Chapter category: RNA
Inhibitors of Aminoacyl-tRNA Synthetases as Antibiotics and Tools for Structural and Mechanistic Studies
Translation Mechanisms
Edited by: Jacques Lapointe and Léa Brakier-GingrasISBN: 0-306-47839-0
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Chapter authors:
Robert Chênevert, Stéphane Bernier and Jacques Lap
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Aminoacyl-tRNA synthetases (aaRS) catalyze the esterification of a particular tRNA with its corresponding amino acid. In the first reaction step, the appropriate amino acid is recognized by the enzyme and reacts with ATP to form an enzyme-bound mixed anhydride; in the second step, this activated amino acid is esterified with one of the two hydroxyl groups of the tRNA. AaRSs are classified into two main groups of ten enzymes each, on the basis of common structural and functional features.
The design of aaRS inhibitors has three main objectives: 1° to facilitate the crystallization and Xray structure determination of these enzymes, 2° to gain mechanistic informations about them, and 3° to discover new antibiotics. Several natural products including pseudomonic acid, SB-203207, SB-219383, indolmycin, capsaicin and ascamycin are selective inhibitors of aaRSs. Pseudomonic acid is a potent inhibitor of bacterial IleRS and is the sole aaRS inhibitor currently marketed as an antibacterial agent. Synthetic inhibitors are usually stable analogues of the mixed anhydride intermediate. The stability is achieved by replacement of the labile anhydride function by non-hydrolyzable bioisosteres. Several aminoalkyl adenylates (replacement of the anhydride by a phosphate ester) and aminoacylsulfamoyl adenosines (replacement of the phosphate by a sulfamoyl group) have been synthesized and shown to be potent inhibitors of aaRSs.
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