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)

Poly(A)-poly(U) synthesis in the absence of template DNA is a unique reaction catalyzed by the RNA polymerase [EC 2.7:7.6] holoenzyme II of Escherichia coli. As one approach to investigating the physiological role of the enzyme, the molecular mechanism of poly(A)-poly(U) synthesis was studied. Streptolydigin, an inhibitor of the elongation of RNA chains, was shown to inhibit poly(A)-poly(U) synthesis, and the inhibition was released by a streptolydigin-resistant mutation on the beta subunit. These observations indicate that the active site for the reaction might be located on the beta subunit. Another antibiotic, rifampicin, which is known to be a specific inhibitor of the initiation of DNA-dependent RNA synthesis, effectively inhibited both initiation and elongation steps in poly(A)-poly(U) synthesis. This suggests that the enzyme conformation during the chain elongation reaction might be different in this case from that in DNA-dependent RNA synthesis. Analysis of the products formed during the initiation reaction indicated that the rate-determining reaction in poly(A)-poly(U) synthesis was the formation of primers of short chain length, and that holoenzyme I was unable to form the first phosphodiester bond in this reaction. Functional properties of holoenzyme II are discussed in connection with these observations.
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PMID:Mechanism of polyadenylate-polyuridylate synthesis by RNA polymerase holoenzyme II of Escherichia coli. 78 Mar 49

During the course of kinetic studies on the synthesis of RNA polymerase subunits in Escherichia coli K12, strain Km7 (CP372), certain anomalies were found that seemed to be associated with the system of reversible inhibition of RNA and protein synthesis by rifampicin. To find a possible explanation for these anomalies, effects of rifampicin on RNA chain elongation and on residual synthesis of polymerase subunits were investigated with several strains including Km7. Examination of mRNA synthesis for the tryptophan operon suggested that RNA chain growth as well as RNA chain initiation is inhibited at high drug concentration (500 mug/ml), wheras RNA chain initiation is inhibited specifically at low concentration (20 mug/ml). Analysis of effect of rifampicin concentration on total RNA synthesis gave results that are also consistent with this conclusion. These results emphasize the need for selecting a proper drug concentration whenever rifampicin or other related antibiotic is used as a specific inhibitor of transcription initiation. When rifampicin was added to a culture of these strains absolute rates of synthesis of all subunits of RNA polymerase increased for several minutes and then decreased. The extent of this transient stimulation varied depending on the strain, drug concentration and other conditions, but was most striking for the beta and sigma subunits with strain Km7 at high drug concentration (500 mug/ml). With a rifampicin-sensitive wild-type strain tested, the maximum stimulation was found at about 50 mug/ml of the drug, with a particularly marked effect for sigma subunit. Streptolydigin, on the other hand, inhibited the synthesis of core subunits much faster than the bulk of protein, but inhibited synthesis of sigma subunit only after a lag. Hence a specific effect of rifampicin but not the inactivation of beta subunit per se appears to be involved in transient stimulation of polymerase synthesis observed. Implications of these findings on the control of RNA polymerase synthesis are discussed.
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PMID:Effects of rifampicin on synthesis and functional activity of DNA-dependent RNA polymerase in Escherichia coli. 78 14

Streptolydigin (1) and tirandamycin A (2) are typical members of the naturally occurring class of 3-dienoyl tetramic acids. These compounds, which possess potent antibacterial activity particularly against anaerobes, have been shown to inhibit bacterial RNA polymerase. In contrast, tenuazonic acid (5), which lacks a complex dioxabicyclononane moiety and diene chromophore present in 1 and 2, exhibits essentially no antimicrobial activity and has no effect on bacterial RNA polymerase, suggesting that one or both of these structural features may be critical for antibacterial activity. In this paper, we report on a novel series of synthetic dienoyl tetramic acids that lack a complex dioxabicyclononane unit. Several of these compounds, particularly 8T-W, exhibit potent antimicrobial activity against Gram-positive and Gram-negative anaerobes as well as staphylococci. We will discuss the structure-activity relationship for this series of compounds which, in contrast to their natural counterparts, do not inhibit significantly RNA polymerase. We will also discuss preliminary results on the biochemical and microbiological properties of this series of compounds, several of which moderately inhibit supercoiling by DNA gyrase isolated from E. coli H560, although this enzyme has not been established as their target in whole cells. Compound 8W, which is not cross-resistant with DNA gyrase subunit A or B inhibitors or tirandamycin, has also been demonstrated to be rapidly bactericidal.
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PMID:Aromatic dienoyl tetramic acids. Novel antibacterial agents with activity against anaerobes and staphylococci. 270 74

We investigated the effects of six drugs on an RNA polymerase III in vitro transcription system. Adriamycin, daunorubicin, heparin, rifamycin AF/013, streptolydigin, and streptovaricin all inhibit RNA synthesis from a tRNA gene or the adenovirus 2 (AD2) VA1 RNA gene. The completed RNA polymerase III transcription complex is formed by the sequential, ordered addition of protein factors. Although both genes reportedly use the same transcription fractions for in vitro RNA synthesis, some of these drugs interfere differentially with these genes. A drug concentration that inhibits transcription from one gene may not inhibit transcription from the other gene. Adriamycin seems to block transcription if added between the binding of the individual transcription fractions. Daunorubicin appears to inhibit VA transcription only if added prior to both transcription fractions, but inhibits tRNA synthesis before and during transcription factor binding. Heparin blocks both genes between factors binding to DNA and after factor binding. Rifamycin blocks VA synthesis more effectively than tRNA synthesis. Streptolydigin blocks transcription of both genes. Streptovaricin probably blocks transcription by inhibiting early transcription complex assembly events. These drugs appear useful as appropriate probes to investigate transcription complexes since several discriminate between complexes formed on different genes during the assembly process.
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PMID:Effects of antibiotics on RNA polymerase III transcription. 290 35

Streptolydigin and rifamycin inhibit the catalytic function of ribonucleic acid (RNA) polymerase. Streptolydigin can inhibit polymerization after the reaction has started, whereas rifamycin is effective only if it is preincubated with RNA polymerase prior to the addition of substrates. The same relationships are observed with respect to these two antibiotics if the nucleoside triphosphate-pyrophosphate exchange reaction is used in the assay system. The inhibitory effect of streptolydigin is reversible by further addition of RNA polymerase but not by addition of deoxyribonucleic acid to the assay system.
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PMID:Mode of action of streptolydigin. 430 12

Streptolydigin interferes with oxidative phosphorylation in rat liver mitochondria. The agent acts primarily as an uncoupler of respiration-associated phosphorylation but also impairs respiration to various degrees depending on the substrate. Streptolydigin partially inhibits electron flow at a point past the cytochrome b and prior to the cytochrome c reduction site. Streptolydigin also inhibits the function of the enzyme ribonucleic acid polymerase in whole bacterial cells and cell-free systems. The streptolydigin concentrations that cause effective inhibition of ribonucleic acid polymerase in cell-free systems are approximately 10 times less than those required to inhibit oxidative phosphorylation in mitochondria.
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PMID:Streptolydigin, an inhibitor of oxidative phosphorylation in rat liver mitochondria. 431 69

In Escherichia coli cells carrying the srnB+ gene of the F plasmid, rifampin, added at 42 degrees C, induces the extensive rapid degradation of the usually stable cellular RNA (Ohnishi, Y., (1975) Science 187, 257-258; Ohnishi, Y., Iguma, H., Ono, T., Nagaishi, H. and Clark, A.J. (1977) J. Bacteriol. 132, 784-789). We have studied further the necessity for rifampin and for high temperature in this degradation. Streptolydigin, another inhibitor of RNA polymerase, did not induce the RNA degradation. Moreover, the stable RNA of some strains in which RNA polymerase is temperature-sensitive did not degrade at the restrictive temperature in the absence of rifampin. These data suggest that rifampin has an essential role in the RNA degradation, possibly by the modification of RNA polymerase function. A protein (Mr 12 000) newly synthesized at 42 degrees C in the presence of rifampin appeared to be the product of the srnB+ gene that promoted the RNA degradation. In a mutant deficient in RNAase I, the extent of the RNA degradation induced by rifampin was greatly reduced. RNAase activity of cell-free crude extract from the RNA-degraded cells was temperature-dependent. The RNAase was purified as RNAase I in DEAE-cellulose column chromatography and Sephadex G-100 gel filtration. Both in vivo and with purified RNAase I, a shift of the incubation mixture from 42 to 30 degrees C, or the addition of Mg2+ ions, stopped the RNA degradation. Thus, an effect on RNA polymerase seems to initiate the expression of the srnB+ gene and the activation of RNAase I, which is then responsible for the RNA degradation of E. coli cells carrying the srnB+ gene.
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PMID:The roles of RNA polymerase and RNAase I in stable RNA degradation in Escherichia coli carrying the srnB+ gene. 618 65

Streptolydigin (stl), a bacteriostatic inhibitor of transcription elongation, interacts with the beta subunit of Escherichia coli RNA polymerase. We have defined the target for stl resistance using chemical mutagenesis and mutagenic polymerase chain reaction. Mutations resulting in stl resistance are confined to a small cluster of contiguous amino acids, amino acids 543 to 546. These stlr mutants differ from one another in their levels of resistance to stl in vivo and in vitro. We have analyzed two of the mutants, A543V and F545S, for their effects on elongation and termination in vivo and in vitro. Neither affected termination at rho-dependent or rho-independent terminators. These mutants were indistinguishable from wild type in a T7 in vitro elongation assay. F545S, however, did exhibit slower elongation kinetics in a lambda tR1 pausing assay. We conclude that mutations in the stlr region can influence transcription elongation, but that these amino acids are not directly involved in catalysis.
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PMID:Four contiguous amino acids define the target for streptolydigin resistance in the beta subunit of Escherichia coli RNA polymerase. 824 69

The antimalarial activity of rifampicin, a specific inhibitor of bacterial ribonucleic acid (RNA) polymerase, was confirmed with Plasmodium falciparum in vitro and with P. chabaudi in vivo. The viability of ring forms of P. falciparum, measured by [3H]hypoxanthine and [14C]isoleucine uptake, was significantly reduced within 5 h of exposure to 2.5 microM rifampicin, the 50% inhibitory concentration. Streptolydigin and tagetitoxin, other specific inhibitors of bacterial RNA polymerase, were much less effective as antimalarials. A rifampicin-tolerant sub-line of P. falciparum was selected in vitro. When released from drug pressure, the tolerant line showed appreciably greater rates of incorporation of precursors and growth than the parent line, but over a period of months these characteristics gradually reverted. Rifampicin was effective against a chloroquine-resistant line of P. falciparum and the rifampicin-tolerant line had increased chloroquine sensitivity. Treatment of patent parasitaemias of P. chabaudi in mice with more than 100 mg/kg rifampicin twice daily significantly reduced the parasitaemia within 24 h and parasites were barely detectable on blood films by the fourth day. Recrudescence occurred on release of drug pressure.
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PMID:Antimalarial activity of rifampicin in vitro and in rodent models. 833 32

Bacterial RNA polymerase is a common target for many antibiotics. In two recent papers in Cell and Molecular Cell, and describe a structural basis for inhibition of bacterial RNA polymerase by the antibiotic streptolydigin. Streptolydigin may prevent distortion of a "bridge" alpha helix postulated to occur during the nucleotide addition cycle of RNA polymerase or may block a small movement of the bridge helix that helps load nucleotide triphosphates into the active site.
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PMID:Inhibition of RNA polymerase by streptolydigin: no cycling allowed. 1612 22


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