An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site

Fernando L. Rock, Weimin Mao, Anya Yaremchuk, Mikhail Tukalo, Thibaut Crépin, Huchen Zhou, Yong Kang Zhang, Vincent Hernandez, Tsutomu Akama, Stephen J. Baker, Jacob J. Plattner, Lucy Shapiro, Susan A. Martinis, Stephen Benkovic, Stephen Cusack, M. R.K. Alley

Research output: Contribution to journalArticle

369 Citations (Scopus)

Abstract

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 tRNA Leu-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's 3′-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.

Original languageEnglish (US)
Pages (from-to)1759-1761
Number of pages3
JournalScience
Volume316
Issue number5832
DOIs
StatePublished - Jun 22 2007

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RNA Editing
Amino Acyl-tRNA Synthetases
Antifungal Agents
RNA, Transfer, Leu
Transfer RNA
Genetic Code
Onychomycosis
Boron
Enzymes
Adenosine
Catalytic Domain
Yeasts
Oxygen
Amino Acids
tavaborole
Pharmaceutical Preparations
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Rock, F. L., Mao, W., Yaremchuk, A., Tukalo, M., Crépin, T., Zhou, H., ... Alley, M. R. K. (2007). An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science, 316(5832), 1759-1761. https://doi.org/10.1126/science.1142189
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 ; Cusack, Stephen ; Alley, M. R.K. / An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. In: Science. 2007 ; Vol. 316, No. 5832. pp. 1759-1761.
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abstract = "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 tRNA Leu-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's 3′-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.",
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Rock, FL, Mao, W, Yaremchuk, A, Tukalo, M, Crépin, T, Zhou, H, Zhang, YK, Hernandez, V, Akama, T, Baker, SJ, Plattner, JJ, Shapiro, L, Martinis, SA, Benkovic, S, Cusack, S & Alley, MRK 2007, 'An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site', Science, vol. 316, no. 5832, pp. 1759-1761. https://doi.org/10.1126/science.1142189

An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. / 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; Cusack, Stephen; Alley, M. R.K.

In: Science, Vol. 316, No. 5832, 22.06.2007, p. 1759-1761.

Research output: Contribution to journalArticle

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AU - Rock, Fernando L.

AU - Mao, Weimin

AU - Yaremchuk, Anya

AU - Tukalo, Mikhail

AU - Crépin, Thibaut

AU - Zhou, Huchen

AU - Zhang, Yong Kang

AU - Hernandez, Vincent

AU - Akama, Tsutomu

AU - Baker, Stephen J.

AU - Plattner, Jacob J.

AU - Shapiro, Lucy

AU - Martinis, Susan A.

AU - Benkovic, Stephen

AU - Cusack, Stephen

AU - Alley, M. R.K.

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N2 - 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 tRNA Leu-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's 3′-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.

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Rock FL, Mao W, Yaremchuk A, Tukalo M, Crépin T, Zhou H et al. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science. 2007 Jun 22;316(5832):1759-1761. https://doi.org/10.1126/science.1142189