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:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide is a free radical (NO) formed biologically through the oxidation of L-arginine by nitric oxide synthases. NO is produced transiently in mammalian cells for intercellular signaling and in copious quantities to cause cytostasis and cytotoxicity. In the latter situation, NO is a deliberate cytotoxic product of activated macrophages, along with other reactive oxygen species such as hydrogen peroxide (H2O2) and superoxide (O2-). Escherichia coli has a complex set of responses to H2O2 and O2- that involves approximately 80 inducible proteins; we wondered whether these bacteria might induce analogous defenses against nitric oxide. We show here that a multigene system controlled by the redox-sensitive transcriptional regulator SoxR is activated by NO in vivo. This induction confers bacterial resistance to activated murine macrophages with kinetics that parallel the production of NO by these cells. Elimination of specific SoxR-regulated genes diminishes the resistance of these bacteria to the cytotoxic macrophages. The required functions include manganese-containing superoxide dismutase, endonuclease IV (a DNA-repair enzyme for oxidative damage), and micF, an antisense regulator of the outer membrane porin OmpF. These results demonstrate that SoxR is a sensor for cellular exposure to NO, and that the soxRS response system may contribute to bacterial virulence.
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PMID:Activation by nitric oxide of an oxidative-stress response that defends Escherichia coli against activated macrophages. 823 47

The unfolded protein response is an intracellular signaling pathway that, in response to accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER), upregulates transcription of ER resident chaperones. A key step in this pathway is the non-conventional, regulated splicing of the mRNA encoding the positive transcriptional regulator Hac1p. In the yeast Saccharomyces cerevisiae, the bifunctional transmembrane kinase/endoribonuclease Ire1p cleaves HAC1 mRNA at both splice junctions and tRNA ligase joins the two exons together. We have reconstituted HAC1 mRNA splicing in an efficient in vitro reaction and show that, in many ways, the mechanism of HAC1 mRNA splicing resembles that of pre-tRNA splicing. In particular, Ire1p endonucleolytic cleavage leaves 2', 3'-cyclic phosphates, the excised exons remain associated by base pairing, and exon ligation by tRNA ligase follows the same chemical steps as for pre-tRNA splicing. To date, this mechanism of RNA processing is unprecedented for a messenger RNA. In contrast to the striking similarities to tRNA splicing, the structural features of the splice junctions recognized by Ire1p differ from those recognized by tRNA endonuclease. We show that small stem-loop structures predicted to form at both splice junctions of HAC1 mRNA are required and sufficient for Ire1p cleavage.
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PMID:Mechanism of non-spliceosomal mRNA splicing in the unfolded protein response pathway. 1035 23

We report the complete sequence of two cosmids, SPBC19C7 (34815 bp insert, Accession No. AL023859) and SPBC15D4 (33203 bp insert, Accession No. AL031349), localized on chromosome II of the S. pombe genome. Twelve open reading frames (ORFs) were identified in SPBC19C7 and 16 in SPBC5D4. Two known genes were found on each cosmid: cyr1 and uve1 on SPBC19C7, encoding adenylate cyclase and a UV-endonuclease, respectively, and gpt and pho2 on SPBC15D4, encoding an N-acetylglucosamine-1-phosphate transferase and a4-nitrophenylphosphatase, respectively. Five ORFs similar to known proteins were found on SPBC19C7, and six on SPBC15D4. They include putative genes for a ubiquitin protein ligase, a prolyl-tRNA synthetase, a tRNA splicing endonuclease, a voltage-gated chloride channel, a mannosyl transferase, a kinesin-like protein, a histone transcriptional regulator, an N-acetyltransferase, a cystathionine gamma-synthase and a TFIID subunit. Two ORF products of SPBC15D4 do not have clear homologues: one encodes a putative transcriptional regulator with a binuclear zinc domain and the other a protein with six transmembrane domains. Two ORFs from SPBC15D4 are similar to unknown ORFs, one from Saccharomyces cerevisiae and the other from Caenorhabditis elegans. Finally, two ORFs of SPBC19C7 and six of SPBC15D4 correspond to orphan genes. The frequent occurrence of introns and the short and degenerated intron-exon boundaries consensus sequences significantly complicated ORF predictions. Two potential ORF-free regions spanning several kb were predicted, and a clustering of ORFs transcribed in the same orientation was observed.
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PMID:Sequence analysis of two cosmids from the right arm of the Schizosaccharomyces pombe chromosome II. 1066 67

The toxic effect of paraquat, mainly caused by production of superoxide radicals, results in the induction of polyamine synthesizing enzymes and their products in cells of exponentially growing E. coli cultures. The activity of ornithine decarboxylase increases approximately twofold and the activity of lysine decarboxylase increases 1.4-fold. Unlike cadaverine, putrescine and spermidine stimulate expression of the soxRS regulon genes, and this depends on the polyamine concentration and is specific for different genes of the regulon. Of six genes studied, the maximum (to 130%), minimum (about 40%), and average (60-80%) stimulation was observed for the stress induction of nfo (endonuclease IV), sodA (superoxide dismutase), and the soxS gene of the transcriptional regulator, respectively. Addition of paraquat to exponentially growing E. coli culture results in oscillations of the topological state of DNA. Putrescine prevents the drop in the extent of DNA supercoiling caused by the damaging effect of free radicals during the first minutes of stress and increases it during the restoration (the peak of the transcriptional activity of the soxRS regulon genes). These effects are due to properties of putrescine as a DNA protector and modulator of its topological state. The ability of putrescine to decrease the mutation rate under conditions of superoxide stress induced by addition of paraquat is shown by the example of rifampicin resistance.
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PMID:Mechanisms of protective functions of Escherichia coli polyamines against toxic effect of paraquat, which causes superoxide stress. 1500 Jun 86

We identified-by randomly amplified polymorphic DNA (RAPD) analysis at the population level followed by DNA differential display, cloning, and sequencing-three prophage DNA fragments (F5, F7, and F10) in Streptococcus agalactiae that displayed significant sequence similarity to the DNA of S. agalactiae and Streptococcus pyogenes. The F5 sequence aligned with a prophagic gene encoding the large subunit of a terminase, F7 aligned with a phage-associated cell wall hydrolase and a phage-associated lysin, and F10 aligned with a transcriptional regulator (ArpU family) and a phage-associated endonuclease. We first determined the prevalence of F5, F7, and F10 by PCR in a collection of 109 strains isolated in the 1980s and divided into two populations: one with a high risk of causing meningitis (HR group) and the other with a lower risk of causing meningitis (LR group). These fragments were significantly more prevalent in the HR group than in the LR group (P < 0.001). Our findings suggest that lysogeny has increased the ability of some S. agalactiae strains to invade the neonatal brain endothelium. We then determined the prevalence of F5, F7, and F10 by PCR in a collection of 40 strains recently isolated from neonatal meningitis cases for comparison with the cerebrospinal fluid (CSF) strains isolated in the 1980s. The prevalence of the three prophage DNA fragments was similar in these two populations isolated 15 years apart. We suggest that the prophage DNA fragments identified have remained stable in many CSF S. agalactiae strains, possibly due to their importance in virulence or fitness.
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PMID:Prophagic DNA fragments in Streptococcus agalactiae strains and association with neonatal meningitis. 1651 93

The gastric pathogen Helicobacter pylori induces a strong inflammatory host response, yet the bacterium maintains long-term persistence in the host. H. pylori combats oxidative stress via a battery of diverse activities, some of which are unique or newly described. In addition to using the well-studied bacterial oxidative stress resistance enzymes superoxide dismutase and catalase, H. pylori depends on a family of peroxiredoxins (alkylhydroperoxide reductase, bacterioferritin co-migratory protein and a thiol-peroxidase) that function to detoxify organic peroxides. Newly described antioxidant proteins include a soluble NADPH quinone reductase (MdaB) and an iron sequestering protein (NapA) that has dual roles - host inflammation stimulation and minimizing reactive oxygen species production within H. pylori. An H. pylori arginase attenuates host inflammation, a thioredoxin required as a reductant for many oxidative stress enzymes is also a chaperon, and some novel properties of KatA and AhpC were discovered. To repair oxidative DNA damage, H. pylori uses an endonuclease (Nth), DNA recombination pathways and a newly described type of bacterial MutS2 that specifically recognizes 8-oxoguanine. A methionine sulphoxide reductase (Msr) plays a role in reducing the overall oxidized protein content of the cell, although it specifically targets oxidized Met residues. H. pylori possess few stress regulator proteins, but the key roles of a ferric uptake regulator (Fur) and a post-transcriptional regulator CsrA in antioxidant protein expression are described. The roles of all of these antioxidant systems have been addressed by a targeted mutant analysis approach and almost all are shown to be important in host colonization. The described antioxidant systems in H. pylori are expected to be relevant to many bacterial-associated diseases, as genes for most of the enzymes carrying out the newly described roles are present in a number of pathogenic bacteria.
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PMID:The diverse antioxidant systems of Helicobacter pylori. 1687 43

Human AP-endonuclease (APE1/Ref-1), a central enzyme involved in the repair of oxidative base damage and DNA strand breaks, has a second activity as a transcriptional regulator that binds to several trans-acting factors. APE1 overexpression is often observed in tumor cells and confers resistance to various anticancer drugs; its downregulation sensitizes tumor cells to such agents. Because the involvement of APE1 in repairing the DNA damage induced by many of these drugs is unlikely, drug resistance may be linked to APE1's transcriptional regulatory function. Here, we show that APE1, preferably in the acetylated form, stably interacts with Y-box-binding protein 1 (YB-1) and enhances its binding to the Y-box element, leading to the activation of the multidrug resistance gene MDR1. The enhanced MDR1 level due to the ectopic expression of wild-type APE1 but not of its nonacetylable mutant underscores the importance of APE1's acetylation in its coactivator function. APE1 downregulation sensitizes MDR1-overexpressing tumor cells to cisplatin or doxorubicin, showing APE1's critical role in YB-1-mediated gene expression and, thus, drug resistance in tumor cells. A systematic increase in both APE1 and MDR1 expression was observed in non-small-cell lung cancer tissue samples. Thus, our study has established the novel role of the acetylation-mediated transcriptional regulatory function of APE1, making it a potential target for the drug sensitization of tumor cells.
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PMID:Regulatory role of human AP-endonuclease (APE1/Ref-1) in YB-1-mediated activation of the multidrug resistance gene MDR1. 1880 83

Bacterial restriction-modification (RM) systems are comprised of two complementary enzymatic activities that prevent the establishment of foreign DNA in a bacterial cell: DNA methylation and DNA restriction. These two activities are tightly regulated to prevent over-methylation or auto-restriction. Many Type II RM systems employ a controller (C) protein as a transcriptional regulator for the endonuclease gene (and in some cases, the methyltransferase gene also). All high-resolution structures of C-protein/DNA-protein complexes solved to date relate to C.Esp1396I, from which the interactions of specific amino acid residues with DNA bases and/or the phosphate backbone could be observed. Here we present both structural and DNA binding data for a series of mutations to the key DNA binding residues of C.Esp1396I. Our results indicate that mutations to the backbone binding residues (Y37, S52) had a lesser affect on DNA binding affinity than mutations to those residues that bind directly to the bases (T36, R46), and the contributions of each side chain to the binding energies are compared. High-resolution X-ray crystal structures of the mutant and native proteins showed that the fold of the proteins was unaffected by the mutations, but also revealed variation in the flexible loop conformations associated with DNA sequence recognition. Since the tyrosine residue Y37 contributes to DNA bending in the native complex, we have solved the structure of the Y37F mutant protein/DNA complex by X-ray crystallography to allow us to directly compare the structure of the DNA in the mutant and native complexes.
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PMID:Structural and mutagenic analysis of the RM controller protein C.Esp1396I. 2488 47

Clostridium difficile infection (CDI) is an urgent public health concern causing considerable clinical and economic burdens. CDI can be treated with antibiotics, but recurrence of the disease following successful treatment of the initial episode often occurs. Surotomycin is a rapidly bactericidal cyclic lipopeptide antibiotic that is in clinical trials for CDI treatment and that has demonstrated superiority over vancomycin in preventing CDI relapse. Surotomycin is a structural analogue of the membrane-active antibiotic daptomycin. Previously, we utilized in vitro serial passage experiments to derive C. difficile strains with reduced surotomycin susceptibilities. The parent strains used included ATCC 700057 and clinical isolates from the restriction endonuclease analysis (REA) groups BI and K. Serial passage experiments were also performed with vancomycin-resistant and vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis. The goal of this study is to identify mutations associated with reduced surotomycin susceptibility in C. difficile and enterococci. Illumina sequence data generated for the parent strains and serial passage isolates were compared. We identified nonsynonymous mutations in genes coding for cardiolipin synthase in C. difficile ATCC 700057, enoyl-(acyl carrier protein) reductase II (FabK) and cell division protein FtsH2 in C. difficile REA type BI, and a PadR family transcriptional regulator in C. difficile REA type K. Among the 4 enterococcal strain pairs, 20 mutations were identified, and those mutations overlap those associated with daptomycin resistance. These data give insight into the mechanism of action of surotomycin against C. difficile, possible mechanisms for resistance emergence during clinical use, and the potential impacts of surotomycin therapy on intestinal enterococci.
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PMID:Mutations associated with reduced surotomycin susceptibility in Clostridium difficile and Enterococcus species. 2594 Dec 17

Three qnrS2-containing isolates of Pseudoalteromonas and Shewanella were collected from the seawater samples of Qingdao in China during 2014. They displayed resistance to ampicillin, ciprofloxacin, kanamycin, nalidixic acid and sulfamethoxazole. The qnrS2 genes were identified in the chromosomes of Pseudoalteromonas strains E8 and S16, and in a 140-kb plasmid in Shewanella strain S14, respectively. In addition, two copies of qnrS2 were identified in the strain E8. Sequence analyses revealed that there was an identical DNA segment located in the downstream of qnrS2 in strain S14 and E8, coding for a TetR transcriptional regulator, two putative integrases and a hypothetical protein. However, different genetic structures were identified in the upstream sequences: the terB gene associated with tellurite resistance in the strain S14, and a putative integron with dfrA6 and aadA13 gene cassettes or the Tn7-related gene complex tnsABC in the strain E8. In Pseudoalteromonas strain S16, qnrS2 was bracketed by the endonuclease I and III genes, and the electron transport complex rsxCDGE was located in the upstream sequences. This is the first report of two copies of the qnrS2 gene existing in one bacterial chromosome, and also the first identification of qnrS2 in Shewanella.
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PMID:Genetic characterization of plasmid-mediated quinolone resistance gene qnrS2 in Pseudoalteromonas and Shewanella isolates from seawater. 2801 38


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