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 search for molecular changes that may be diagnostic of malignancy in the colonic epithelium is complicated by the diversity of cell types and complex cell kinetics of a tissue in which most of the cells are destined to leave within hours or days. Methods for cell separation and nuclear fractionation now permit biochemical studies of those cells that retain or regain the capacity for DNA synthesis and that are likely to include the transformed cell population. Among the changes associated with malignant transformation to be described are alterations in nuclear protein composition and metabolism, qualitative and quantitative differences in adenosine deaminase activities, activation of the guanylate/cyclic GMP system, and modification of both DNA and chromosomal proteins by alkylating carcinogens. DNA modification to produce O6-methylguanine correlates well with the incidence of tumor induction by methylazoxymethanol. Modifications of chromosomal proteins to produce methylated derivatives of lysine and arginine have been observed after the administration of 1,2-dimethylhydrazine. Such changes are likely to lead to aberrant interactions between DNA and regulatory elements in chromatin, and may not be subject to repair.
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PMID:Overview: molecular changes associated with large bowel cancer and their potential as markers and chemotherapeutic agents. 20 Mar 43

We have identified a previously unrecognized missense mutation in a patient with severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID). The mutation is a G646-to-A transition at a CG dinucleotide and predicts a glycine-to-arginine substitution at codon 216. Computer analysis of secondary structure predicts a major alteration with loss of a beta-pleated sheet in a highly conserved region of the protein. The basepair substitution also generates a new site for the restriction enzyme BstXI in exon 7 of the genomic DNA. Digestion of genomic DNA from the patient and from his parents revealed that he was homozygous for the mutation and that his mother and father were carriers. This mutation in homozygous form appears to be associated with very severe disease, since the patient had perinatal onset of clinical manifestations of SCID, the highest concentration of the toxic metabolite deoxyATP in nine patients studied, and a relatively poor immunologic response during the initial 2 years of therapy with polyethylene glycol-adenosine deaminase. Analysis of DNA from 21 additional patients with ADA-SCID and from 19 unrelated normals revealed that, while none of the normal individuals showed the abnormal restriction fragment, two of the 21 patients studied were heterozygous for the G646-to-A mutation.
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PMID:Homozygosity for a newly identified missense mutation in a patient with very severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID). 168 Feb 89

We have measured cyclic GMP accumulation in co-cultures of bovine aortic endothelial cells and rat smooth muscle cells as an index of endothelium-derived relaxing factor (EDRF) production. Adenosine deaminase (EC 3.5.4.4, Sigma type VI) produced a 5- to 10-fold increase in the basal and bradykinin-stimulated cyclic GMP content of co-cultures but had no effect on smooth muscle cells alone. Cyclic GMP accumulation in response to adenosine deaminase was not blocked by adenosine deaminase inhibitors or affected by adenosine, the products of adenosine deamination (inosine and ammonia), or adenosine receptor antagonists. Since superoxide anion is known to destroy EDRF and nitric oxide (NO) (which is similar or identical to EDRF in composition), we tested for superoxide dismutase (SOD, EC 1.15.1.1) in single lots of eight commercial sources of adenosine deaminase by measuring inhibition of the superoxide-mediated reduction of cytochrome c. SOD activity was found in all sources of adenosine deaminase, but varied widely. One lot of Sigma type VI enzyme contained 0.08 units SOD/unit adenosine deaminase. The EC50 values of purified SOD (0.23 units/mL) and Sigma type VI adenosine deaminase (2.1 units/mL) needed to increase the cyclic GMP content of co-cultures differed by a similar factor, 0.11. Thus, the SOD activity in adenosine deaminase is sufficient to account for its effect on cyclic GMP accumulation. One lot of Boehringer Mannheim adenosine deaminase contained much less SOD contamination (0.006 units SOD/unit adenosine deaminase) and produced much less accumulation of cyclic GMP in co-cultures. Cyclic GMP accumulations in response to adenosine deaminase and SOD were both abolished by the NO synthetase inhibitor NG-monomethyl-L-arginine (0.1 mM), consistent with the idea that these enzymes act by stabilizing EDRF. Adenosine deaminase and the SOD activity contaminating it were found to have similar molecular masses of 33-34 kD as assessed by gel permeation chromatography. When run under reducing conditions to dissociate homodimeric SOD into monomers, a 16.6 kD peptide which co-migrates with purified cupro-zinc SOD was visible in silver-stained sodium dodecyl sulfate-polyacrylamide gels of the Sigma type VI but not the Boehringer Mannheim adenosine deaminase. We conclude that commercial sources of adenosine deaminase are variably contaminated by SOD. Since EDRF is synthesized by many tissues, the use of adenosine deaminase contaminated with SOD may produce numerous effects not attributable to the deamination of adenosine.
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PMID:Contamination of adenosine deaminase by superoxide dismutase. Stabilization of endothelium-derived relaxing factor. 184 47

Crude preparations of histones had insulin-like actions in isolated adipocytes. This activity was attributed to the arginine-rich histones, H3 and H4. The metabolic effects of purified H3 and H4 on isolated adipocytes were similar to those of insulin in a number of respects. Like insulin, H3 and H4 stimulated the incorporation of both glucose and pyruvate in isolated cells and stimulated intercellular oxidation of glucose; in contrast, the lipolytic agents ACTH and isoproterenol actually inhibited the incorporation of pyruvate into adipocytes. In contrast to the effects of the lipolytic hormones, the effects of H3 and H4, like insulin, were not blocked by the presence of adenosine deaminase in the medium. The same concentrations of phenylarsine oxide were required to inhibit the stimulation of glucose incorporation whether by insulin or by histones. Furthermore, the addition of H4 or insulin to isolated adipocytes resulted in the increased phosphorylation of 17 kDa phosphoproteins as detected by two-dimensional electrophoresis. The insulin-like effect of the active histones was specific to their structure. Lysine-rich histones (H1, H2A and H2B), various polycations, and proteolytic fragments of purified H3 or H4 were all inactive. It is unknown whether this phenomenon might imply a physiological function for such endogenous molecules; however, a comparison of the detailed effects of insulin and histones might be informative in terms of common intracellular transduction systems.
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PMID:Insulin-like effects of histones H3 and H4 on isolated rat adipocytes. 254 Aug 34

Effects of repeated administration of benthiocarb on the nitrogen metabolism of hepatic and neuronal systems have been studied. Repeated benthiocarb treatment was associated with significant decrease in proteins with a concomitant increase in free amino acids (FAA) and specific activity levels of proteases suggesting impaired protein synthesis or elevated proteolysis. The glycogenic aminotransferases showed a significant elevation in both the tissues indicating high feeding of ketoacids into oxidative pathway for efficient operation of TCA cycle to combat energy crisis during induced benthiocarb stress. However, the activity levels of branched-chain aminotransferases decreased suggesting their reduced contribution of intermediates to TCA cycle. A comparative evaluation of the activity levels of ammonogenic enzymes, AMP deaminase, adenosine deaminase and glutamate dehydrogenase (GDH) indicated that ammonia was mostly contributed by nucleotide deamination rather than by oxidative deamination. GDH exhibited reduced activity due to low availability of glutamate. In accordance with increased levels of urea, the activity levels of arginase, a terminal enzyme of urea cycle was increased suggesting increased urea cycle operation in order to combat the increased ammonia content. As the presence of urea cycle in the brain is rather doubtful, the conversion of ammonia to glutamine for the synthesis of GABA is envisaged in brain whereas in liver, excess ammonia was converted to urea through ornithine-arginine reacting system. The increased glutaminase activity observed during benthiocarb intoxication is accounted for counteracting acidosis or maintenance of metabolic homeostasis. Arginase, a terminal enzyme of ornithine cycle showed increased activity denoting the efficient potentiality of tissues to avert ammonia toxicity. The changes observed in tissues of rat administered with benthiocarb reflects a shift in nitrogen metabolism for efficient mobilization of end products of protein catabolism.
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PMID:Perturbations in nitrogen metabolism of brain and liver of rat following repeated benthiocarb administration. 266 46

We have cloned and sequenced an adenosine deaminase (ADA) gene from a patient with severe combined immunodeficiency (SCID) caused by inherited ADA deficiency. Two point mutations were found, resulting in amino acid substitutions at positions 80 (Lys to Arg) and 304 (Leu to Arg) of the protein. Hybridization experiments with synthetic oligonucleotide probes showed that the determined mutations are present in both DNA and RNA from the ADA-SCID patient. In addition, wild-type sequences could be detected at the same positions, indicating a compound heterozygosity. Studies with ADA expression clones mutagenized in vitro showed that the mutation at position 304 is responsible for ADA inactivation.
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PMID:One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity. 300 8

Adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4) deficiency is one cause of the genetic disease severe combined immunodeficiency. To identify mutations responsible for ADA deficiency, we synthesized cDNAs to ADA mRNAs from two cell lines, GM2756 and GM2825A, derived from ADA-deficient immunodeficient patients. Sequence analysis of GM2756 cDNA clones revealed a different point mutation in each allele that causes amino acid changes of alanine to valine and arginine to histidine. One allele of GM2825A also has a point mutation that causes an alanine to valine substitution. The other allele of GM2825A was found to produce an mRNA in which exon 4 had been spliced out but had no other detrimental mutations. S1 nuclease mapping of GM2825A mRNAs showed equal abundance of the full-length ADA mRNA and the ADA mRNA that was missing exon 4. Several of the ADA cDNA clones extended 5' of the major initiation start site, indicating multiple start sites for ADA transcription. The point mutations in GM2756 and GM2825A and the absence of exon 4 in GM2825A appear to be directly responsible for the ADA deficiency. Comparison of a number of normal and mutant ADA cDNA sequences showed a number of changes in the third base of codons. These changes do not affect the amino acid sequence. Analyses of ADA cDNAs from different cell lines detected aberrant RNA species that either included intron 7 or excluded exon 7. Their presence is a result of aberrant splicing of pre-mRNAs and is not related to mutations that cause ADA deficiency.
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PMID:Mutations in the human adenosine deaminase gene that affect protein structure and RNA splicing. 347 10

Deficiency of adenosine deaminase (ADA) is the cause of an autosomal recessive form of immunodeficiency. We sought to define, at a molecular level, the mutations responsible for ADA deficiency in the cell line GM-1715, derived from an immunodeficient patient. Full-length complementary DNA (cDNA) for ADA was synthesized and cloned from the cell line. Sequence analysis of the clones revealed a point mutation in codon 101 (CGG to CAG) that predicts an amino acid change from arginine to glutamine. Southern blot analysis, based on silent polymorphisms in the cDNA sequence, indicated that only one of the defective alleles of the GM-1715 line had been sequenced. The mutation that was identified appears to be responsible for the loss of function in this allele, since the predicted primary structure of the enzyme is otherwise entirely normal.
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PMID:Identification of a point mutation in the adenosine deaminase gene responsible for immunodeficiency. 383 2

Leung, Hazel Barner (University of Pennsylvania School of Medicine, Philadelphia), Alice McGovern Doering, and Seymour S. Cohen. Effect of 9-beta-d-arabinofuranosyladenine on polymer synthesis in a polyauxotrophic strain of Escherichia coli. J. Bacteriol. 92:558-564. 1966.-Adenine-requiring mutants have been obtained from Escherichia coli strain 15 TAU, which also needs thymine, arginine, and uracil for growth. Some of these are killed by 9-beta-d-arabinofuranosyladenine (ara-A) in the absence of exogenous adenine; a particular mutant of this type, designated TAUAd, has been used in our studies. The lethality of ara-A, d-arabinosylhypoxanthine, and the 1-n-oxide of ara-A has been compared; ara-A is equally toxic in the presence or absence of thymine. Although the absence of uracil reduces ara-A toxicity, the lack of arginine almost eliminates lethality. It was found that ara-A completely inhibits deoxyribonucleic acid synthesis without markedly affecting ribonucleic acid (RNA) synthesis. Some inhibition of protein synthesis can be detected. However, the interpretation of these results is complicated because (i) exogenous adenine must be excluded, (ii) endogenous adenine is made available from RNA turnover, and (iii) ara-A is being rapidly converted to only slightly less toxic arabinosylhypoxanthine by the adenosine deaminase of E. coli. A suitable inhibitor for the bacterial deaminase has not yet been found.
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PMID:Effect of 9-beta-D-arabinofuranosyladenine on polymer synthesis in a polyauxotrophic strain of Escherichia coli. 533 77

We have investigated the specificity of the tRNA modifying enzyme that transforms the adenosine at position 34 (wobble position) into inosine in the anticodon of several tRNAs. For this purpose, we have constructed sixteen recombinants of yeast tRNAAsp harboring an AXY anticodon (where X or Y was one of the four nucleotides A, G, C or U). This was done by enzymatic manipulations in vitro of the yeast tRNAAsp, involving specific hydrolysis with S1-nuclease and RNAase A, phosphorylation with T4-polynucleotide kinase and ligation with T4-RNA ligase: it allowed us to replace the normal anticodon GUC by trinucleotides AXY and to introduce simultaneously a 32P-labelled phosphate group between the uridine at position 33 and the newly inserted adenosine at position 34. Each of these 32P-labelled AXY "anticodon-substituted" yeast tRNAAsp were microinjected into the cytoplasm of Xenopus laevis oocytes and assayed for their capacity to act as substrates for the A34 to I34 transforming enzyme. Our results indicate that: 1/ A34 in yeast tRNAAsp harboring the arginine anticodon ACG or an AXY anticodon with a purine at position 35 but with A, G or C but not U at position 36 were efficiently modified into I34; 2/ all yeast tRNAAsp harboring an AXY anticodon with a pyrimidine at position 35 (except ACG) or uridine at position 36 were not modified at all. This demonstrates a strong dependence on the anticodon sequence for the A34 to I34 transformation in yeast tRNAAsp by the putative cytoplasmic adenosine deaminase of Xenopus laevis oocytes.
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PMID:Enzymatic conversion of adenosine to inosine in the wobble position of yeast tRNAAsp: the dependence on the anticodon sequence. 636 51


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