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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epolactaene (compound 1), a neuritogenic compound found in human neuroblastoma cells, was found to show anti-inflammatory activity in vivo in this study. DNA polymerases and DNA topoisomerase II (topo II) were some of the major molecular targets of compound 1. Since the agent seems to be a potential pharmaceutical medicine, we synthesized derivatives chemically and obtained seven compounds, 1 to 7 to screen clinically more efficient epolactaene derivatives. A comparison of its structural derivatives revealed that the long alkyl side chain seemed to have an important role in the inhibitory effect. Notably, C18-alkyl chain conjugated epolactaene (compound 5) was the strongest inhibitor of DNA polymerase alpha, beta, lambda (pol alpha, beta, lambda) and topo II, with IC50 values of 13, 135, 4.4 and 5 microM, respectively, and 500 microg of compound 5 caused a marked reduction in TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation (inhibitory effect, 65.0%). Compound 5 did not influence the activities of plant or prokaryotic DNA polymerases, or of other DNA metabolic enzymes such as telomerase, RNA polymerase and deoxyribonuclease I. Based on these results, the relationship among the three-dimensional structure of epolactaene derivatives and the inhibition of polymerases and topo II, and anti-inflammation is discussed.
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PMID:Structural analysis of epolactaene derivatives as DNA polymerase inhibitors and anti-inflammatory compounds. 1580 99

Isosteviol (ent-16-ketobeyeran-19-oic acid) is a hydrolysis product of stevioside, which is a natural sweetener produced in the leaves of Stevia rebaudiana (Bertoni) Bertoni. In this report, we prepared isosteviol and related compounds from stevioside by microbial transformation and chemical conversion and assayed the inhibitory activities toward DNA metabolic enzymes and human cancer cell growth. Among twelve compounds obtained, only isosteviol (compound 3) potently inhibited both mammalian DNA polymerases (pols) and human DNA topoisomerase II (topo II), and IC50 value for pol alpha was 64.0 microM. This compound had no inhibitory effect on higher plant (cauliflower) pols, prokaryotic pols, human topo I, and DNA metabolic enzymes such as human telomerase, T7 RNA polymerase, and bovine deoxyribonuclease I. With pol alpha, isosteviol acted non-competitively with the DNA template-primer and nucleotide substrate. Isosteviol prevented the growth of human cancer cells, with LD50 values of 84-167 microM, and 500 microg of the compound caused a marked reduction in TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation (inhibitory effect, 53.0%). The relationship between the structure of stevioside-based compounds and these activities were discussed.
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PMID:Structural analysis of isosteviol and related compounds as DNA polymerase and DNA topoisomerase inhibitors. 1593 96

Alteration in the target sites of antibiotics is a common mechanism of resistance. Examples of clinical strains showing resistance can be found for every class of antibiotic, regardless of the mechanism of action. Target site changes often result from spontaneous mutation of a bacterial gene on the chromosome and selection in the presence of the antibiotic. Examples include mutations in RNA polymerase and DNA gyrase, resulting in resistance to the rifamycins and quinolones, respectively. In other cases, acquisition of resistance may involve transfer of resistance genes from other organisms by some form of genetic exchange (conjugation, transduction, or transformation). Examples of these mechanisms include acquisition of the mecA genes encoding methicillin resistance in Staphylococcus aureus and the various van genes in enterococci encoding resistance to glycopeptides.
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PMID:Bacterial resistance to antibiotics: modified target sites. 1596 98

All known chlamydiae are either proven human or animal pathogens or possess such potential. Due to increasing reports of chlamydiae diversity in the environment, it is important to develop reliable means for identifying and characterizing Chlamydiales species. The identification of environmental chlamydiae at present relies on their branching pattern in 16S rRNA trees, as well as 16S/23S consensus motifs which display variability. At present, no reliable molecular signatures are known which are unique to all Chlamydiales species. Besides the rRNAs, sequence information for different Chlamydiales is not available for any other gene sequence. In this report, a number of molecular signatures are described that consist of conserved inserts and deletions (indels), in widely distributed proteins [RNA polymerase alpha subunit (RpoA), elongation factor (EF)-Tu, EF-P, DNA gyrase B subunit (GyrB) and lysyl-tRNA synthetase (LysRS)], that are distinctive characteristics of all available chlamydiae homologues (from Chlamydiaeceae species and Parachlamydiae sp. UWE25) and not found in any other bacteria. Using PCR primers for highly conserved regions in these proteins, the corresponding fragments of these genes from Simkania negevensis, Waddlia chondrophila, and in a number of cases for Neochlamydia hartmanellae, covering all families within the phylum Chlamydiae, have been cloned and sequenced. The shared presence of the identified signatures in these species provides strong evidence that these molecular signatures are distinctive characteristics of the entire order Chlamydiales and can be used to reliably determine the presence of chlamydiae or chlamydia-related organisms in environmental samples. The sequence information for these protein fragments was also used to determine the interrelationships among chlamydiae species. In a phylogenetic tree based on a combined dataset of sequences from RpoA, EF-Tu, EF-P and GyrB, the environmental chlamydiae (i.e. Simkania, Waddlia and Parachlamydia) and the traditional Chlamydiaceae (i.e. Chlamydophila and Chlamydia) formed two distinct clades. Similar relationships were also observed in individual protein phylogenies, as well as in a 16S rRNA tree for the same species. These results provide evidence that the divergence between the traditional Chlamydiaceae species and the other chlamydiae families occurred very early in the evolution of this group of bacteria.
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PMID:Conserved indels in essential proteins that are distinctive characteristics of Chlamydiales and provide novel means for their identification. 1607 43

Polyphasic analysis of four new Vibrio isolates originating from the haemolymph of diseased cultured oysters is described. The new isolates were closely related to Vibrio splendidus, having 98 % 16S rRNA gene sequence similarity. Phylogenetic analysis based on DNA gyrase subunit B (gyrB), RNA polymerase sigma70 factor (rpoD), replication origin-binding protein (rctB) and transmembrane regulatory protein (toxR) genes, fluorescent amplified fragment length polymorphism and DNA-DNA hybridization experiments clearly showed that the new isolates form a tight genomic group that is different from the currently known Vibrio species. It is proposed that these new isolates should be accommodated in a novel species, Vibrio gigantis sp. nov. Phenotypic features that differentiate V. gigantis from other known Vibrio species include arginine dihydrolase, gelatinase and beta-galactosidase activities, NO(2) production, growth at 35 degrees C, and utilization of sucrose, melibiose, amygdalin, glycerol, galactose, starch and glycogen. The type strain is LGP 13T (=LMG 22741T=CIP 108656T).
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PMID:Vibrio gigantis sp. nov., isolated from the haemolymph of cultured oysters (Crassostrea gigas). 1628 Apr 78

We report here the existence of a complex between RNA polymerase (RNAP) and DNA gyrase in Mycobacterium smegmatis. The interaction between the two enzymes was detected during our attempts to purify DNA gyrase from M. smegmatis. RNAP subunits co-eluted along with DNA gyrase in two different affinity chromatography column procedures employed to purify the latter enzyme. A complex containing both the enzymes was isolated through gel filtration chromatography and sucrose density gradient centrifugation of the cell free extracts. The complex exhibited both DNA supercoiling and transcription activities. Reduction in the transcription activity of the complex in the presence of DNA gyrase inhibitor indicates a role for DNA gyrase in stimulating transcription.
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PMID:A complex of DNA gyrase and RNA polymerase fosters transcription in Mycobacterium smegmatis. 1657 74

The DNA topoisomerase II (topo2) inhibitor mitoxantrone (MXT) and topo1 inhibitor topotecan (TP) are antitumor drugs widely used to treat different types of cancer. Their mechanism of action is thought to stabilize otherwise transient ("cleavable") complexes between topo2 or topo1 and DNA; the collisions of the DNA replication fork during replication, or RNA polymerase during transcription, with these complexes convert them into double-strand DNA breaks (DSBs), potentially lethal lesions that may trigger apoptosis. In the present study we observed that treatment of human lung carcinoma A549 or promyelocytic leukemic HL-60 cells with MXT led to ATM activation and phosphorylation of histone H2AX on Ser-139, the reporters of induction of DSBs, in all phases of the cell-cycle. Only S-phase cells, however, underwent apoptosis after treatment with MXT, which implied that DSBs in the cells replicating DNA were more effective in triggering apoptosis than DSBs in G(1) or G(2)M phase cells. Unlike MXT, the treatment with TP induced ATM activation and H2AX phosphorylation almost exclusively in S-phase cells and only S phase cells underwent apoptosis. The induction of both ATM activation and H2AX phosphorylation by MXT was prevented to a large extent by N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS). The protective effect of NAC was observed for cells in all phases of the cell cycle. NAC offered no protection at all against TP. The induction of DSBs by MXT, thus, appears to be predominantly mediated through ROS, while DSBs generated during treatment with TP most likely are a consequence of collisions of replication forks with the "cleavable" complexes.
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PMID:Activation of ATM and histone H2AX phosphorylation induced by mitoxantrone but not by topotecan is prevented by the antioxidant N-acetyl-L-cysteine. 1696 72

Coenzyme Q (CoQ) is an isoprenoid quinine that functions as an electron carrier in the mitochondrial respiratory chain in eukaryotes. CoQ having shorter isoprenoid chains, especially CoQ1 and CoQ2, selectively inhibited the in vitro activity of eukaryotic DNA polymerase (pol) gamma, which is a mitochondrial pol. These compounds did not influence the activities of nuclear DNA replicative pols such as alpha, delta and epsilon, and nuclear DNA repair-related pols such as beta, eta, iota, kappa and lambda. CoQ also inhibited DNA topoisomerase II (topo II) activity, although the enzymatic characteristics, including modes of action, amino acid sequences and three-dimensional structures, were markedly different from those of pol gamma. These compounds did not inhibit the activities of procaryotic pols such as Escherichia coli pol I, and other DNA metabolic enzymes such as human immunodeficiency virus reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. CoQ1, which has the shortest isoprenoid chains, had the strongest inhibitory effect on pol gamma and topo II activities among CoQ1-CoQ10, with 50% inhibitory concentration (IC50) values of 12.2 and 15.5 microM, respectively. CoQ1 could prevent the growth of human promyelocytic leukemia cells, HL-60, and the 50% lethal dose (LD50) value was 14.0 microM. The cells were halted at S phase and G1 phase in the cell cycle, and suppressed mitochondrial proliferation. From these results, the relationship between the inhibition of pol gamma/topo II and cancer cell growth by CoQ is discussed.
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PMID:Inhibitory effect of coenzyme Q on eukaryotic DNA polymerase gamma and DNA topoisomerase II activities on the growth of a human cancer cell line. 1686 5

Iridoviruses (IVs) are classified into five genera: Iridovirus and Chloriridovirus, whose members infect invertebrates, and Ranavirus, Lymphocystivirus, and Megalocytivirus, whose members infect vertebrates. Until now, Chloriridovirus was the only IV genus for which a representative and complete genomic sequence was not available. Here, we report the genome sequence and comparative analysis of a field isolate of Invertebrate iridescent virus type 3 (IIV-3), also known as mosquito iridescent virus, currently the sole member of the genus Chloriridovirus. Approximately 20% of the 190-kbp IIV-3 genome was repetitive DNA, with DNA repeats localized in 15 apparently noncoding regions. Of the 126 predicted IIV-3 genes, 27 had homologues in all currently sequenced IVs, suggesting a genetic core for the family Iridoviridae. Fifty-two IIV-3 genes, including those encoding DNA topoisomerase II, NAD-dependent DNA ligase, SF1 helicase, IAP, and BRO protein, are present in IIV-6 (Chilo iridescent virus, prototype species of the genus Iridovirus) but not in vertebrate IVs, likely reflecting distinct evolutionary histories for vertebrate and invertebrate IVs and potentially indicative of genes that function in aspects of virus-invertebrate host interactions. Thirty-three IIV-3 genes lack homologues in other IVs. Most of these encode proteins of unknown function but also encode IIV3-053L, a protein with similarity to DNA-dependent RNA polymerase subunit 7; IIV3-044L, a putative serine/threonine protein kinase; and IIV3-080R, a protein with similarity to poxvirus MutT-like proteins. The absence of genes present in other IVs, including IIV-6; the lack of obvious colinearity with any sequenced IV; the low levels of amino acid identity of predicted proteins to IV homologues; and phylogenetic analyses of conserved proteins indicate that IIV-3 is distantly related to other IV genera.
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PMID:Genome of invertebrate iridescent virus type 3 (mosquito iridescent virus). 1691 94

We developed a multi-locus quantitative PCR approach to minimize problems of precision, sensitivity and primer specificity for quantifying a targeted microbial group in nature. This approach also avoids a systematic error in population quantitation when 16S rRNA genes are used because of copy number heterogeneity. Specific primers were designed to assess the abundance of psychrotrophic and mesophilic Exiguobacterium spp. that excluded the thermophilic members of the genus. The chosen primers targeted genes for DNA gyrase B (gyrB), the beta subunit of the RNA polymerase gene (rpoB) and a hypothetical gene so far found only in this group. The results demonstrate that the multiple primer approach provides a more reliable estimate of population density; that the targeted Exiguobacterium group is found at a median density of 50,000 gene copies per mug of total community DNA in 27 of 29 permafrost soils but was found in only one of the four temperate and tropical soils tested.
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PMID:Multi-locus real-time PCR for quantitation of bacteria in the environment reveals Exiguobacterium to be prevalent in permafrost. 1715 79


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