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)

CI-920 is a structurally novel, phosphate-containing polyene lactone antitumor agent isolated from a previously undescribed subspecies of Streptomyces pulveraceus cultured from a Brazilian soil sample. CI-920 was active against murine leukemia P388, and highly active and curative against L1210 leukemia in vivo. CI-920 was less active or inactive against the murine solid tumors tested. Daily administration for five to nine days was more effective against L1210 leukemia than a single dose or doses every four days. Given three times daily for five days, CI-920 was more toxic and less active. CI-920 had similar activity intravenously and intraperitoneally. Oral administration was inactive and nontoxic. Subcutaneous treatment was less effective and more toxic. Structure-activity relationship studies showed that the phosphate group was essential for antitumor activity in vivo and in vitro. Hydrolyzing the lactone ring also resulted in loss of antitumor activity, as did acetylation of the 6-hydroxyl group. Hydroxylation at the 5-position of the lactone ring resulted in partial retention of antitumor activity, but in greater toxicity to mice. Removal of the 13-hydroxyl group resulted in retention of high antitumor activity with approximately three-fold improvement in dose-potency. CI-920 is not cytotoxic to prokaryotic cells. CI-920 causes inhibition of biosynthesis of RNA and DNA in intact L1210 cells. Protein synthesis is also inhibited at higher drug concentrations. The inhibition of nucleic acid synthesis is not an antimetabolite effect, since pools of ribonucleoside triphosphates and deoxyribonucleoside triphosphates are not depleted. CI-920 does not cause DNA strand breakage, as measured by alkaline elution, and is not mutagenic in the Ames test at concentrations up to 200 micrograms/ml. CI-920 does not cause direct inhibition of RNA polymerase or DNA polymerase in permeabilized cells. It is possible that CI-920 must be metabolically activated within the target cells; alternatively it may interact with a component of chromatin other than DNA or the polymerases. Flow cytometry studies showed that growth-inhibitory levels of CI-920 caused accumulation of cells in the G2+M region. Higher drug concentrations caused an S-phase block. CI-920 is an inhibitor and irreversible inactivator of reduced folate membrane transport, and appears to enter cells by this receptor. L1210 cells selected for resistance to CI-920 are cross-resistant to methotrexate, and deficient in reduced folate transport.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The biochemical pharmacology of CI-920, a structurally novel antibiotic with antileukemic activity. 384 Sep 49

Highly purified RNA polymerase B (II) from calf thymus catalyses the synthesis of dinucleoside tetraphosphates from ribonucleoside triphosphates in the absence of an oligonucleotide primer or additional protein factors. The reaction requires a DNA template and bivalent cations such as Mn2+ or Mg2+. It is strongly inhibited by heparin and high concentrations of alpha-amanitin but not by rifampicin. On a given template various dinucleoside tetraphosphates of different sequence are formed although the yield depends on the nature of the template.
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PMID:Synthesis of dinucleoside tetraphosphates by RNA polymerase B (II) from calf thymus. 386 46

Dissociation of RNA and DNA from Escherichia coli RNA polymerase in transcription complexes prepared with enzyme molecules located within and near a rho-dependent transcription termination region on bacteriophage T7 D111 DNA has been studied using a membrane filter-binding assay. Rho protein with ATP present mediated rapid (half-time approximately 27 s) simultaneous dissociation of about 50% of both RNA and DNA. RNA molecules were preferentially released from enzyme molecules located within the termination region. Rapid release of RNA and DNA depended on a nucleoside triphosphate but did not depend on sigma factor. Pretreatment of complexes with ribonuclease prevented dissociation of DNA. Nearly simultaneous dissociation of both RNA and DNA was also detected after a lag of 3 min when the isolated transcription complexes were incubated with all four ribonucleoside triphosphates in the absence of rho factor. In this case, release presumably occurred at the rho-independent termination site that is 5990 nucleotides downstream from the A1 promoter. Thus, the dissociation of DNA from RNA polymerase at rho-dependent and rho-independent transcription termination sites is coupled with or occurs spontaneously soon after the release of transcripts at both sites.
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PMID:Transcription termination factor rho mediates simultaneous release of RNA transcripts and DNA template from complexes with Escherichia coli RNA polymerase. 388 62

Highly purified RNA polymerase B (II) from wheat germ catalyses the formation of dinucleoside tetraphosphates from ribonucleoside triphosphates in the absence of an oligonucleotide primer or additional protein factors. The reaction requires bivalent cations such as Mn2+ or Mg2+ and proceeds linearly for several hours. It is strongly inhibited by 1 microgram/ml alpha-amanitin or 2 micrograms/ml heparin. The reaction strictly depends on the addition of a specific linear or circular DNA template, such as the plasmid pSmaF or a DNA fragment containing the gene for nopaline dehydrogenase. Bacteriophage T7 D111 DNA has almost no template activity. The start sites for dinucleotide synthesis on the template are limited. With the DNA fragment containing the gene for nopaline dehydrogenase only pppApA and pppApU are synthesised substantially whereas pppUpU is formed only in trace amounts. No significant dinucleotide synthesis is observed with other ribonucleoside triphosphates either singly or in a combination of two. The various regions of the DNA fragment differ distinctly in template activity.
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PMID:Primer-independent abortive initiation by wheat-germ RNA polymerase B (II). 388 25

Monoclonal antibodies directed against antigenic determinants on the beta and beta' subunits of the Escherichia coli RNA polymerase were characterized by using d(A-T)n-directed transcription assays. Antibodies were prepared by using purified subunits as immunogens, and seven anti-beta and five anti-beta' monoclonal antibodies were generated. Inhibitory anti-beta monoclonal antibodies were found to affect RNA polymerase during synthesis of r(A-U)n, abortive initiation of pApU and UpApU, and elongation by preformed ternary complexes. A comparative enzyme study of r(A-U)n synthesis showed the core polymerase to be more sensitive to inhibition by the anti-beta monoclonal antibody than was the holoenzyme. In contrast, the inhibition effected by the anti-beta' monoclonal antibody was found to be 90% or greater for each of the d(A-T)n-directed assays used. The different inhibitory patterns exhibited by the anti-beta and anti-beta' monoclonal antibodies suggest that the beta and beta' subunits engage in different roles during transcription. Kinetic analysis of the abortive initiation reaction in the presence and absence of the inhibitory antibodies resulted in distinctive but complex modes of inhibition. Inhibition by the anti-beta monoclonal antibody 210E8 was noncompetitive with regard to UTP and competitive for UpA incorporation; at increased UpA concentration, the inhibition was completely reversed. Inhibition of the abortive synthesis of UpApU by the anti-beta' monoclonal antibody 311G2 was noncompetitive with regard to both UpA and UTP incorporation. When the preformed ternary elongation complex was used, inhibition by the anti-beta monoclonal antibody was mixed with regard to the ribonucleoside triphosphate substrates.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of effects of anti-beta and anti-beta' monoclonal antibodies on the activity of the RNA polymerase from Escherichia coli. 389 8

The specific transcription of a cloned Drosophila melanogaster tRNAVal4 gene and a tRNASer7 gene by extracts from a homologous embryonic cell line showed lag periods of about 30 min before maximum rates were reached. This lag appeared to represent the time to form an active transcription complex. Thus, when extracts were incubated with template DNA for 30 min at 22 degrees C and stored in the cold, the subsequent transcription rate was linear with time and without a lag. After ultracentrifugation of a preincubated reaction mixture on a sucrose step gradient consisting of 20, 30, 40, and 60% shelves, about 40% of the transcription activity in the extract was found in the 40% shelf. This fraction formed almost exclusively RNA I, the unprocessed tRNA gene transcript, and transcription required only addition of ribonucleoside triphosphates. The rate of formation of RNA by the 40% sucrose fraction was linear against time, with no lag, and linear with the quantity of fraction. The yield of activity isolated on the gradient was directly proportional to the quantity of cloned gene in the preincubation mixture. At a limiting concentration of the gene in the preincubation mixture, the turnover number of the isolated complex was approximately 50 transcripts/gene/h. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of fractions containing the complex still showed many bands, although the complex activity was greatly purified compared to the extract. From the sedimentation behavior of the isolated active transcription complex and from its stability and transcriptional properties, we conclude that the 40% sucrose fraction contains an active transcription complex containing a cloned tRNA gene, RNA polymerase III, and the accessory protein factors required for transcription.
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PMID:Partial purification of stable transcription complexes with cloned tRNA genes of Drosophila melanogaster. 392 73

Globin messenger RNA, isolated from human peripheral blood reticulocytes, was transcribed into complementary DNA by use of the RNA-dependent DNA polymerase of avian myeloblastosis virus. The complementary DNA was then transcribed into (32)P-labeled complementary RNA by E. coli RNA polymerase in the presence of alpha-(32)P-labeled ribonucleoside triphosphates. The fingerprint pattern obtained from ribonuclease T1 digests of human globin complementary RNA was specific and reproducible. Different patterns were obtained from digests of duck, mouse, and rabbit globin complementary RNA. The fingerprint patterns obtained from digests of purified natural human 10S globin messenger RNA, labeled in vitro with (125)I or with [gamma-(32)P]ATP and polynucleotide kinase, were similar to that of the complementary RNA but contained some additional oligonucleotides. Sufficient nucleotide sequence information has been obtained from about 50% of the intermediate sized oligonucleotides (8-14 base residues long), to make possible examination of correspondence between these nucleotide sequences and globin amino-acid sequences. Approximately 70% of these oligonucleotide sequences can be matched to unique amino-acid sequences in the alpha- or beta-globin chains. The other 30% do not match known amino-acid sequences and presumably correspond to untranslated portions of the mRNA; some of these sequences, however, can be matched to amino-acid sequence in the abnormally long segment of the alpha chain of hemoglobin Constant Spring, which is thought to result from a chain-termination mutation.
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PMID:Nucleotide sequences of human globin messenger RNA. 413 9

The presence of adenosine triphosphate, guanosine triphosphate, cytosine triphosphate, or uridine triphosphate reduced the rate of inactivation of vaccinia when heated at 50 C. The virus-associated nucleoside triphosphate phosphohydrolases (adenosine triphosphatase, guanosine triphosphatase, cytosine triphosphatase, and uridine triphosphatase) and ribonucleic acid polymerase were also protected from heat inactivation by these compounds. These obervations are best explained by postulating that ribonucleoside triphosphates bind to enzymes in the virus particle, and that these enzyme-substrate complexes are more resistant to thermal denaturation than are the enzymes without their substrates. The kinetics of heat inactivation of the vaccinia ATP phosphohydrolase activity is biphasic, suggesting that there are two proteins in the vaccinia particle that have this enzyme activity but they have different kinetics of heat inactivation. Any of the vaccinia-associated nucleotide phosphohydrolase activities are protected from heat inactivation by the presence of any one of the respective nucleoside triphosphates. This observation suggests that there is a single enzymatic site in vaccinia that is able to react with any ribonucleoside triphosphate.
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PMID:Protection of vaccinia from heat inactivation by nucleotide triphosphates. 431 59

In vitro reaction conditions have been determined for the maximal synthesis of product ribonucleic acid by the influenza (WSN) virion ribonucleic acid polymerase. The reaction requires the presence of all four triphosphates, Mg(2+) and Mn(2+) ions, monovalent cations, nonionic detergent, and ribonucleoside triphosphates at concentrations above certain threshold values. The optimum pH for the reaction is around 8.0 to 8.2 and the kinetics of product synthesis are linear through at least 6 hr when incubated at 31 to 33 C.
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PMID:Transcription of the influenza ribonucleic acid genome by a virion polymerase. I. Optimal conditions for in vitro activity of the ribonucleic acid-dependent ribonucleic acid polymerase. 432 17

Synthesis of Rous sarcoma virus RNA was examined in vitro with a new assay for radioactive virus-specific RNA. Nuclei from infected and uninfected cells were incubated with ribonucleoside [alpha-(32)P]triphosphates, Mn(++), Mg(++) and (NH(4))(2)SO(4). Incorporation into total and viral RNA proceeded with similar kinetics for up to 25 min at 37 degrees . About 0.5% of the RNA synthesized by the infected system was scored as virus-specific, compared to 0.03% of the RNA from the uninfected system and 0.005% of the RNA synthesized by monkey kidney cell nuclei. Preincubation with DNase or actinomycin D completely suppressed total and virus-specific RNA synthesis. alpha-Amanitin, a specific inhibitor of eukaryotic RNA polymerase II, completely inhibited virus-specific RNA synthesis, while reducing total RNA synthesis by only 50%. We conclude that tumor virus-specific RNA is synthesized on a DNA template, most probably by the host's RNA polymerase II.
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PMID:In vitro synthesis of Rous sarcoma virus-specific RNA is catalyzed by a DNA-dependent RNA polymerase. 436 1


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