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  Polyamines affect diversely the antibiotic potency: insight gained from kinetic studies of the blasticidin S and spiramycin interactions with functional ribosomes

Petropoulos, A. D., Xaplanteri, M. A., Dinos, G. P., Wilson, D. N., & Kalpaxis, D. L. (2004). Polyamines affect diversely the antibiotic potency: insight gained from kinetic studies of the blasticidin S and spiramycin interactions with functional ribosomes. Journal of Biological Chemistry, 279(25), 26518-26525. doi:10.1074/jbc.M313634200.

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Genre: Journal Article
Alternative Title : J Biol Chem

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Petropoulos, Alexandros D., Author
Xaplanteri, Maria A., Author
Dinos, George P., Author
Wilson, Daniel N.1, Author           
Kalpaxis, Dimitrios L., Author
Affiliations:
1Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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 Abstract: The effects of spermine on peptidyltransferase inhibition by an aminohexosylcytosine nucleoside, blasticidin S, and by a macrolide, spiramycin, were investigated in a model system derived from Escherichia coli, in which a peptide bond is formed between puromycin and AcPhe-tRNA bound at the P-site of poly(U)-programmed ribosomes. Kinetics revealed that blasticidin S, after a transient phase of interference with the A-site, is slowly accommodated near to the P-site so that peptide bond is still formed but with a lower catalytic rate constant. At high concentrations of blasticidin S (>10 x Ki), a second drug molecule binds to a weaker binding site on ribosomes, and this may account for the onset of a subsequent mixed-noncompetitive inhibition phase. Spermine enhances the blasticidin S inhibitory effect by facilitating the drug accommodation to both sites. On the other hand, spiramycin (A) was found competing with puromycin for the A-site of AcPhe-tRNA·poly(U)·70 S ribosomal complex (C) via a two-step mechanism, according to which the fast formation of the encounter complex CA is followed by a slow isomerization to a tighter complex, termed C*A. In contrast to that observed with blasticidin S, spermine reduced spiramycin potency by decreasing the formation and stability of complex C*A. Polyamine effects on drug binding were more pronounced when a mixture of spermine and spermidine was used, instead of spermine alone. Our kinetic results correlate well with cross-linking and crystallographic data and suggest that polyamines bound at the vicinity of the antibiotic binding pockets modulate diversely the interaction of these drugs with ribosomes.

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Language(s): eng - English
 Dates: 2004-04-09
 Publication Status: Issued
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 Identifiers: eDoc: 225177
DOI: 10.1074/jbc.M313634200
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Title: Journal of Biological Chemistry
  Alternative Title : J Biol Chem
Source Genre: Journal
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Pages: - Volume / Issue: 279 (25) Sequence Number: - Start / End Page: 26518 - 26525 Identifier: ISSN: 0021-9258