Publikationsdatum:
2007-06-26
Beschreibung:
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's3'-terminal adenosine. The trapping of enzyme-bound tRNA(Leu) in the editing site prevents catalytic turnover, thus inhibiting synthesis of leucyl-tRNA(Leu) and consequentially blocking protein synthesis. This result establishes the editing site as a bona fide target for aminoacyl-tRNA synthetase inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rock, Fernando L -- Mao, Weimin -- Yaremchuk, Anya -- Tukalo, Mikhail -- Crepin, 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 -- R01 DE16835/DE/NIDCR NIH HHS/ -- New York, N.Y. -- Science. 2007 Jun 22;316(5832):1759-61.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Anacor Pharmaceuticals, Incorporated, 1060 East Meadow Circle, Palo Alto, CA 94303, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17588934" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
Antifungal Agents/chemistry/*pharmacology
;
Bicyclo Compounds, Heterocyclic/chemistry/*pharmacology
;
Boron/chemistry
;
Boron Compounds/chemistry/*pharmacology
;
Drug Resistance, Fungal/genetics
;
Enzyme Inhibitors/chemistry/*pharmacology
;
Leucine-tRNA Ligase/*antagonists & inhibitors/genetics/metabolism
;
Mutation
;
Protein Synthesis Inhibitors/chemistry/pharmacology
;
*RNA Editing/drug effects
;
RNA, Transfer, Leu/*antagonists & inhibitors/metabolism
;
Saccharomyces cerevisiae/drug effects/enzymology/genetics
Print ISSN:
0036-8075
Digitale ISSN:
1095-9203
Thema:
Biologie
,
Chemie und Pharmazie
,
Informatik
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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