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The ribosomal A-site: decoding, drug target and disease


Matt, T; Akbergenov, R; Shcherbakov, D; Böttger, E C (2010). The ribosomal A-site: decoding, drug target and disease. Israel Journal of Chemistry, 50(1):60-70.

Abstract

Accurate decoding is central in protein synthesis. It occurs at the aa-tRNA decoding site (A-site) on the small ribosomal subunit to recognize the interactions between the aa-tRNA anticodon and the mRNA codon. Ribosomal RNA sequence polymorphism in the mitoribosomal A-site is associated with maternally transmitted deafness and hypersusceptibility to aminoglycoside-induced ototoxicity. Aminoglycosides, an important class of broad-range antimicrobial agents, bind to the A-site of the small ribosomal subunit. These compounds preferentially target the prokaryotic over the eukaryotic ribosome and affect protein synthesis by inducing codon misreading and inhibiting tRNA translocation. The therapeutic use of these compounds is compromised by significant toxicity, in particular ototoxicity. Recent evidence converges on mitochondrial mistranslation as a key element in both mitochondrial rRNA polymorphism-associated and aminoglycoside-induced deafness. It constitutes a formidable challenge to build upon this insight and to develop aminoglycosides which are more selective and consequently may not be plagued by mechanism of action related toxicity.

Abstract

Accurate decoding is central in protein synthesis. It occurs at the aa-tRNA decoding site (A-site) on the small ribosomal subunit to recognize the interactions between the aa-tRNA anticodon and the mRNA codon. Ribosomal RNA sequence polymorphism in the mitoribosomal A-site is associated with maternally transmitted deafness and hypersusceptibility to aminoglycoside-induced ototoxicity. Aminoglycosides, an important class of broad-range antimicrobial agents, bind to the A-site of the small ribosomal subunit. These compounds preferentially target the prokaryotic over the eukaryotic ribosome and affect protein synthesis by inducing codon misreading and inhibiting tRNA translocation. The therapeutic use of these compounds is compromised by significant toxicity, in particular ototoxicity. Recent evidence converges on mitochondrial mistranslation as a key element in both mitochondrial rRNA polymorphism-associated and aminoglycoside-induced deafness. It constitutes a formidable challenge to build upon this insight and to develop aminoglycosides which are more selective and consequently may not be plagued by mechanism of action related toxicity.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2010
Deposited On:24 Jan 2011 14:33
Last Modified:05 Apr 2016 14:27
Publisher:Wiley-Blackwell
ISSN:0021-2148
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/ijch.201000003

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