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:3.1.27.4 (ribonuclease)
6,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bovine immunodeficiency virus (BIV) is a lentivirus with no proven pathogenesis in infected cattle. Yet, in experimentally infected rabbits, it causes an AIDS-like disease. Consequently, we expressed two recombinant isoforms of BIV reverse transcriptase (RT), which differ in their C-termini, and studied their catalytic properties. Both isoforms prefer Mg(+2) over Mn(+2) with most DNA polymerase and ribonuclease-H substrates. The processivity of DNA synthesis by the BIV RTs is higher than that of HIV-1 RT, whereas the fidelity of synthesis is even lower than that of the HIV-1 enzyme. The ribonuclease-H cleavage pattern suggests that the spatial distance between the polymerase and ribonuclease-H active sites of the two BIV RT isoforms equals 20 nt, unlike the 17 nt distance observed in almost all other RTs. The longer BIV RT version is somewhat less active than the shorter version, suggesting that the extra 74 residues (with homology to dUTPases) might obstruct efficient catalysis.
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PMID:The catalytic properties of the recombinant reverse transcriptase of bovine immunodeficiency virus. 1663 Dec 25

Ribonucleases (RNases) have therapeutic potential against cancer and viral diseases and have been reported to inhibit replication of the human immunodeficiency virus type 1 (HIV-1) in chronically infected cell lines. The ribonuclease eosinophil-derived neurotoxin (EDN) is responsible for the anti-HIV-1 activity of a soluble factor produced in response to human alloantigens (ASF). Four recombinant RNases (EDN; a four amino acid extension of the N-terminus EDN, -4EDN; RNase A; and angiogenin) were tested for inhibition of HIV-1 replication in PHA blasts. All RNases showed anti-HIV-1 activity, irrespective of whether the RNases were added before, during, or 2 h after infection. Polyclonal antibodies against the four RNases blocked the antiviral activity. ASF inhibited HIV-1 replication in vitro if added up to 4 h after infection. We demonstrated that allostimulation induced EDN, RNase A, and angiogenin mRNA expression in peripheral blood mononuclear cells (PBMCs), although only EDN protein was detected. We identified monocytes and dendritic cells, but not macrophages or T cells, as EDN-producing cells. These findings raise the possibilities that multiple naturally occurring RNases may contribute to protection against HIV-1 infection and could be considered for utilization in HIV-1 therapy.
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PMID:Ribonucleases in HIV type 1 inhibition: effect of recombinant RNases on infection of primary T cells and immune activation-induced RNase gene and protein expression. 1698 16

Hot water extracts of 16 species of mushrooms, including both edible and medicinal mushrooms, were screened for human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) inhibitory activity. Extracts of Lactarius camphoratus, Trametes suaveolens, Sparassis crispa, Pleurotus sajor-caju, Pleurotus pulmonarius, and Russula paludosa elicited over 50% inhibition when tested at the concentration of 1 mg/ml. The extract of R. paludosa demonstrated the highest inhibitory activity on HIV-1 RT (97.6%). Fraction SU2, purified from R. paludosa extract by anion exchange chromatography on DEAE-cellulose and gel filtration on Superdex 75, exhibited potent inhibitory activity on HIV-1 RT. At the concentrations of 1 mg/ml, 0.2 mg/ml, and 0.04 mg/ml, the inhibition ratios were 99.2%, 89.3%, and 41.8%, respectively, giving an IC50 of 11 microM. The molecular mass of SU2 was 4.5 kDa and its N-terminal amino acid sequence was determined to be KREHGQHCEF. The peptide was devoid of hemagglutinating, ribonuclease, antifungal, protease, protease inhibitory, and laccase activities.
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PMID:A peptide with HIV-1 reverse transcriptase inhibitory activity from the medicinal mushroom Russula paludosa. 1711 95

Previous studies show that the reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1) and RT-derived peptides interact with and inhibit the viral integrase (IN). In the present study, we have performed the complementary study by screening a complete library of HIV-1 IN-derived peptides for their effects on the RT. We have identified a 20-residues long peptide, derived from the IN (residues 46-65) that binds the RT and inhibits its DNA-polymerase activities (without affecting the ribonuclease-H activity). The full 20-residues sequence is required for maximal inhibition. This inhibition is non-competitive and probably results from obstructing the formation of RT-DNA complexes by the peptide. The data and the molecular docking model presented suggest that this inhibition is probably caused by a steric hindrance or conformational changes of the RT. These results can facilitate the development of novel and specific peptide-based HIV-1 RT inhibitors that might help in the fight against AIDS.
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PMID:Inhibition of human immunodeficiency virus type-1 reverse transcriptase by a novel peptide derived from the viral integrase. 1725 75

Mutations in the RMRP gene lead to a wide spectrum of autosomal recessive skeletal dysplasias, ranging from the milder phenotypes metaphyseal dysplasia without hypotrichosis and cartilage hair hypoplasia (CHH) to the severe anauxetic dysplasia (AD). This clinical spectrum includes different degrees of short stature, hair hypoplasia, defective erythrogenesis, and immunodeficiency. The RMRP gene encodes the untranslated RNA component of the mitochondrial RNA-processing ribonuclease, RNase MRP. We recently demonstrated that mutations may affect both messenger RNA (mRNA) and ribosomal RNA (rRNA) cleavage and thus cell-cycle regulation and protein synthesis. To investigate the genotype-phenotype correlation, we analyzed the position and the functional effect of 13 mutations in patients with variable features of the CHH-AD spectrum. Those at the end of the spectrum include a novel patient with anauxetic dysplasia who was compound heterozygous for the null mutation g.254_263delCTCAGCGCGG and the mutation g.195C-->T, which was previously described in patients with milder phenotypes. Mapping of nucleotide conservation to the two-dimensional structure of the RMRP gene revealed that disease-causing mutations either affect evolutionarily conserved nucleotides or are likely to alter secondary structure through mispairing in stem regions. In vitro testing of RNase MRP multiprotein-specific mRNA and rRNA cleavage of different mutations revealed a strong correlation between the decrease in rRNA cleavage in ribosomal assembly and the degree of bone dysplasia, whereas reduced mRNA cleavage, and thus cell-cycle impairment, predicts the presence of hair hypoplasia, immunodeficiency, and hematological abnormalities and thus increased cancer risk.
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PMID:Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. 1770 97

The interaction between human immunodeficiency virus type 1 (HIV-1) and RNA silencing pathways is complex and multifaceted. Essential for efficient viral transcription and supporting Tat-mediated transactivation of viral gene expression, the trans-activation responsive (TAR) element is a structured RNA located at the 5' end of all transcripts derived from HIV-1. Here, we report that this element is a source of microRNAs (miRNAs) in cultured HIV-1-infected cell lines and in HIV-1-infected human CD4+ T lymphocytes. Using primer extension and ribonuclease (RNase) protection assays, we delineated both strands of the TAR miRNA duplex deriving from a model HIV-1 transcript, namely miR-TAR-5p and miR-TAR-3p. In vitro RNase assays indicate that the lack of a free 3' extremity at the base of TAR may contribute to its low processing reactivity in vivo. Both miR-TAR-5p and miR-TAR-3p down-regulated TAR miRNA sensor activity in a process that required an integral miRNA-guided RNA silencing machinery. miR-TAR-3p exerted superior gene downregulatory effects, probably due to its preferential release from HIV-1 TAR RNA by the RNase III Dicer. Our study suggests that the TAR element of HIV-1 transcripts releases functionally competent miRNAs upon asymmetrical processing by Dicer, thereby providing novel insights into viral miRNA biogenesis.
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PMID:Identification of functional microRNAs released through asymmetrical processing of HIV-1 TAR element. 1829 84

The incidence of maternal-to-fetal human immunodeficiency virus type 1 (HIV-1) transmission is 25-30% in absence of antiretroviral therapy, and is inversely associated with Human leukocyte antigens (HLA) class-I discordance. Based on our earlier report that mixed lymphocyte reactions (MLR) induce a ribonuclease (RNase) that inhibits HIV-1 replication, we proposed that maternal-fetal alloantigen stimulation activates factors that protect the fetus against vertically-transmitted infections. We investigate here whether the degree of mother-infant HLA discordance associates with the ability to produce anti-HIV-1 alloantigen-stimulated factor (ASF), and affects placental RNases. We also determine whether such HLA association is influenced by the mother's HIV-1 status. Paired maternal and cord blood leukocytes were tested for the induction of ASF by MLR, and typed for HLA-A and -B. The placentas were tested for mRNA expression of three RNases. Neonate anti-mother, but not mother anti-neonate MLR generated supernatants with anti-HIV-1 activity, that was associated with HLA class I discordance. This HLA association was not seen in the HIV-infected cohort. HLA class I discordance was also associated with expression of placental RNase 1. Our findings are consistent with the hypothesis that HLA class I discordance induces expression of RNases in the placenta that contribute to innate host resistance to HIV-1 and other viral infections.
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PMID:Fetal-maternal HLA-A and -B discordance is associated with placental RNase expression and anti-HIV-1 activity. 1869 Oct 36

Ribonucleases are evoking medical interest because of their intrinsic cytotoxic activity. Most notably, ranpirnase, which is an amphibian ribonuclease, is in advanced clinical trials as a chemotherapeutic agent for the treatment of cancer. Here, we describe a strategy to create a novel antiviral agent based on bovine pancreatic ribonuclease (RNase A), a mammalian homologue of ranpirnase. Specifically, we have linked the N- and C-termini of RNase A with an amino acid sequence that is recognized and cleaved by human immunodeficiency virus (HIV) protease. This linkage obstructs the active site, forming an HIV-specific RNase A zymogen. Cleavage by HIV-1 protease increases ribonucleolytic activity by 50-fold. By relying on the proper function of HIV-1 protease, rather than its inhibition, our approach will not engender known mechanisms of resistance. Thus, we report an initial step toward a new class of agents for the treatment of HIV/AIDS.
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PMID:Design and characterization of an HIV-specific ribonuclease zymogen. 1902 16

Reverse transcriptase of the human immunodeficiency virus possesses DNA polymerase and ribonuclease (RNase) H activities. Although the nucleic acid binding cleft separating these domains can accommodate structurally diverse duplexes, it is currently unknown whether regular DNA/RNA hybrids can simultaneously contact both active sites. In this study, we demonstrate that ligands capable of trapping the 3'-end of the primer at the polymerase active site affect the specificity of RNase H cleavage without altering the efficiency of the reaction. Experiments under single-turnover conditions reveal that complexes with a bound nucleotide substrate show specific RNase H cleavage at template position -18, while complexes with the pyrophosphate analogue foscarnet show a specific cut at position -19. This pattern is indicative of post-translocated and pre-translocated conformations. The data are inconsistent with models postulating that the substrate toggles between both active sites, such that the primer 3'-terminus is disengaged from the polymerase active site when the template is in contact with the RNase H active site. In contrast, our findings provide strong evidence to suggest that the nucleic acid substrate can engage both active sites at the same time. As a consequence, the bound and intact DNA/RNA hybrid can restrict access of RNase H active site inhibitors. We have mapped the binding site of the recently discovered inhibitor beta-thujaplicinol between the RNase H active site and Y501 of the RNase H primer grip, and have shown that the inhibitor is unable to bind to a preformed reverse transcriptase-DNA/RNA complex. In conclusion, the bound nucleic acid substrate and in turn, active DNA synthesis can represent an obstacle to RNase H inhibition with compounds that bind to the RNase H active site.
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PMID:HIV-1 reverse transcriptase can simultaneously engage its DNA/RNA substrate at both DNA polymerase and RNase H active sites: implications for RNase H inhibition. 1928 31

Cartilage hair hypoplasia (CHH) is an autosomal recessive disorder caused by mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene. Although its most constant feature is metaphyseal dysplasia with short stature, CHH is associated with extraskeletal defects such as thin hair, anemia, immunodeficiency, and increased incidence of lymphomas. The spectrum of immunologic phenotypes in CHH translates into clinical severity. Whereas T-cell deficiency may remain subclinical or may result in severe combined immunodeficiency or Omenn syndrome, humoral immunodeficiency has only rarely been noted in these patients. Here we report the diagnosis of CHH in a woman who presented with severe short stature and a full-blown antibody deficiency, clinically resembling common variable immunodeficiency. Sequencing of the RMRP gene revealed compound heterozygosity for two novel mutations (g.68_69delinsTT and g.76C>T). Despite the late onset of immunodeficiency in the patient, its clinical course was severe, and the patient died 3 years after the first diagnosis.
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PMID:Fatal adult-onset antibody deficiency syndrome in a patient with cartilage hair hypoplasia. 2053 26


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