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Accuracy of initiator tRNA selection in initiation of eubacterial protein synthesis
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-93568OAI: oai:DiVA.org:uu-93568DiVA: diva2:167089
Available from: 2005-10-05 Created: 2005-10-05 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Macrolide Antibiotics in Bacterial Protein Synthesis
Open this publication in new window or tab >>Macrolide Antibiotics in Bacterial Protein Synthesis
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Makrolidantibiotika i Bakteriell Proteinsyntes
Abstract [en]

Macrolides are a large group of clinically relevant antibiotics that inhibit protein synthesis by binding to the large ribosomal subunit in the peptide exit tunnel, close to the peptidyl transferase center (PTC). We have shown that the peptide length of the resulting peptidyl-tRNA drop-off products is proportional to the distance between the PTC and the respective macrolide in the tunnel. This indicates that macrolides act by sterically blocking the nascent peptide exit path.

A substantial amount of read-through into full-length product was observed for some macrolides and depends on the relation between the dissociation rate constants for peptidyl-tRNA and the macrolide, respectively. The dissociation rate constant for josamycin is 60 times lower than the dissociation rate constant for erythromycin, which explains why no read-through is seen for josamycin in contrast to erythromycin.

Macrolides do not compete with binding of ternary complexes, hence they are non-competitive inhibitors. However, the text-book description is not valid for macrolide antibiotics, and we show that this is due to the equilibrium assumption generally used to describe non-competitive inhibitors. Our results suggest that a more thorough mechanistic investigation is required to classify inhibitors than what has been proposed previously.

Further, we have examined the phenomenon of peptide mediated resistance to macrolides. Our results show that expression of a resistance peptide increases the dissociation rate constant for erythromycin.

In addition, we have examined the accuracy of protein synthesis on three different levels: (i) How do the three initiation factors accomplish fast and accurate initiation of protein synthesis, (ii) how does proof-reading work on the isoleucyl-tRNA synthetase, and (iii) what is the accuracy in the tRNA selection and how is it accomplished? Our data propose a change of the view on all these mechanisms.

In conclusion this thesis presents new results on protein synthesis, macrolide antibiotics and macrolide resistance.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 75 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 99
Biochemistry, protein synthesis, macrolides, resistance, initiation of translation, non-competitive inhibitors, kinetics, translation accuracy, proof-reading, Biokemi
National Category
Biochemistry and Molecular Biology
urn:nbn:se:uu:diva-6009 (URN)91-554-6361-4 (ISBN)
Public defence
2005-10-28, B41, BMC, Husargatan 3, Uppsala, 10:15
Available from: 2005-10-05 Created: 2005-10-05Bibliographically approved

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