Antifungal Agent Inhibits an Aminoacyl-tRNA Synthetase by Trapping tRNA in the Editing Site

Aminoacyl-transfer RNA (tRNA) synthetases, which catalyze the attachment of the correct amino acid to its corresponding tRNA during translation of the genetic code, are proven antimicrobial drug targets. We show that the broad-spectrum antifungal 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2007-06, Vol.316 (5832), p.1759-1761
Main Authors: Rock, Fernando L, Mao, Weimin, Yaremchuk, Anya, Tukalo, Mikhail, Crépin, Thibaut, Zhou, Huchen, Zhang, Yong-Kang, Hernandez, Vincent, Akama, Tsutomu, Baker, Stephen J, Plattner, Jacob J, Shapiro, Lucy, Martinis, Susan A, Benkovic, Stephen J, Cusack, Stephen, Alley, M.R.K
Format: Article
Language:English
Subjects:
Active sites
Adducts
Amino acids
Analytical, structural and metabolic biochemistry
Antifungal Agents - chemistry
Antifungal Agents - pharmacology
Antifungals
Atoms
Biochemistry
Biological and medical sciences
Boron
Boron - chemistry
Boron Compounds - chemistry
Boron Compounds - pharmacology
Bridged Bicyclo Compounds, Heterocyclic - chemistry
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Catalysis
Drug Resistance, Fungal - genetics
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzymes
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Genetic code
Genetic mutation
Genetics
Leucine-tRNA Ligase - antagonists & inhibitors
Leucine-tRNA Ligase - genetics
Leucine-tRNA Ligase - metabolism
Ligases
Mutation
Protein synthesis
Protein Synthesis Inhibitors - chemistry
Protein Synthesis Inhibitors - pharmacology
Ribonucleic acid
RNA
RNA Editing - drug effects
RNA, Transfer, Leu - antagonists & inhibitors
RNA, Transfer, Leu - metabolism
Saccharomyces cerevisiae - drug effects
Saccharomyces cerevisiae - enzymology
Saccharomyces cerevisiae - genetics
Transfer RNA
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Summary:Aminoacyl-transfer RNA (tRNA) synthetases, which catalyze the attachment of the correct amino acid to its corresponding tRNA during translation of the genetic code, are proven antimicrobial drug targets. We show that the broad-spectrum antifungal 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), in development for the treatment of onychomycosis, inhibits yeast cytoplasmic leucyl-tRNA synthetase by formation of a stable tRNALeu-AN2690 adduct in the editing site of the enzyme. Adduct formation is mediated through the boron atom of AN2690 and the 2'- and 3'-oxygen atoms of tRNA's3'-terminal adenosine. The trapping of enzyme-bound tRNALeu in the editing site prevents catalytic turnover, thus inhibiting synthesis of leucyl-tRNALeu and consequentially blocking protein synthesis. This result establishes the editing site as a bona fide target for aminoacyl-tRNA synthetase inhibitors.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1142189