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)

The human lymphoblast line WI-L2 is subject to growth inhibition by a combination of the adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4.) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and adenosine. Although adenosine-induced pyrimidine starvation appears to contribute to this effect, uridine only partially reverses adenosine toxicity in WI-L2 and not at all in strain 107, an adenosine kinase-(ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) deficient derivative of WI-L2. Treatment of both cell lines with EHNA and adenosine leads to striking elevations in intracellular S-adenosyl-L-homocysteine (AdoHcy), a potent inhibitor of S-adenosyl-L-methionine (AdoMet)-dependent methylation reactions. The methylation in vivo of both DNA and RNA is inhibited by concentrations of EHNA and adenosine that elevate intracellular AdoHcy. Addition of 100 muM L-homocysteine thiolactone to cells treated with EHNA and adenosine enhances adenosine toxicity and further elevates AdoHcy to levels approximately 60-fold higher than those obtained in the absence of this amino acid, presumably by combining with adenosine to form AdoHcy in a reaction catalyzed by S-adenosylhomocysteine hydrolase (EC 3.3.1.1). In the adenosine kinase-deficient strain 107, a combination of ADA inhibition and L-homocysteine thiolactone markedly increases intracellular AdoHcy and inhibits growth even in the absence of exogenous adenosine. These results demonstrate a form of toxicity from endogenously produced adenosine and support the view that AdoHcy, by inhibiting methylation, is a mediator of uridine-resistant adenosine toxicity in these human lymphoblast lines. Furthermore, they suggest that AdoHcy may play a role in the pathogenesis of the severe combined immunodeficiency disease found in most children with heritable ADA deficiency.
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PMID:S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin. 22 26

The inherited deficiency of adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4) activity in humans is associated with an immunodeficiency. Some of the immunodeficient and enzyme-deficient patients respond immunologically to periodic infusions of irradiated erythrocytes containing adenosine deaminase. It has been previously reported that erythrocytes and lymphocytes from immunodeficient ane enzyme-deficient children contained increased concentrations of ATP, and in the one child studied after erythrocyte infusion therapy, the intracellular level of ATP diminished. Using high-pressure liquid chromatography that resolves ATP and 2'-dATP, we have observed greater than 50-fold elevations of dATP in the erythrocytes of immunodeficient, adenosine deaminase-deficient patients but not in the erythrocytes of an immunocompetent adenosine deaminase-deficient patient. The erythrocyte dATP in two unrelated adenosine deaminase-deficient, immunodeficient patients disappeared after infusion of normal erythrocytes. We propose that deoxyadenosine, a substrate of adenosine deaminase, is the potentially toxic substrate in adenosine deaminase deficiency, and that the mediator of the toxic effect is dATP, a recognized potent inhibitor of ribonucleotide reductase.
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PMID:Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. 27 65

Two human choriocarcinoma cell lines were shown to be deficient in adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4) such that they did not produce bands on starch gels after electrophoresis and histochemical staining. Radiometric assay indicated that their ADA specific activity was approximately 2% that of HeLa (human) cell controls. Subclone analysis of one of the lines indicated that this deficiency was representative of individual cells of the line. After fusion of these cells with mouse fibroblasts having high ADA activity, most independently isolated hybrid clones expressed one of two, or both, additional (to the mouse) bands of ADA activity after electrophoresis. The expression of these extra bands in hybrids was dependent upon actual fusion. The phenomenon was observed in 30 of 45 independently derived hybrid clones from four different fusion experiments involving two different parental lines from each species. The pattern of appearance of the extra bands in independent hybrid clones and the tendency of a hybrid clone to lose one of the extra bands through subsequent passages suggests that the bands were the products of human genetic material. The extra bands electrophoretically comigrated with human ADA 1 and 2 from human ADA-1-2 heterozygotes and the faster-migrating of the two extra bands comigrated with human ADA 1 from HeLa cells. Therefore, we suggest that the bands appearing in hybrids are the products of the 1 and 2 alleles of the human ADA locus. The human cells used for fusion were deficient in ADA activity but contained the genetic information for ADA 1 and 2. Fusion with mouse cells having ADA activity resulted in the activation of both human gene products coded for on separate homologous chromosomes. We conclude that the human ADA locus is under manipulatable genetic regulation.
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PMID:Expression of human adenosine deaminase after fusion of adenosine deaminase-deficient cells with mouse fibroblasts. 27 55

In human tissues, adenosine deaminase (ADA) (adenosine aminohydrolase; EC 3.5.4.4) activity can be separated by gel electrophoresis into several isozymes. A structural gene (ADA) on chromosome 20 codes for the "erythrocyte" isozyme, ADA-1, which is also expressed in some nonerythroid tissues. Nonerythroid cells also differentially express five ADA "tissue isozymes" of a greater molecular weight than ADA-1. Each ADA tissue isozyme has a characteristic electrophoretic mobility and tissue distribution. It has been suggested that these ADA tissue isozymes are composed of ADA-1 and other components. We report that the expression of one of these tissue isozymes, ADA-d, is dependent upon ADA on chromosome 20 and another gene on chromosome 6 which functions in the assembly of the ADA tissue isozymes. In human-mouse hybrids segregating human chromosomes, chromosome 6(+),20(+) hybrids express both ADA-1 and ADA-d; chromosome 6(-),20(+) hybrids express only ADA-1; while 6(+),20(-) hybrids have no human ADA activity. ADA-d formation also occurs in vitro by self-assembly when an extract of human erythrocytes or chromosome 6(-),20(+) hybrids is mixed with a homogenate of chromosome 6(+),20(-) hybrids. The gene on chromosome 6, designated ADCP, codes for an adenosine deaminase complexing protein. The product of ADCP presumably combines with ADA-1 to form the ADA tissue isozymes. The data are consistent with the hypothesis that the distribution of enzymatic activity between ADA-1 and the tissue isozymes depends on the expression of the gene for ADA complexing protein, while the differences in the electrophoretic mobilities of the ADA isozymes, except ADA-1, are generated, as suggested by others, by the degree of glycosylation of the complexing protein.
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PMID:A gene on human chromosome 6 functions in assembly of tissue-specific adenosine deaminase isozymes. 27 3

Adenine aminohydrolase (EC 3.5.4.2) from four species of Leishmania and from Crithidia fasciculata was examined for specific activities, affinity for substrate (adenine), and stability to heat. All were found to be strongly and non-competitively inhibited by both coformycin and deoxycoformycin, two tight-binding inhibitors of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4). Deoxycoformycin is the more potent inhibitor of the two. Neither inhibitor was active against the purine phosphoribosyltransferases. When deoxycoformycin was added to the defined growth medium containing hypoxanthine as the purine source, the growth of C. fasciculata was unaffected, but when adenine was the purine source for the organism, severe inhibition resulted. This implies that hypoxanthine is the obligatory base for nucleotide synthesis and that the adenine phosphoribosyltransferase (AMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.7) is, in some manner,idenied access to exogenous substrate.
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PMID:Adenine aminohydrolase: occurrence and possible significance in trypanosomid flagellates. 29 Oct 31

Deoxyadenosine at low concentrations and in the presence of an inhibitor of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) is markedly toxic to lymphoblast cell lines of T cell origin but does not impair growth of B cell lines. Deoxyguanosine is also more toxic for T lymphoblasts. 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. The addition of deoxycytidine or dipyridamole results in lower dATP and dGTP levels and prevents deoxyribonucleoside toxicity. These findings provide a molecular basis for the immunodeficiency observed in individuals with several inborn errors of purine metabolism.
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PMID:Purinogenic immunodeficiency diseases: selective toxicity of deoxyribonucleosides for T cells. 31 Oct 4

Deoxyadenosine, a cytotoxic purine nucleoside, is excreted in large amounts by patients with severe combined immunodeficiency disease associated with deficiency of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4). To identify the source of the purine nucleoside, purine excretion by macrophages was studied by using mouse peritoneal macrophages as an experimental model system. Normally, macrophages excrete a large quantity of uric acid into the culture medium. However, in the presence of deoxycoformycin, a potent inhibitor of adenosine deaminase, these macrophages also excreted deoxyadenosine. Furthermore, phagocytosis of nucleated erythrocytes augmented the excretion of deoxyadenosine. Macrophages are involved in the phagocytosis of nuclei that are extruded from normoblasts during erythropoiesis and also of senescent cells in lymphoid organs. A hypothesis is proposed that macrophages of the reticuloendothelial system are a source of deoxyadenosine, which is one of the two cytotoxic purine nucleosides (the other is adenosine) apparently responsible for the suppression of immune functions in patients with adenosine deaminase deficiency.
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PMID:Purine excretion by mouse peritoneal macrophages lacking adenosine deaminase activity. 31 77

A role for the enzymes adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) and purine-nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyl-transferase, EC 2.4.2.1) in the functional maturation of lymphoid cells has been revealed by the association of inherited deficiencies of these enzymes and profound immune deficiency. Previous studies have suggested that the selective toxicity for lymphocytes may be mediated by the accumulation of toxic deoxynucleoside metabolites, likely through the action of specific kinases enriched in lymphoid cells. In order to study possible mechanisms whereby lymphocyte function may be impaired in these disorders, we have studied the effect of nucleosides and their deoxy analogues on both T and B lymphocyte growth and function. In the presence of deoxyguanosine, there was marked inhibition of T lymphoblast growth, phytohem-agglutinin-induced cell proliferation, and T suppressor cell activity. T helper cell activity and the differentiation of B cells to an antibody-secreting stage were unaffected. Deoxyadenosine was much less inhibitory, but in the presence of an inhibitor of adenosine deaminase, its effects on lymphocyte growth and function were markedly potentiated. The addition of deoxycytidine prevented deoxyadenosine toxicity in all assays, whereas it only interfered with deoxyguanosine effects on T lymphoblast growth. These studies provide some initial understanding for the selective loss of specific lymphocyte functions in individuals with inborn errors of purine metabolism.
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PMID:Selective toxicity of purine deoxynucleosides for human lymphocyte growth and function. 31 53

A series of nucleoside dialdehydes have been obtained as powders after treatment of various adenine nucleosides with paraperiodic acid. Thus, oxidation gave dialdehydes derived from adenosine (1), 9-alpha-D-mannopyranosyladenine (2), 9-(5-deoxy-alpha-D-arabinofuranosyl)adenine (3), 9-alpha-L-rhamnopyranosyladenine (4), 9-beta-L-fucopyranosyladenine (5), 9-beta-D-fucopyranosyladenine (6), 9-alpha-D-arabinopyranosyladenine (7), 9-beta-D-ribopyranosyladenine (8), and 9-(5-deoxy-beta-D-erythro-pent-4-enofuranosyl)adenine (9). Nucleoside dialdehydes 1-3 and 6-8 were weak substrates for adenosine aminohydrolase from calf intestinal mucosa. Dialdehyde 8 had the strongest affinity, but 1 had the highest Vmax. All of the dialdehydes except 5 were inhibitors of the enzyme. The best inhibitors were 9 (Ki = 4 microM) and 4 (ki = 28 microM), and neither were substrates. The inhibitors did not exhibit time-dependent inhibition and did not appear to form covalent bonds with the protein. The data strongly suggest that the active form of the dialdehydes is as the open-chain dihydrates. The alcohol obtained by reduction of 9 (compound 10) was the strongest inhibitor (Ki = 0.9 microM among the related alcohols and the nucleoside dialdehydes.
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PMID:Dialdehydes derived from adenine nucleosides as substrates and inhibitors of adenosine aminohydrolase. 47 55

In serially independent samples of blood from apparently healthy subjects controlled as to clock-hour of blood withdrawal but not as to any circannual changes in circadian state, human erythrocyte adenosine aminohydrolase undergoes a statistically significant circannual rhythm, which may or may not be aliased. This rhythm is also demonstrated in patients with a variety of neoplastic diseases and it occurs around a statistically significantly lower mesor in patients with a variety of malignant tumors investigated.
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PMID:Circannual variation in human erythrocyte adenosine aminohydrolase. 59 70


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