Mini Review From the Molecular Base to the Diagnostic Value of Adenosine Deaminase (original) (raw)
Clinical expression, genetics and therapy of adenosine deaminase (ADA) deficiency
Journal of Inherited Metabolic Disease, 1997
Adenosine deaminase (ADA) deficiency was the first known cause of primary immunodeficiency. Over the past 25 years the basis for immune deficiency has largely been established. Now it appears that ADA deficiency may also cause hepatic toxicity, raising new questions about its pathogenesis. The ADA gene has been sequenced and the ADA three-dimensional structure solved. The relationship between genotype and phenotype is being analysed, and ADA deficiency has become a focus for novel approaches to enzyme replacement and gene therapy.
Nucleic Acids Research, 1984
In order to determine the molecular basis of adenosine deaminase (ADA) deficiency in cells derived from patients with severe combined immunodeficiency (SCID) disease, we used a human ADA cDNA clone (1) to analyse the organization and transcription of the ADA gene in both normal and ADA SCID cells. In five lymphoblastoid ADA SCID cell lines we could detect no deletions or rearrangements in the ADA gene and its flanking sequences. Furthermore, synthesis and processing of ADA mRNA appeared to be normal in the ADA-SCID cells, and ADA-specific mRNA from two ADA SCID cells could be translated in vitro into a protein with the molecular weight of normal ADA; this protein, however, could hardly be precipitated with an ADA antiserum. The results indicate that in these two ADA SCID cell lines, the lack of ADA activity is not due to transcriptional or translational defects, but to subtle changes in the configuration of the protein affecting both its enzymatic and immunological characteristics.
Molecular Evidence of Adenosine Deaminase Linking Adenosine A2A Receptor and CD26 Proteins
Frontiers in Pharmacology, 2018
Adenosine is an endogenous purine nucleoside that acts in all living systems as a homeostatic network regulator through many pathways, which are adenosine receptor (AR)-dependent and-independent. From a metabolic point of view, adenosine deaminase (ADA) is an essential protein in the regulation of the total intracellular and extracellular adenosine in a tissue. In addition to its cytosolic localization, ADA is also expressed as an ecto-enzyme on the surface of different cells. Dipeptidyl peptidase IV (CD26) and some ARs act as binding proteins for extracellular ADA in humans. Since CD26 and ARs interact with ADA at opposite sites, we have investigated if ADA can function as a cell-to-cell communication molecule by bridging the anchoring molecules CD26 and A 2A R present on the surfaces of the interacting cells. By combining site-directed mutagenesis of ADA amino acids involved in binding to A 2A R and a modification of the bioluminescence resonance energy transfer (BRET) technique that allows detection of interactions between two proteins expressed in different cell populations with low steric hindrance (NanoBRET), we show direct evidence of the specific formation of trimeric complexes CD26-ADA-A 2A R involving two cells. By dynamic mass redistribution assays and ligand binding experiments, we also demonstrate that A 2A R-NanoLuc fusion proteins are functional. The existence of this ternary complex is in good agreement with the hypothesis that ADA could bridge T-cells (expressing CD26) and dendritic cells (expressing A 2A R). This is a new metabolic function for ecto-ADA that, being a single chain protein, it has been considered as an example of moonlighting protein, because it performs more than one functional role (as a catalyst, a costimulator, an allosteric modulator and a cell-to-cell connector) without partitioning these functions in different subunits.
The Human Gene for Adenosine Deaminase
Annals of the New York Academy of Sciences, 1985
We are investigating the human gene for adenosine deaminase (ADA) in order to obtain insight into (1) its structural organization, expression and regulation, (2) the basic molecular defect of the gene causing ADA-SCID disease, and (3) the possibility of transferring the human ADA gene into mouse bone marrow cells and its subsequent expression in mouse blood cells.
Moonlighting Adenosine Deaminase: A Target Protein for Drug Development
Medicinal Research Reviews, 2014
Interest in adenosine deaminase (ADA) in the context of medicine has mainly focused on its enzymatic activity. This is justified by the importance of the reaction catalyzed by ADA not only for the intracellular purine metabolism, but also for the extracellular purine metabolism as well, because of its capacity as a regulator of the concentration of extracellular adenosine that is able to activate adenosine receptors (ARs). In recent years, other important roles have been described for ADA. One of these, with special relevance in immunology, is the capacity of ADA to act as a costimulator, promoting T-cell proliferation and differentiation mainly by interacting with the differentiation cluster CD26. Another role is the ability of ADA to act as an allosteric modulator of ARs. These receptors have very general physiological implications, particularly in the neurological system where they play an important role. Thus, ADA, being a single chain protein, performs more than one function, consistent with the definition of a moonlighting protein. Although ADA has never been associated with moonlighting proteins, here we consider ADA as an example of this family of multifunctional proteins. In this review, we discuss the different roles of ADA and their pathological implications. We propose a mechanism by which some of their moonlighting functions can be coordinated. We also suggest that drugs modulating ADA properties may act as modulators of the moonlighting functions of ADA, giving them additional potential medical interest.
Journal of Medical Genetics, 1987
A karyotype 46,XY,del(20)(q1123q13-11) was found in a three year old boy with mental and growth retardation, low set ears, broad nasal bridge, and macrostomia. Adenosine deaminase (ADA) activity was reduced by about 50%, assigning the gene locus to the deleted segment. A review of the previously reported regional assignments suggests that the ADA gene is in the region of band 20q13-11. Long arm deletion of chromosome 20 (20q-) has been reported as a marker in certain haematological diseases like polycythaemia vera.' Constitutional 20q-, however, is extremely rare. Only one case of terminal deletion 20q has been published previously.2 The gene locus for the enzyme adenosine deaminase (ADA) has been assigned to chromosome 20,3 and there are several reports on the regional localisation of the gene on 20q.4-1 Purine nucleo- side phosphorylase (PNP), another purine enzyme measured as a control, has been localised on chromosome 14.12 We present a case of interstitial deletion 20q where the ADA activity was investigated. Methods QFQ and GTG banding of chromosomes from peripheral lymphocyte and skin fibroblast cultures was performed in the usual way. High resolution banding was performed from RBA banded prometaphases using methotrexate synchronised peripheral lymphocyte cultures.'3 ADA activity was determined by measuring the formation of inosine and hypoxanthine from adenosine by a radioisotopic method, as described previously." ADA was measured in skin fibroblasts and in granulocytes, which were isolated from peripheral blood.'4 To ensure that enzyme activity
Genome Biology, 2012
Adenosine deaminases acting on RNA (ADARs) are enzymes that catalyze the chemical conversion of adenosines to inosines in double-stranded RNA (dsRNA) substrates. Because the properties of inosine mimic those of guanosine (inosine will form two hydrogen bonds with cytosine, for example), inosine is recognized as guanosine by the translational cellular machinery . Adenosine-toinosine (A-to-I) RNA 'editing, ' therefore, eff ectively changes the primary sequence of RNA targets.
Subcellular, regional and immunohistochemical localization of adenosine deaminase in various species
Immunohistochemical and subcellular fractionation techniques were employed to compare the cellular and subcellular localization of adenosine deaminase (ADA) in various brain regions of several mammalian species. A relatively restricted distribution of ADA-immunoreactive neurons in rat brain was previously reported. Mouse brain exhibited a pattern similar in many respects to rat and, in addition, contained intensely immunostained neurons in lateral habenula and hippocampus. Glial immunostaining was absent or very light in rat but evident in mouse. Prominent immunoreactive fibers and neurons were observed in hamster spinal cord and anterior hypothalamus, respectively. ADA-immunostaining in guinea-pig was localized to presumptive fibers in the superficial layers of spinal cord dorsal horn and to glial cells throughout the brain. Demonstration of specific immunostaining in rabbit was not possible. ADA activity was far more heterogeneously distributed in rat and most brain areas in guinea-pig and rabbit contained up to 5-fold and 10-fold higher levels of activity, respectively, compared with rat. Crude synaptosomal (P2) fractions of rat cortex contained a greater proportion of ADA activity than those of rabbit cortex. Within rat, relatively high activity was found in P2 fractions of whole hypothalamus, cerebellum, and hippocampus. ADA activity was greater in P2 fractions of rat anterior compared with whole hypothalamus and the greatest proportion of the enzyme in this fraction was localized to purified synaptosomes. The large variations in the activity and cellular location of ADA in the animals examined suggest species differences in mechanisms governing adenosine metabolism in brain and possible differences in the relationships between cellular metabolism, ADA and the neuroregulatory role of adenosine in the CNS. © 1987.