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:3.5.1.4 (deaminase)
5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular adenosine and its related nucleotides have been referred to as retaliatory metabolites that can be released into the extracellular environment during inflammation, wounding, and other pathologic states. We have previously reported that these compounds reversibly inhibit the proliferation of normal keratinocyte cultures and we now demonstrate that these compounds also arrest the proliferation of transformed keratinocytes. Although our study shows that keratinocytes express mRNA corresponding to the A2B purinoreceptors and that adenosine or AMP treatment elevates intracellular cAMP in these cells, our study also demonstrates that dipyridamole-inhibitable transport of adenosine into the keratinocyte is central to the mechanism by which adenosine and adenine nucleotides arrest proliferation in these cells. In support of this mechanism, our results demonstrate that human keratinocytes express mRNA corresponding to the recently cloned dipyridamole-sensitive human equilibrative nucleoside transporter. Interestingly, coincubation with adenosine deaminase reverses the antiproliferative action of adenosine and exerts no effect on the antiproliferative activity of the adenine nucleotides, thus supporting a model in which adenine nucleotides are enzymatically converted to adenosine and transported into the keratinocyte in a tightly coupled and adenosine-deaminase-resistant manner. Analysis of adenosine- and adenosine-monophosphate-treated keratinocytes demonstrated that quiescence is induced within 12-24 h, and fluorescence-activated cell sorter analysis suggests that treatment with these compounds may result in the inhibition of keratinocyte proliferation at both G1 and S phases of the cell cycle. In addition to their documented antiproliferative action on other cell types, adenosine, adenine nucleotides, and related analogs may also represent a potential new class of pharmacologic regulators of keratinocyte proliferation in vivo.
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PMID:Adenosine- and adenine-nucleotide-mediated inhibition of normal and transformed keratinocyte proliferation is dependent upon dipyridamole-sensitive adenosine transport. 1106 23

The RNA-specific adenosine deaminase (ADAR1) and the RNA-dependent protein kinase (PKR) are both interferon-inducible double-stranded (ds) RNA-binding proteins. ADAR1, an RNA editing enzyme that converts adenosine to inosine, possesses three copies of a dsRNA-binding motif (dsRBM). PKR, a regulator of translation, has two copies of the highly conserved dsRBM motif. To assess the functional selectivity of the dsRBM motifs in ADAR1, we constructed and characterized chimeric proteins in which the dsRBMs of ADAR1 were substituted with those of PKR. Recombinant PKR-ADAR1 chimeras retained significant RNA adenosine deaminase activity measured with a synthetic dsRNA substrate when the spacer region between the RNA-binding and catalytic domains of the deaminase was exactly preserved. However, with natural substrates, substitution of the first two dsRBMs of ADAR1 with those from PKR dramatically reduced site-selective editing activity at the R/G and (+)60 sites of the glutamate receptor B subunit pre-RNA and completely abolished editing of the serotonin 2C receptor (5-HT(2C)R) pre-RNA at the A site. Chimeric deaminases possessing only the two dsRBMs from PKR were incapable of editing either glutamate receptor B subunit or 5-HT(2C)R natural sites but edited synthetic dsRNA. Finally, RNA antagonists of PKR significantly inhibited the activity of chimeric PKR-ADAR1 proteins relative to wild-type ADAR1, further demonstrating the functional selectivity of the dsRBM motifs.
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PMID:Chimeric double-stranded RNA-specific adenosine deaminase ADAR1 proteins reveal functional selectivity of double-stranded RNA-binding domains from ADAR1 and protein kinase PKR. 1107 79

The human ADAR1 gene specifies two size forms of RNA-specific adenosine deaminase, an interferon (IFN) inducible approximately 150 kDa protein and a constitutively expressed N-terminally truncated approximately 110 kDa protein, encoded by transcripts with alternative exon 1 structures that initiate from different promoters. We have now identified a new class of ADAR1 transcripts, with alternative 5'-structures and a deduced coding capacity for the approximately 110 kDa protein. Nuclease protection and 5'-rapid amplification of cDNA ends (5'-RACE) revealed five major ADAR1 transcriptional start sites that mapped within the previously identified and unusually large (approximately 1.6 kb) exon 2. These transcripts were observed with RNA from human amnion U cells and placenta tissue. Their abundance was not affected by IFN-alpha treatment of U cells in culture. Transfection analysis identified a functional promoter within human genomic DNA that mapped to the proximal exon 2 region of the ADAR1 gene. Promoter activity was not affected by IFN. These results suggest that transcripts encoding the constitutively expressed approximately 110 kDa form of the ADAR1 editing enzyme are initiated from multiple promoters, including one within exon 2, that collectively contribute to the high basal level of deaminase activity observed in nuclei of mammalian cells.
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PMID:Human RNA-specific adenosine deaminase (ADAR1) gene specifies transcripts that initiate from a constitutively active alternative promoter. 1111 Oct 54

The RNA-specific adenosine deaminase (ADAR1) is an interferon-inducible editing enzyme that converts adenosine to inosine. ADAR1 contains three distinct domains: a N-terminal Z-DNA binding domain that includes two Z-DNA binding motifs; a central double-stranded RNA binding domain that includes three dsRNA binding motifs (dsRBM); and a C-terminal catalytic domain responsible for A-to-I enzymatic activity. The E3L protein of vaccinia virus mediates interferon resistance. E3L, similar to ADAR1, also contains Z-DNA binding and dsRNA binding motifs. To assess the possible role of E3L in modulating RNA editing by ADAR1, we examined the effect of E3L on ADAR1 deaminase activity. Wild-type E3L protein was a potent inhibitor of ADAR1 deaminase enzymatic activity. Analysis of mutant E3L proteins indicated that the carboxy-proximal dsRBM of E3L was essential for antagonism of ADAR1. Surprisingly, disruption of the Z-DNA binding domain of E3L by double substitutions of two highly conserved residues also abolished its antagonistic activity, whereas deletion of the entire Z domain had little effect on the inhibition. With natural neurotransmitter pre-mRNA substrates, E3L weakly inhibited the site-selective editing activity by ADAR1 at the R/G site of the glutamate receptor B subunit (GluR-B) pre-mRNA and the A site of serotonin 2C receptor (5-HT2CR) pre-mRNA; editing of the intronic hotspot (+)60 site of GluR-B was not affected by E3L. These results demonstrate that the A-to-I RNA editing activity of the IFN-inducible adenosine deaminase is impaired by the product of the vaccinia virus E3L interferon resistance gene.
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PMID:Vaccinia virus E3L interferon resistance protein inhibits the interferon-induced adenosine deaminase A-to-I editing activity. 1168 59

The dry powdered of Sinapis arvensis, Thymelaea hirsuta, Callistemon lanceolatus and Peganum harmala showed molluscicidal activity against Biomphalaria alexandrina, specific intermediate hosts to Schistosoma mansoni. Effect of LC25 of dry powdered plant molluscicides on hexokinase (HK), glucose phosphate isomerase (GPI), AMP deaminase, adenosine deaminase and phenol oxidase (PO) of B. alexandrina was traced. C. lanceolatus showed the highest molluscicidal activity as it has the lowest LC50 compared to S. arvensis, T. hirsuta, and P. harmala. LC25 of the latter three plants resulted in more significant inhibition of HK, GPI, AMP-deaminase and PO than C. lanceolatus. Treatment of snails with LC10 of these plants markedly affected compatibility of B. alexandrina to S. mansoni infection. Significant decrease in cercarial production recorded in snails treated with sublethal concentrations of S. arvensis, T. hirsuta, and P. harmala. Remarkable impairment of the egg laying capacity of molluscicide-treated snails was also recorded. Correlation between activity levels of HK, GPI and AMP deaminase and compatibility to parasitic infection and role of PO in the egglaying capacity of these snail species were discussed.
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PMID:In vivo, attenuation of schistosome cercarial development and disturbance of egg laying capacity in Biomphalaria alexandrina using sublethal concentrations of plant molluscicides. 1177 93

Cytosine deaminase (CD) catalyzes the deamination of cytosine, producing uracil. This enzyme is present in prokaryotes and fungi (but not multicellular eukaryotes) and is an important member of the pyrimidine salvage pathway in those organisms. The same enzyme also catalyzes the conversion of 5-fluorocytosine to 5-fluorouracil; this activity allows the formation of a cytotoxic chemotherapeutic agent from a non-cytotoxic precursor. The enzyme is of widespread interest both for antimicrobial drug design and for gene therapy applications against tumors. The structure of Escherichia coli CD has been determined in the presence and absence of a bound mechanism-based inhibitor. The enzyme forms an (alphabeta)(8) barrel structure with structural similarity to adenosine deaminase, a relationship that is undetectable at the sequence level, and no similarity to bacterial cytidine deaminase. The enzyme is packed into a hexameric assembly stabilized by a unique domain-swapping interaction between enzyme subunits. The active site is located in the mouth of the enzyme barrel and contains a bound iron ion that coordinates a hydroxyl nucleophile. Substrate binding involves a significant conformational change that sequesters the reaction complex from solvent.
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PMID:The structure of Escherichia coli cytosine deaminase. 1181 40

The RNA-editing enzyme adenosine deaminase that acts on RNA (ADAR1) deaminates adenosines to inosines in double-stranded RNA substrates. Currently, it is not clear how the enzyme targets and discriminates different substrates in vivo. However, it has been shown that the deaminase domain plays an important role in distinguishing various adenosines within a given substrate RNA in vitro. Previously, we could show that Xenopus ADAR1 is associated with nascent transcripts on transcriptionally active lampbrush chromosomes, indicating that initial substrate binding and possibly editing itself occurs cotranscriptionally. Here, we demonstrate that chromosomal association depends solely on the three double-stranded RNA-binding domains (dsRBDs) found in the central part of ADAR1, but not on the Z-DNA-binding domain in the NH2 terminus nor the catalytic deaminase domain in the COOH terminus of the protein. Most importantly, we show that individual dsRBDs are capable of recognizing different chromosomal sites in an apparently specific manner. Thus, our results not only prove the requirement of dsRBDs for chromosomal targeting, but also show that individual dsRBDs have distinct in vivo localization capabilities that may be important for initial substrate recognition and subsequent editing specificity.
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PMID:Distinct in vivo roles for double-stranded RNA-binding domains of the Xenopus RNA-editing enzyme ADAR1 in chromosomal targeting. 1271 72

Cytosine deaminase (CD) catalyzes the deamination of cytosine and is only present in prokaryotes and fungi, where it is a member of the pyrimidine salvage pathway. The enzyme is of interest both for antimicrobial drug design and gene therapy applications against tumors. The structure of Saccharomyces cerevisiae CD has been determined in the presence and absence of a mechanism-based inhibitor, at 1.14 and 1.43 A resolution, respectively. The enzyme forms an alpha/beta fold similar to bacterial cytidine deaminase, but with no similarity to the alpha/beta barrel fold used by bacterial cytosine deaminase or mammalian adenosine deaminase. The structures observed for bacterial, fungal, and mammalian nucleic acid deaminases represent an example of the parallel evolution of two unique protein folds to carry out the same reaction on a diverse array of substrates.
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PMID:The 1.14 A crystal structure of yeast cytosine deaminase: evolution of nucleotide salvage enzymes and implications for genetic chemotherapy. 1290 27

Adenosine-to-inosine (A-to-I) RNA editing is a post-transcriptional process that amplifies the repertoire of protein production. Recently, the induction of this process through up-regulation of the editing enzyme RNA-specific adenosine deaminase 1 (ADAR1) was documented during acute inflammation. Here we report that the inflammation-induced up-regulation of ADAR1 involves differential production and intracellular localization of several isoforms with distinct RNA-binding domains and localization signals. These include the full-length ADAR1 (p150) and two functionally active short isoforms (p80 and p110). ADAR1 p80 starts at a methionine 519 (M519) due to alternative splicing in exon 2, which deletes the putative nuclear localization signal, the Z-DNA binding domain, and the entire RNA binding domain I. ADAR1 p110 is the mouse homologue of the human ADAR1 110-kDa variant (M246), which retains the second half of the Z-DNA binding domain, all RNA binding domains, and the deaminase domain. Additional variations are found in the third RNA binding domain of ADAR1; they are differentially regulated during inflammation, generating isoforms with different levels of activities. Studies in several cell types transfected with ADAR1-EGFP chimeras demonstrated that the p150 and p80 variants are localized in the cytoplasm and nucleolus, respectively. In agreement with this observation, endogenous ADAR1 was identified in the cytoplasm and nucleolus of mouse splenocytes and HeLa cells. Since the ADAR1 variants are differentially regulated during acute inflammation, it suggests that the localization of these variants and of A-to-I RNA editing in the cytoplasm, nucleus, and nucleolus is intracellularly reorganized in response to inflammatory stimulation.
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PMID:Intracellular localization of differentially regulated RNA-specific adenosine deaminase isoforms in inflammation. 1295 22

The bacterial tRNA adenosine deaminase (TadA) generates inosine by deaminating the adenosine residue at the wobble position of tRNA(Arg-2). This modification is essential for the decoding system. In this study, we determined the crystal structure of Aquifex aeolicus TadA at a 1.8-A resolution. This is the first structure of a deaminase acting on tRNA. A. aeolicus TadA has an alpha/beta/alpha three-layered fold and forms a homodimer. The A. aeolicus TadA dimeric structure is completely different from the tetrameric structure of yeast CDD1, which deaminates mRNA and cytidine, but is similar to the dimeric structure of yeast cytosine deaminase. However, in the A. aeolicus TadA structure, the shapes of the C-terminal helix and the regions between the beta4 and beta5 strands are quite distinct from those of yeast cytosine deaminase and a large cavity is produced. This cavity contains many conserved amino acid residues that are likely to be involved in either catalysis or tRNA binding. We made a docking model of TadA with the tRNA anticodon stem loop.
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PMID:Crystal structure of tRNA adenosine deaminase (TadA) from Aquifex aeolicus. 1567 68


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