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)

Pentostatin (dCF), an inhibitor of adenosine deaminase, has shown activity in the treatment of several lymphoid malignancies, even in the earliest phase I trials. An analysis of the first 300 patients treated in such trials shows a high incidence of severe infection (8%) during the relatively brief period of treatment. Of 24 patients in whom infection was diagnosed, 17 had no evidence of myelosuppression. The causative organisms included viruses, fungi, and bacteria of both high and low pathogenicity. Two-thirds of the infections were fatal. It is suggested that dCF may cause a syndrome similar to severe combined immunodeficiency during the course of treatment. Patients treated with dCF who show evidence of infection, even in the absence of neutropenia, should receive vigorous and rapid diagnostic evaluation to establish the cause of their infection, and aggressive treatment of suspected organisms.
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PMID:Association of severe and fatal infections and treatment with pentostatin. 348 5

The mechanism by which 2'-deoxyguanosine is toxic for lymphoid cells is relevant both to the severe cellular immune defect of inherited purine nucleoside phosphorylase (PNP) deficiency and to attempts to exploit PNP inhibitors therapeutically. We have studied the cell cycle and biochemical effects of 2'-deoxyguanosine in human lymphoblasts using the PNP inhibitor 8-aminoguanosine. We show that cytostatic 2'-deoxyguanosine concentrations cause G1-phase arrest in PNP-inhibited T lymphoblasts, regardless of their hypoxanthine guanine phosphoribosyltransferase status. This effect is identical to that produced by 2'-deoxyadenosine in adenosine deaminase-inhibited T cells. 2'-Deoxyguanosine elevates both the 2'-deoxyguanosine-5'-triphosphate (dGTP) and 2'-deoxyadenosine-5'-triphosphate (dATP) pools; subsequently pyrimidine deoxyribonucleotide pools are depleted. The time course of these biochemical changes indicates that the onset of G1-phase arrest is related to increase of the dATP rather than the dGTP pool. When dGTP elevation is dissociated from dATP elevation by coincubation with 2'-deoxycytidine, dGTP does not by itself interrupt transit from the G1 to the S phase. It is proposed that dATP can mediate both 2'-deoxyguanosine and 2'-deoxyadenosine toxicity in T lymphoblasts.
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PMID:Deoxyadenosine triphosphate as a mediator of deoxyguanosine toxicity in cultured T lymphoblasts. 349 Apr 93

We have investigated the structural gene for adenosine deaminase (ADA) in a female infant with ADA deficiency associated severe combined immune deficiency (ADA-SCID) disease and her family by DNA restriction-fragment-length analysis. In this family a new ADA-specific restriction-fragment-length variant was detected, which involves a 3.2-kb deletion spanning the ADA promoter as well as the first exon. It was found that the patient, who was born to a consanguineous couple, was homozygous and both her parents and her brother were heterozygous for the deletion. No ADA-specific mRNA could be detected by hybridization in fibroblasts derived from this patient. Thus the patient was established to be homozygous for a true null ADA allele. In the light of the apparently normal development of most tissues except the lymphoid tissue the above finding directly questions the classification of ADA as a 'housekeeping' enzyme.
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PMID:Severe combined immune deficiency due to a homozygous 3.2-kb deletion spanning the promoter and first exon of the adenosine deaminase gene. 368 97

The dynamics of lymphocyte response in peripheral blood, the tumor draining lymph node, spleen and thymus, was followed in a model system of syngeneically transplanted rat MC-1 tumor. Electrophoretic mobility (EPM) of lymphoid cells was determined by the automatic mode of measurement. The results revealed a two-phase pattern of EPM changes during the course of cancer growth. The first phase (day 3 to 6 following intramuscular injection of tumor cells) was characterized by a prevalence of high-mobility cells, while in the second phase (day 14 to 20), depletion of high-mobility cells was compensated for by an increased number of low-mobility cells. The mean EPM value was found to be increased only in the thymus at that time. Changes in the adenosine deaminase activity proved to be most expressive in the tumor draining lymph node and in the second phase also in splenic and thymic lymphocytes. An increased percentage of active lymphocytes with compact nucleoli with nucleolonemas became evident already on the 3rd day in all the lymphoid organs followed. The response was two-phasic only in the lymphocyte population of the peripheral blood, while their percentage in the other organs remained higher even on day 20. Changes in the proportion of high- and low-mobility cells in the lymphoid organs followed here, in correlation with the adenosine deaminase activity and the percentage of active lymphocytes, were interpreted as a response of immunocompetent cells in animals with a growing tumor.
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PMID:Kinetics of some immunological and biochemical changes of immunocompetent cells during tumor growth in rats. 378 65

Human adenosine deaminase (ADA) is an important purine catabolic enzyme which irreversibly deaminates adenosine and deoxyadenosine. Severe genetic deficiency of ADA leads to an immunological deficiency state in which T-lymphoid cells are selectively destroyed by the accumulation of toxic levels of deoxyadenosine and deoxy-ATP. In preparation for transfer of ADA sequences into a variety of cell types, we explored expression of ADA cDNAs transfected into cultured cells within a simian virus 40-based expression vector. After transfection into monkey kidney (COS) cells, ADA cDNA encompassing the entire coding region of the protein generated human ADA activity. An unexpected finding, however, was the identification of a cDNA clone that failed to produce either human enzyme activity or immunoreactive ADA protein. As this pattern is typical of many naturally occurring mutant ADA alleles, we characterized the molecular defect in this clone. DNA sequence analysis revealed a single nucleotide substitution in amino acid position 50 (glycine-valine). Northern blotting with a unique 17-mer oligonucleotide demonstrated the absence of the mutant sequence in the mRNA from which the cDNA library giving rise to the mutant cDNA was constructed. Therefore, the substitution in the variant cDNA was created during cloning. These data define one critical region of the human ADA protein molecule and suggest a convenient strategy for characterization of the phenotypes associated with naturally occurring mutant alleles.
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PMID:Transient expression of human adenosine deaminase cDNAs: identification of a nonfunctional clone resulting from a single amino acid substitution. 383 97

It remains unclear how lympholysis occurs in children with an inherited deficiency of adenosine deaminase (ADA) and in leukemic patients undergoing treatment with an inhibitor of ADA, deoxycoformycin. Adenosine deaminase deficiency with subsequent lympholysis can be simulated in vitro by treatment of lymphoid cells with deoxyadenosine plus deoxycoformycin. We found that such in vitro treatment caused fragmentation of the nucleus, disintegration of nuclear chromatin, and the formation of cytoplasmic blebs in T-lymphoblast lines, but not in B-lymphoblast lines. For all but one of the cell lines tested, the extent of morphological changes paralleled the sensitivity to growth inhibition by deoxyadenosine plus deoxycoformycin. Similar morphological changes were observed in normal peripheral blood lymphocytes treated with deoxyadenosine plus deoxycoformycin. These morphological changes were energy-dependent processes. They were preceded by inhibition of DNA synthesis and deoxyadenosine triphosphate (dATP) accumulation, but followed by depletion of adenosine triphosphate (ATP) and cell lysis. These changes may represent an intermediate step between metabolic alterations and lympholysis.
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PMID:Morphological changes in leukemic lymphoblasts and normal lymphocytes treated with deoxyadenosine plus deoxycoformycin. 387 81

Inherited deficiency of the enzyme adenosine deaminase (ADA) has been found in a significant proportion of patients with severe combined immunodeficiency disease and inherited defect generally characterized by a deficiency of both B and T cells. Two questions are central to understanding the pathophysiology of this disease: (1) at what stage or stages in lymphocyte development are the effects of the enzyme deficiency manifested; (2) what are the biochemical mechanisms responsible for the selective pathogenicity of the lymphoid system. We have examined the stage or stages of rat T-cell development in vivo which are affected by an induced adenosine deaminase deficiency using the ADA inhibitors, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and 2'-deoxycoformycin (DCF). In normal rats given daily administration of an ADA inhibitor, cortical thymocytes were markedly depleted; peripheral lymphocytes and pluripotent hemopoietic stem cells (CFU-S) all were relatively unaffected. Since a deficiency of ADA affects lymphocyte development, the regeneration of cortical and medullary thymocytes and their precursors after sublethal irradiation was used as a model of lymphoid development. By Day 5 after irradiation the thymus was reduced to 0.10-0.5% of its normal size; whereas at Days 9 and 14 the thymus was 20-40% and 60-80% regenerated, respectively. When irradiated rats were given daily parenteral injections of the ADA inhibitor plus adenosine or deoxyadenosine, thymus regeneration at Days 9 and 14 was markedly inhibited, whereas the regeneration of thymocyte precursors was essentially unaffected. Thymus regeneration was at least 40-fold lower than in rats given adenosine or deoxyadenosine alone. Virtually identical results were obtained with both ADA inhibitors, EHNA and DCF. The majority of thymocytes present at Day 9 and at Day 14 in inhibitor-treated rats had the characteristics of subcapsular cortical thymocytes which are probably the most ancestral of the thymocytes. Thus, an induced ADA deficiency blocked the proliferation and differentiation of subcapsular cortical thymocytes which are the precursors of cortical and medullary thymocytes.
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PMID:The effects of an induced adenosine deaminase deficiency on T-cell differentiation in the rat. 387 60

Complete genetic deficiency of adenosine deaminase (ADA) results in a fatal syndrome of severe combined immunodeficiency (SCID). Genetic partial deficiency of ADA, with no detectable enzyme activity in erythrocytes but with variable amounts of enzyme activity detectable in other cells, is usually associated with normal immunologic function but can give rise to a late-onset, cellular immunodeficiency syndrome. We have previously described four different mutant alleles in four such partially ADA-deficient children. We have now examined ADA in lymphoid cells from five additional newly ascertained children with partial ADA deficiency with respect to electrophoretic mobility in starch gel, isoelectric point, heat-stability, and apparent Km and Vmax. These techniques identify at least five different abnormal alleles in these five additional unrelated subjects. Three of these abnormal alleles result in expression of abnormal allelic isozymes (allozymes) different from those previously described. These are: (1) an acidic allozyme that is less acidic than the acidic allozyme we have previously reported; (2) an allozyme that is even less acidic than (1); and (3) an allozyme with apparently normal charge but which is so heat sensitive that the lability to heat can easily be detected at physiologic to febrile temperatures. Two abnormal alleles detected in these five children could correspond with previously reported mutants. These are (4) a basic allozyme that could (but probably doesn't) correspond to the basic allozyme we have previously reported and (5) a "null" allele that cannot be differentiated by these methods from any other "null" allele seen in complete ADA- -SCIDs. Three of the five new patients are genetic compounds, identified either by the presence of two electrophoretically distinguishable allozymes or by family studies that demonstrate presence of a "null" allele in addition to an electrophoretically abnormal allozyme. In three patients, one or both allozymes are phenotypically indistinguishable from an abnormal allozyme also seen in a different individual. Determination of the nucleotide sequence will be required to determine whether or not the phenotypically indistinguishable mutations are indeed genotypically identical. The newly ascertained individuals appear to share a common ethnic West Indian background, out of proportion to the frequency of this ethnic background in the newborn population from which they were ascertained, suggesting that partial ADA deficiency may confer a selective advantage to the homozygous or heterozygous phenotype.
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PMID:Genetic heterogeneity in adenosine deaminase (ADA) deficiency: five different mutations in five new patients with partial ADA deficiency. 394 19

The purine enzyme, adenosine deaminase, is essential for the maturation of lymphocytes, cell growth and normal immune function. Since adenosine deaminase has the highest activity in the thymus and in T lymphocytes, it is hypothesized that a defective or altered enzyme may be a cause of myasthenia gravis, a lymphoid dyscrasia. It is proposed that the alteration is on the non-catalytic portion of adenosine deaminase concerned with the normal immune function of T lymphocytes. Lymphocytes, particularly suppressor T lymphocytes containing a defective adenosine deaminase will function improperly. They will lose their normal immune regulatory function, allowing immunoglobulin-producing B lymphocytes to produce autoantibodies against the nicotinic acetylcholine receptor, with resultant induction and perpetuation of the autoimmune state. In an attempt to compensate for the defect, there may be hypertrophy of the thymus and lymphoid system, with overproduction of a defective adenosine deaminase. Since many of the functions of thymosin, the alleged active principle in thymus are identical to those of adenosine deaminase, it is postulated that thymosin may be a subunit of adenosine deaminase.
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PMID:A molecular hypothesis concerning the pathogenesis of myasthenia gravis. 401 May 75

We have established the DU.528 cell line from the pretreatment leukemia cells of a patient who underwent a T lymphoblastic-to-promyelocytic phenotype conversion during treatment with the adenosine deaminase inhibitor, deoxycoformycin. The cell line and clones obtained from it by limiting dilution have the same karyotype previously found in the patient's pretreatment T lymphoblasts and post-deoxycoformycin treatment promyelocytes. DU.528 cells in continuous culture for greater than 2 yr display a predominant undifferentiated T lymphoblastoid phenotype. These cells spontaneously generate progeny of at least three lineages, T lymphoid, granulocytic/monocytic, and erythroid. The surface marker most consistently expressed by DU.528 cells in the undifferentiated state is the 3A1 antigen, which has been found on prothymocytes in the embryonic thymus. Some undifferentiated DU.528 cells also expressed the IL-2 receptor, but no other T cell differentiation antigens. Exposure of DU.528 cells to a variety of agents induced myeloid maturation; adenosine and deoxyadenosine, in the presence of deoxycoformycin, induced expression of myeloid differentiation antigens. Our results suggest that DU.528 is a lymphohematopoietic stem cell line and support the hypothesis that differentiation of pluripotent stem cells may be altered by genetic deficiency of adenosine deaminase. DU.528 cells may provide a useful model for examining factors that regulate stem cell proliferation and differentiation.
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PMID:Establishment of the DU.528 human lymphohemopoietic stem cell line. 405 59


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