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)

Throughout the world tuberculosis is associated with poverty, deprivation, and human immunodeficiency virus infection. Abdominal tuberculosis is usually of insidious onset with diverse symptoms and signs. A few present with acute complications of perforation, obstruction, or bleeding. The diagnosis is difficult, especially in areas where the disease is less common, as many patients do not have evidence of pulmonary tuberculosis or a positive skin test. The main differential diagnosis ranges from Crohn's disease in the young and advanced malignancy in the elderly. Delayed diagnosis is common, resulting in high mortality. Many investigations provide findings suggestive but not diagnostic of tuberculosis. With peritoneal tuberculosis, assay of ascitic fluid adenosine deaminase activity is a valuable, simple method of diagnosis that may reduce the need for laparoscopic biopsy. If the clinical suspicion of abdominal tuberculosis is high, a trial of medical treatment is appropriate. Surgery should be reserved for the complications of the disease. All patients require treatment with three antituberculous drugs over a 6-month course.
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PMID:Abdominal tuberculosis. 920 36

Application of gene therapy to treat genetic and infectious diseases may have several advantages if performed in newborns. Because of the minimal adverse effect of the underlying disease on cells of the newborn, the relatively small size of infants, and the large amount of future growth, gene therapy may be more successful in newborns than in older children or adults. The presence of umbilical cord blood from newborns provides a unique and susceptible target for the genetic modification of hematopoietic stem cells. In our first trial of gene therapy in newborns, we inserted a normal adenosine deaminase gene into umbilical cord blood cells of three neonates with a congenital immune deficiency. The trial demonstrated the successful transduction and engraftment of stem cells, which continue to contribute to leukocyte production more than 3 years later. A similar approach may be taken to insert genes that inhibit replication of HIV-1 into umbilical cord blood cells of HIV-1-infected neonates. Many other metabolic and infectious disorders could be treated by gene therapy during the neonatal period if prenatal diagnoses are made and the appropriate technical and regulatory requirements have been met.
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PMID:Gene therapy for newborns. 924 Sep 65

CD26, known to be the adenosine deaminase (ADA) binding protein, has been implicated in HIV infection. In human B and T cell lines we show that, irrespective of CD4 expression, 125I-labeled ADA binding to CD26 is inhibited by recombinant soluble HIV-1 envelope glycoprotein gp120 and by HIV-1 infectious particles. Overlapping synthetic peptides covering the entire gp120 sequence were tested to map the region in gp120 responsible for ADA binding inhibition. Only peptides in the C3 region significantly inhibited the binding of ADA to CD26. These results indicate that a specific function of gp120 is the inhibition of ADA binding to CD26 in both CD4+ and CD4- cells. Since the interaction ecto-ADA/CD26 is required for the activation of T cells, it remains possible that HIV particle-mediated blockade of ecto-ADA/CD26 interaction may have significant consequences in the pathogenesis of AIDS disease.
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PMID:HIV-1 envelope gp120 and viral particles block adenosine deaminase binding to human CD26. 933 Jun 96

Recent studies in populations with a high prevalence of tuberculosis and HIV infection report that tuberculous pleurisy occurs in approximately 30% of patients with tuberculosis. However, the fraction of patients with tuberculosis who have tuberculous pleurisy is comparable in HIV-positive and HIV-negative individuals. It appears that tuberculous pleurisy mostly develops in patients with HIV who have CD4 counts above 200/microL. Primary tuberculous pleurisy is thought to occur as a result of a delayed hypersensitivity reaction to mycobacterial antigens. Recent studies highlight the way in which pleural cells become activated and produce cytokines as a response to mycobacteria. Intramacrophage and direct cytotoxic elimination of mycobacteria, granuloma formation, and fibrosis are the main facets of this reaction. Many studies have investigated the usefulness of measuring different parameters in pleural fluid for an early diagnosis of tuberculous pleurisy. It has been shown that the most useful diagnostic tests are the levels of adenosine deaminase and interferon gamma in the pleural fluid. Elevation of either of these compounds in lymphocytic pleural effusions is virtually diagnostic of tuberculous pleurisy. Although theoretically, detection of mycobacterial DNA in the pleural fluid by the polymerase chain reaction would appear to be useful, the usefulness of this test still needs further demonstration. Patients with tuberculous pleurisy must receive antituberculous treatment. The current recommendation for immunocompetent patients is a 6-month regimen of isoniazid and rifampin supplemented in the first 2 months by pyrazinamide. HIV-infected patients should be treated with this same regimen for a longer time period. Serial thoracentesis or corticosteroid treatment are not warranted for the majority of patients.
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PMID:Pleural tuberculosis: incidence, pathogenesis, diagnosis, and treatment. 936 61

Adenosine deaminase (ADA, EC 3.5.4.4) is an enzyme of the purine metabolism which has been the object of considerable interest mainly because the congenital defect causes severe combined immunodeficiency (SCID). In the last 10 years, ADA, which was considered to be cytosolic, has been found on the cell surface of many cells and, therefore, it can be considered an ecto-enzyme. There is recent evidence about a specific role of ecto-ADA, which is different from that of intracellular ADA. Apart from degrading extracellular adenosine (Ado) or 2'-deoxyadenosine (dAdo), which are toxic for lymphocytes, ecto-ADA has an extraenzymatic function via its interaction with CD26. ADA/CD26 interaction results in co-stimulatory signals in T cells. This co-stimulation is blocked by HIV-1, thus evidencing a role for ecto-ADA in the pathophysiology of AIDS. The fact that, besides CD26, ADA can interact with different cell-surface proteins opens new perspectives in the research for a role of ecto-ADA in the function of the immune system and in the interactions that take place between different cells in the development of the immune system. The most interesting aspect is the possible participation of the ecto-enzyme in cell-to-cell contacts during ontogenesis and maturation of immunocompetent cells.
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PMID:Enzymatic and extraenzymatic role of ecto-adenosine deaminase in lymphocytes. 955 62

CD26 is a widely distributed 110 kD cell-surface glycoprotein with known dipeptidyl-peptidase IV (DPP-IV) activity in its extracellular domain. This ecto-enzyme is capable of cleaving amino terminal dipeptides from polypeptides with either L-proline or L-alanine in the penultimate position. On human T cells, CD26 expression appears late in thymic differentiation and is preferentially restricted to the CD4+ helper/memory population, and CD26 can deliver a potent co-stimulatory T-cell activation signal. The cDNA sequence of CD26 predicts a type II membrane protein with only 6 amino acids in its cytoplasmic region, suggesting that, in addition to DPP-IV enzyme activity, other signal-inducing molecules may be associated with CD26. Considerable evidence exists that CD26 interacts, presumably in its extracellular domain, with both CD45, a protein tyrosine phosphatase, and adenosine deaminase (ADA), each of which is capable of functioning in a signal transduction pathway. In addition, CD26 is the receptor for ADA, and ADA on the cell surface is involved in an important immunoregulatory mechanism by which released ADA binds to the cell-surface ADA. This multifunctional molecule may be involved in cell migration and the HIV-1-associated loss of CD4+ cells through the process of programmed cell death. Thus, CD26 appears to play a key role in a number of aspects of lymphocyte function.
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PMID:The structure and function of CD26 in the T-cell immune response. 955 64

Previous in situ perfusion studies in rat ileal segments have demonstrated that high concentrations (>40 microg/mL) of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), a semitight binding inhibitor of adenosine deaminase (ADA), are effective in completely inhibiting the intestinal metabolism of 6-chloro-2',3'-dideoxypurine (6-Cl-ddP), an ADA activated prodrug of the anti-HIV agent 2', 3'-dideoxyinosine (ddI) designed for improved targeting to the central nervous system. However, the intestinal absorption of EHNA results in complete inhibition of the ADA activity in the mesenteric blood draining the isolated intestinal segment being perfused and may lead to complete inhibition of ADA present in the systemic circulation and other sites, an unacceptable outcome since bioconversion in the target tissue is required for prodrug efficacy. This study examines the feasibility of locally inhibiting ADA present in the intestinal wall using EHNA to increase the intestinal absorption of 6-Cl-ddP. Transport experiments conducted in isolated ileal segments from mesenteric cannulated rats using perfusate containing prodrug and various concentrations of EHNA demonstrated that a 0.1 microg/mL logarithmic mean lumenal concentration of EHNA was effective in increasing the intestinal bioavailability of Cl-ddP to > 90%. Intestinal uptake parameters for EHNA and pharmacokinetic parameters generated in vivo in chronically catheterized rats given intravenous infusions ranging from 12.5 to 310 microg/kg/min were used to demonstrate that <10% of systemic ADA would be inhibited at steady state using the optimal perfusate concentration of EHNA. Thus, in continuous perfusions it is possible to increase the intestinal bioavailability of 6-Cl-ddP to >90% with minimal (<10%) inhibition of systemic ADA. Local inhibition of enzymes may be an effective strategy to increase the oral bioavailability of tissue enzyme-activated prodrugs or other drugs which may also be substrates for intestinal enzymes.
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PMID:Optimization of the local inhibition of intestinal adenosine deaminase (ADA) by erythro-9-(2-hydroxy-3-nonyl)adenine: enhanced oral delivery of an ADA-activated prodrug for anti-HIV therapy. 957 8

By using tissue and blood from mice and mice themselves, biological behavior of 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG) and 6-chloro-2',3'-dideoxyinosine (6-Cl-ddI) was examined in vitro and in vivo. Both compounds resemble each other in chemical structure. They are converted to ddG and ddI, respectively, by adenosine deaminase in the cells, and express their anti-HIV activity in vitro. According to our recent data about their biological behaviour in vivo; however, it was revealed that they are fairly different especially as the agent working in the brain. After injection of each drug into the body of mice, ddG, or metabolite of 6-Cl-ddG, was observed in the brain, while ddI was not found there.
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PMID:Biological behaviour of 6-chloro-2',3'-dideoxyguanosine and 6-chloro-2',3'-dideoxyinosine in the brains of mice. 958 55

Serum beta 2-microglobulin, neopterin, immunoglobulins A, G and M, adenosine deaminase and CD4+ lymphocyte count were evaluated as predictors of progression of HIV-1 infection to AIDS. A population of HIV-1 seropositive, initially asymptomatic men (n = 213) and women (n = 101) was followed up quarterly. We estimated the AIDS-free time using the actuarial method (median survival time 47.2 months). Cox proportional hazard analysis revealed that all markers studied were significant (p < 0.05) in relation to progression to AIDS. The best markers for predicting progression to AIDS were, in descending order, CD4+ lymphocyte count, beta 2-microglobulin, IgA, neopterin, IgG, IgM and adenosine deaminase. On stratifying population into four groups (divided at percentiles 25, 50 and 75--from group 1, with values nearest to reference ranges, to group 4, with most abnormal values) we observed statistically significant differences (p < 0.05) for all markers except for adenosine deaminase. The relative risk from the Cox proportional hazards model were used to quantify the effects of the best markers and compared to the risk obtained in group 1. CD4+ lymphocyte count was the best predictor of progression to AIDS. When considering beta 2-microglobulin and CD4+ together, the relative risk in the group with lowest CD4+ cell count (group 4) ranged from 25.6% (with lower beta 2-microglobulin values) to 41.1% (with higher beta 2-microglobulin values). Similar results were obtained when considering neopterin and CD4+ together. The addition of beta 2-microglobulin or neopterin values to CD4+ lymphocyte count improved the predictive value of CD4+ lymphocyte count.
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PMID:The predictive value of several markers in the progression to acquired immunodeficiency syndrome. 958 5

1. This manuscript describes two different strategies to progress from the clinical assessment of patients to the identification of disease-causing mutations. In the first disease, recognition of a metabolic abnormality allowed direct molecular analysis of the causal gene. In contrast, localization of the second disease gene by linkage analysis was critical to implicate a gene with a previously unsuspected disease role. 2. Two sisters with chronic respiratory disease and recurrent infections were identified as the first cases of adult onset immunodeficiency due to adenosine deaminase deficiency. Autosomal recessive inheritance of two mutations in the adenosine deaminase gene was demonstrated. Enzyme replacement therapy improved the patients' immunological and clinical status. 3. Individuals with pulmonary arteriovenous malformations were used to identify families with hereditary haemorrhagic telangiectasia (HHT, Rendu-Osler-Weber Syndrome). Linkage studies mapped the HHT disease gene in some families to chromosome 9, and demonstrated genetic heterogeneity. The chromosome 9 disease interval was refined, and several candidate genes were assessed. Following the first description of disease-segregating mutations, a complete analysis of the endoglin gene (which encodes an endothelial cell transforming growth factor-beta receptor) identified seven novel mutations. Two mutations did not produce mutant mRNA, and disease severity was comparable between families, indicating that HHT results from stoichiometric insufficiency of endoglin. 4. Each study has implications extending beyond the relatively rare disease analysed. The adenosine-deaminase-deficient patients highlight a treatable cause of HIV-negative CD4+ lymphopenia in adults, perhaps accounting for further cases of 'non-HIV AIDS'. The HHT studies have illuminated a novel area of vascular pathophysiology, with potential relevance to further disease states.
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PMID:Glaxo/MRS Young Investigator Medal. Molecular studies on adenosine deaminase deficiency and hereditary haemorrhagic telangiectasia. 961 53


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