.5 years as enzyme replacement therapy for immunodeficiency due to ADA deficiency. PEG-ADA restores a metabolic environment necessary for recovery of immune function. In most cases, the level of function achieved has been sufficient to protect against opportunistic and life-threatening infections. To date, mortality and morbidity with PEG-ADA have been less than for haploidentical bone marrow transplantation. As a true "orphan drug" used to treat a very small patient population, the cost per patient of PEG-ADA is very high, but it has been well tolerated, free of adverse reactions, and effective as an alternative for patients who lack an HLA-identical marrow donor, but are considered too ill to undergo haploidentical marrow transplantation. Concomitant treatment with PEG-ADA has also permitted investigation of gene therapy to be carried out safely.
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PMID:PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years. 755 73

A series of 1-deazaadenine nucleosides with the N6 nitrogen unsubstituted or bearing methyl or cycloalkyl substituents, with or without a chloro group in the 2-position, and with the glycosylic moiety being ribose (1-16), 2'-deoxyribose (17-32), or 2', 3'-dideoxyribose (33-48) were designed and synthesized starting from 5,7-dichloro-3H-imidazo[4,5-b] pyridine (50). These compounds were evaluated for their in vitro activity against human immunodeficiency virus type-1 (HIV-1) and herpes simplex virus type-1 (HSV-1). In addition they were tested for their ability to inhibit adenosine deaminase (ADA) from calf intestine. While the parent compounds 1-deazaadenosine (9), 2'-deoxy-1-deazaadenosine (25), and 2',3'-dideoxy-1- deazaadenosine (41) and the corresponding 2-chloro derivatives were inactive, nucleosides bearing cycloalkyl substituents on N6 exhibited moderate to good anti-HIV-1 activity, compared to 2',3'-dideoxyadenosine, with the degree and pattern of improvement depending on the structure of the sugar moiety. In general, 2'-deoxy- and 2',3'-dideoxy derivatives were more potent compounds than the corresponding ribose nucleosides. Compounds bearing a 6-cycloheptyl or cyclooctylamine were the most active in every series. The presence of a chloro group in the 2-position improved both activity and therapeutic index in every series, the most active compound being 2'-deoxy-2-chloro-N6-cycloheptyl-1-deazaadenosine (23; ED50 = 0.2 microM). On the other hand, most of these derivatives were inactive as anti-HSV-1 agents, showing a high degree of virus selectivity. The 1-deazaadenine derivatives were not substrates of adenosine deaminase, and some of them proved to be good inhibitors of the enzyme. However, the ADA inhibitory activity does not account for the antiviral potency since increased lipophilicity and steric hindrance of substituents resulted in derivatives much less active than the parent compounds.
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PMID:Synthesis and biological evaluation of N6-cycloalkyl derivatives of 1-deazaadenine nucleosides: a new class of anti-human immunodeficiency virus agents. 756 37


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