Inhibition of peptide chain initiation in Escherichia coli by thermorubin

Pirali, G.; Somma, Sarah Di; Lancini, Giancarlo; Sala, F.

doi:10.1016/0005-2787(74)90291-3

Cited by 16 publications

(36 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thermorubin has relatively little effect on in vitro poly(U) dependent poly-phenylalanine synthesis, a process that bypasses the normal route of translation initiation 6; 9 , whereas thermorubin effectively inhibits the in vitro translation of an endogenous mRNA containing a start codon and Shine-Dalgarno sequence 6 . While poly(U) dependent poly-phenylalanine synthesis is not inhibited by thermorubin under physiological magnesium concentrations (6mM), the drug is able to block poly-phenylalanine synthesis under elevated magnesium concentrations (12mM) 9 .…”

Section: Discussionmentioning

confidence: 99%

“…First, it does not inhibit poly(U)-directed poly(Phe) synthesis at low magnesium concentrations (5mM) or in the absence of initiation factors 6 , nor does it affect the reactivity of puromycin with the 70S ribosome complex with AcPhe-tRNA and poly(U) 9 . However, when initiation factors are also present, thermorubin inhibits both poly(U)-directed poly(Phe) synthesis and the binding of fMet-tRNA to the 70S ribosome 6 . Interestingly, it is also able to block poly(U)-directed poly(Phe) synthesis when the magnesium concentration is raised to 12 mM 9 .…”

Section: Introductionmentioning

confidence: 99%

“…Besides having antibiotic properties, it has been shown also to be a potent aldose reductase inhibitor 5 . Its mechanism of action as an antibiotic is the inhibition of protein synthesis in both Gram-positive and Gram-negative bacteria, but it is inactive against yeast, fungi and higher eukaryotes 6 . Relatively strong activity has been reported against several bacteria, including Staphylococcus aureus (MIC = 0.006 μg/mL), Streptococcus pyogenes (MIC = 0.025 μg/mL) and Streptococcus pneumonia (MIC = 0.05 μg/mL) 7 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Antibiotic Thermorubin Inhibits Protein Synthesis by Binding to Inter-Subunit Bridge B2a of the Ribosome

Bulkley

Johnson

Steitz

2012

Journal of Molecular Biology

View full text Add to dashboard Cite

Thermorubin is a small molecule inhibitor of bacterial protein synthesis, but relatively little is known about the molecular mechanism by which it blocks translation. The structure of the complex between thermorubin and the 70S ribosome from Thermus thermophilus reported here shows that thermorubin interacts with the ribosome in a way that is distinct from any other known class of ribosome inhibitor. Though it is structurally similar to tetracycline, it binds to the ribosome at an entirely different location - the interface between the small and large subunits that is formed by intersubunit bridge B2a. This region of the ribosome is known to play a role in the initiation of translation, and thus the binding site we observe is consistent with evidence suggesting that thermorubin inhibits the initiation stage of protein synthesis. The binding of thermorubin induces a rearrangement of two bases on helix 69 of the 23S rRNA and presumably this rearrangement blocks the binding of an A-site tRNA, thereby inhibiting peptide bond formation. Due in part to its low solubility in aqueous media, thermorubin has not been used clinically, although it is a potent antibacterial agent with low toxicity (Theraputic Index > 200). The interactions between thermorubin and the ribosome, as well as its adjacency to the observed binding sites of three other antibiotic classes, may enable the design of novel derivatives that share thermorubin’s mode of action but possess improved pharmacodynamic properties.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Antibiotic Thermorubin Inhibits Protein Synthesis by Binding to Inter-Subunit Bridge B2a of the Ribosome

Bulkley

Johnson

Steitz

2012

Journal of Molecular Biology

View full text Add to dashboard Cite

show abstract

“…112 The structure 80 was rmly established by single crystal X-ray analysis, 113 and numerous derivatives of thermorubin have been prepared 114 and used for structure activity studies. Thermorubin 80, produced by the bacterium Thermoactinomyces antibioticus, 111 possesses strong antibiotic properties resulting from blocking the initiation phase of bacterial protein synthesis.…”

Section: Naphthopyranones With Extended Ring Systemsmentioning

confidence: 99%

Naphthopyranones – isolation, bioactivity, biosynthesis and synthesis

Donner

2015

Nat. Prod. Rep.

View full text Add to dashboard Cite

The 1H-naphtho[2,3-c]pyran-1-one (naphthopyranone) moiety forms the structural framework of a group of secondary metabolites that have been isolated from a range of organisms including fungi, bacteria, lichen and plants. This review documents the known naturally occurring naphthopyranones - their isolation, biosynthesis and biological activity. A survey of methods reported for the synthesis of naphthopyranone natural products is presented.

show abstract

“…The mechanism of action of thermorubin was studied first by PIRALI et al 2) who showed that it is bacteriostatic and acts on the protein synthesis by inhibiting the formation of the complex f Met-tRNAribosome -mRNA before the formation of the first peptidic bond. Recent studies3,4) on the nature of the complex thermorubin-ribosome showed that the inhibition occurs only in the presence of the initiation factors.…”

Section: Thermorubinmentioning

confidence: 99%