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Science 22 June 2007:
Vol. 316. no. 5832, pp. 1759 - 1761
DOI: 10.1126/science.1142189
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Reports

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

Fernando L. Rock,1* Weimin Mao,1* Anya Yaremchuk,2,3 Mikhail Tukalo,2,3 Thibaut Crépin,2 Huchen Zhou,1,4 Yong-Kang Zhang,1 Vincent Hernandez,1 Tsutomu Akama,1 Stephen J. Baker,1 Jacob J. Plattner,1 Lucy Shapiro,5 Susan A. Martinis,6 Stephen J. Benkovic,7 Stephen Cusack,2 M. R. K. Alley1{dagger}

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.

1 Anacor Pharmaceuticals, Incorporated, 1060 East Meadow Circle, Palo Alto, CA 94303, USA.
2 European Molecular Biology Laboratory, Grenoble Outstation 6 rue Jules Horowitz, BP181, 38042 Grenoble Cedex 9, France.
3 Institute of Molecular Biology and Genetics, National Academy of Science (NAS) of Ukraine, 252627 Kiev, 3143, Ukraine.
4 School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
5 Department of Developmental Biology, Beckman Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
6 Department of Biochemistry, University of Illinois, Urbana, IL 61801–3732, USA.
7 Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: dalley{at}anacor.com

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Characterization of Two Seryl-tRNA Synthetases in Albomycin-Producing Streptomyces sp. Strain ATCC 700974.
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Defects in Transient tRNA Translocation Bypass tRNA Synthetase Quality Control Mechanisms.
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J. Biol. Chem. 284, 11478-11484
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Evolutionary Basis for the Coupled-domain Motions in Thermus thermophilus Leucyl-tRNA Synthetase.
K. M. E. Weimer, B. L. Shane, M. Brunetto, S. Bhattacharyya, and S. Hati (2009)
J. Biol. Chem. 284, 10088-10099
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From the Cover: CP1-dependent partitioning of pretransfer and posttransfer editing in leucyl-tRNA synthetase.
M. T. Boniecki, M. T. Vu, A. K. Betha, and S. A. Martinis (2008)
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Unique Residues Crucial for Optimal Editing in Yeast Cytoplasmic Leucyl-tRNA Synthetase Are Revealed by Using a Novel Knockout Yeast Strain.
P. Yao, X.-L. Zhou, R. He, M.-Q. Xue, Y.-G. Zheng, Y.-F. Wang, and E.-D. Wang (2008)
J. Biol. Chem. 283, 22591-22600
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Aminoacyl tRNA synthetases and their connections to disease.
S. G. Park, P. Schimmel, and S. Kim (2008)
PNAS 105, 11043-11049
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