Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Procedures are described for the isolation and identification of 1-methyladenine from the urine of an adult female with adenosine deaminase deficiency but no immunodeficiency. Evidence is provided indicating that much of the usual urinary excretion product, 1-methyladenosine, is converted to 1-methyladenine in this subject prior to excretion. Since the nucleoside phosphorylases present in normal individuals do not act on 1-methyladenosine, this suggests that a phosphorylase with unusual properties is present in this adenosine deaminase-deficient subject. A possible role for this phosphorylase in removal of deoxyadenosine in this subject is discussed.
 ...
PMID:1-Methyladenine in urine of an adenosine deaminase-deficient adult without immunodeficiency. 259 38

Certain disorders of the immune system seem to be associated with skeletal defects. The association was first recorded by McKusick et al. (Bulletin of the Johns Hopkins Hospital 116:285-326, 1964). A number of relationships between lymphocytes and osteocytes can be proposed. These include a common environment for development, common metabolic needs and effects upon osteocytes by products (cytokines) elaborated from lymphocytes or monocytes during immune responses. Thus, bony defects of varying degrees of severity are seen in short-limb dwarfs, cartilage-hair hypoplasia, and adenosine deaminase (ADA) deficiency. Cytokine activation of osteoclasts accounts for the lytic lesions seen in malignancies and the excessive bone resorption which accompanies autoimmune disorders such as rheumatoid arthritis. Correction of primary immune deficiency is accomplished by bone marrow transplantation. If the bony abnormality is subtle (as in some cases of ADA deficiency) the skeletal problem is resolved; if the bone defect is major as in short-limb dwarfism, no improvement is seen.
 ...
PMID:Associations of the skeletal and immune systems. 268 81

Adenosine deaminase is found primarily in the cytoplasm of many cell types. In the human erythrocyte, about 30 per cent of the total adenosine deaminase activity is membrane associated, and about two-thirds of this is inactivated by treatment of intact erythrocytes with the nonpenetrating reagent diazotized sulfanilic acid, without affecting lactate dehydrogenase, a soluble cytoplasmic enzyme. This indicates that within the cell membranes, the catalytic site of about two-thirds of the adenosine deaminase faces the external medium, i.e., ecto adenosine deaminase. Localization of adenosine deaminase activity at the cell membrane is demonstrated directly by electron microscopy by use of the substrate 6-Chloropurine ribonucleoside, which is dechlorinated by adenosine deaminase to produce Cl-, which is precipitated at its locus of formation by added Ag+, and the precipitated AgCl converted into the electron dense Ag0 upon exposure to light. From the Hydropathic Profile of the amino acid sequence of adenosine deaminase it is evident that there are two hydrophobic domains of sufficient length to span a biological membrane, and it is proposed that these domains could function to anchor the enzyme to the membrane. The importance of adenosine deaminase is indicated by the fatal immuno-deficiency which results from untreated genetic adenosine deaminase deficiency. It may be important to determine whether the amount of ecto adenosine deaminase activity is better suited to assess the clinical status of adenosine deaminase deficient patients that the currently used total cellular enzyme activity.
 ...
PMID:Ecto-enzyme activity of human erythrocyte adenosine deaminase. 277 Jul 11

In 15%-20% of children with severe combined immunodeficiency (SCID), the underlying defect is adenosine deaminase (ADA) deficiency. The overall goal of our research has been to identify the precise molecular defects in patients with ADA-deficient SCID. In this study, we focused on a patient whom we found to have normal sized ADA mRNA by Northern analysis and an intact ADA structural gene by Southern analysis. By cloning and sequencing this patient's ADA cDNA, we found a C-to-T point mutation in exon 11. This resulted in the amino acid substitution of a valine for an alanine at position 329 of the ADA protein. Sequence analysis revealed that this mutation created a new BalI restriction site. Using Southern analyses, we were able to directly screen individuals to determine the frequency of this mutation. By combining data on eight families followed at our institution with data on five other families reported in the literature, we established that five of 13 patients (seven of 22 alleles) with known or suspected point mutations have this defect. This mutation was found to be associated with three different ADA haplotypes. This argues against a founder effect and suggests that the mutation is very old. In summary, a conservative amino acid substitution is found in a high proportion of patients with ADA deficiency; this can easily be detected by Southern analysis.
 ...
PMID:A high proportion of ADA point mutations associated with a specific alanine-to-valine substitution. 277 32

Deoxyadenosine metabolism was investigated in rabbit growth plate and articular cartilage to elucidate the biochemical basis for the chondro-osseous dysplasia observed in adenosine deaminase (ADA) deficiency. Models of ADA deficiency, the combination of deoxy-adenosine and either of 2 ADA inhibitors, were selectively toxic to immature cartilage, supporting the hypothesis that the chondro-osseous dysplasia of ADA deficiency is the consequence of the enzyme deficiency. Depletion of ATP may play a role in the altered chondrocyte viability and function observed in this model.
 ...
PMID:Differential deoxyadenosine toxicity to immature rabbit cartilage in vitro. A model for the chondro-osseous dysplasia of adenosine deaminase deficiency. 278 22

Severe combined immunodeficiency disease (SCID) in patients with adenosine deaminase (ADA) deficiency is thought to result from increased levels of purine metabolites. We attempted to immunosuppress a patient with ADA deficiency and SCID using a continuous infusion of deoxyadenosine to obtain engraftment of a T cell-depleted haplocompatible parental bone marrow graft. Before administering the drug in vivo, we investigated hematopoietic colony formation in two children with ADA deficiency (including the potential recipient), the obligate heterozygote donor (father), and normal controls using deoxyadenosine and erythro-9-(2-hydroxy-3-nanyl)adenosine (EHNA), and inhibitor of ADA. Deoxyadenosine alone in concentrations as high as 100 microM had no significant affect on erythroid (BFU-E) or myeloid (CFU-c) colony formation. However, in the presence of EHNA there was a significant reduction in BFU-E and CFU-c growth in all subjects and controls. Increasing doses of deoxyadenosine were given to one patient with ADA deficiency and SCID as a continuous 24-hr intravenous infusion. We found that there was a linear relationship between the dose administered and the plasma level; however, doses greater than 100 mg/day were required to increase erythrocyte dATP levels. We were able to raise intracellular dATP levels to more than three times baseline with doses of deoxyadenosine of 200 mg/day. However, there were no significant effects on the absolute lymphocyte counts or the lymphocyte responses to mitogen or alloantigen, and the haploidentical marrow failed to engraft. Our results suggest that the bone marrow of ADA-deficient patients is normal with respect to standard colony formation, that inhibitors of ADA do not adequately model the deficient state, and that the immunodeficiency in ADA deficiency is not proportionately related to either the deoxyadenosine or dATP levels, both of which were significantly elevated at the time of transplantation.
 ...
PMID:Rejection of bone marrow transplant and resistance of alloantigen reactive cells to in vivo deoxyadenosine in adenosine deaminase deficiency. 297 90

The importance of intact adenosine deaminase (ADA) activity in the generation of superoxide anion by xanthine oxidase has been disputed in studies using human neutrophils or mouse macrophages. The latter demonstrated a positive correlation between ADA activity and superoxide production during phagocytosis. The immunodeficiency in inherited ADA deficiency was related to a defect in this process. Since there is considerable interspecies variation in the tissue distribution of xanthine oxidase, the metabolism of [8-14C]deoxyadenosine (dAR), the toxic metabolite which accumulates in inherited ADA deficiency, was investigated in human peritoneal macrophages. Evaluation of the distribution of radiolabel in both cell and medium demonstrated that human macrophages with intact ADA metabolize dAR under physiological conditions to deoxyinosine and hypoxanthine exclusively. The hypoxanthine is further metabolized within the cell to ATP and GTP, via IMP. No xanthine or uric acid could be detected, confirming that in human macrophages xanthine oxidase activity is insignificant, as it is in most other human cells and tissues, except liver and intestinal mucosa. Thus production of superoxide radicals in such cells via this route would be impossible, and consequently unaffected either by ADA deficiency or the xanthine oxidase inhibitor allopurinol.
 ...
PMID:Superoxide radicals, immunodeficiency and xanthine oxidase activity: man is not a mouse! 298 25

Bone marrow transplantation provides an important modality for "enzyme replacement" and the immune reconstitution of patients with adenosine deaminase (ADA) deficiency and severe combined immunodeficiency disease. We report a patient with ADA deficiency who develops severe varicella pneumonia 6 years after successful bone marrow transplantation and immune reconstitution. Marked abnormalities in T-cell mitogen responsiveness and pokeweed mitogen-induced polyclonal immunoglobulin synthesis occurred. Coculture experiments suggested the presence of increased suppressor activity. T-cell phenotyping showed decreased T3 and T4 subsets. These abnormalities slowly resolved over several months as the patient recovered from the varicella infection. ADA enzyme levels and metabolite concentrations in urine and erythrocytes remained unchanged. These findings, together with the chromosome and immune studies, suggested that the bone marrow graft remained intact. These studies indicate that immunologically reconstituted ADA-deficient patients may be at higher risk for complications related to varicella infection and suggest that the institution of preventive measures is important.
 ...
PMID:Varicella pneumonia in a bone marrow-transplanted, immune-reconstituted adenosine deaminase-deficient patient with severe combined immunodeficiency disease. 298 24

"Immune regulation: what immunodeficiency disease has taught us" is reviewed by discussing three immuno-deficiency disorders. Hypogammaglobulinemia, the first documented primary immunodeficiency disorder, has a well defined and uniform clinical presentation which reflects a variety of underlying abnormalities involving the B cell, T cell, and monocyte. X-linked hypogammaglobulinemia, transient hypogammaglobulinemia of infancy common variable immunodeficiency, and their pathogenesis are discussed. Combined immunodeficiency with adenosine deaminase (ADA) deficiency first led to the now accepted concept that a biochemical abnormality may result in immunodeficiency. The clinical presentation, possible biochemical abnormalities resulting in the observed immunodeficiency, relative selectivity of the defect for the immune system, and potential applications of knowledge gained from the study of ADA deficiency are presented. Acquired immunodeficiency (AIDS) has resulted in the concept that a virus is cytopathic for a specific population of T cells and that this, at least in part, results in the immunodeficiency seen in AIDS.
 ...
PMID:Immune regulation: what immunodeficiency disease has taught us. 298 76

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.
 ...
PMID:One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity. 300 8


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>