Eukaryotic cytosolic and mitochondrial phenylalanyl-tRNA synthetases catalyze the charging of tRNA with the
            <i>meta</i>
            -tyrosine

Klipcan, Liron; Moor, Nina; Kessler, Naama; Safro, Mark

doi:10.1073/pnas.0905212106

Cited by 67 publications

(82 citation statements)

References 32 publications

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“…These tRNA aminoacylation levels are comparable to those previously reported in other bacterial systems using similar methods, as is the observed increase in deacylated tRNA upon starvation (20)(21)(22). When the strains were grown under amino acid stress conditions in the presence of physiologically relevant levels of the natural noncognate PheRS substrate m-Tyr (3,23,24), levels of aa-tRNA Phe were 23% higher in the editing-deficient strain than in the wild type. These results also revealed that the cellular ratio of aminoacylated to deacylated tRNA increases significantly in the absence of PheRS editing, particularly under amino acid stress conditions ( Fig.…”

Section: Ablation Of Phers Editing Alters the Cellular Ratio Of Aminosupporting

confidence: 72%

Translation quality control is critical for bacterial responses to amino acid stress

Bullwinkle

Ibba

2016

Proc. Natl. Acad. Sci. U.S.A.

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Gene expression relies on quality control for accurate transmission of genetic information. One mechanism that prevents amino acid misincorporation errors during translation is editing of misacylated tRNAs by aminoacyl-tRNA synthetases. In the absence of editing, growth is limited upon exposure to excess noncognate amino acid substrates and other stresses, but whether these physiological effects result solely from mistranslation remains unclear. To explore if translation quality control influences cellular processes other than protein synthesis, an Escherichia coli strain defective in Tyr-tRNA Phe editing was used. In the absence of editing, cellular levels of aminoacylated tRNA Phe were elevated during amino acid stress, whereas in the wild-type strain these levels declined under the same growth conditions. In the editing-defective strain, increased levels of aminoacylated tRNA Phe led to continued synthesis of the PheL leader peptide and attenuation of pheA transcription under amino acid stress. Consequently, in the absence of editing, activation of the phenylalanine biosynthetic operon becomes less responsive to phenylalanine limitation. In addition to raising aminoacylated tRNA levels, the absence of editing lowered the amount of deacylated tRNA Phe in the cell. This reduction in deacylated tRNA was accompanied by decreased synthesis of the second messenger guanosine tetraphosphate and limited induction of stringent response-dependent gene expression in editing-defective cells during amino acid stress. These data show that a single qualitycontrol mechanism, the editing of misacylated aminoacyl-tRNAs, provides a critical checkpoint both for maintaining the accuracy of translation and for determining the sensitivity of transcriptional responses to amino acid stress.translation | quality control | stress | stringent response

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Section: Ablation Of Phers Editing Alters the Cellular Ratio Of Aminosupporting

confidence: 72%

Translation quality control is critical for bacterial responses to amino acid stress

Bullwinkle

Ibba

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Modifi ed amino acids could originate from protein-bound amino acids [ 11 ] or may be incorporated into proteins during their synthesis resulting in a polypeptide without direct oxidative damage of the protein itself [ 15 -17 ] . In line with these fi ndings, free m -Tyr was shown to be incorporated into cellular proteins, possibly via protein synthesis, which then can exert cytotoxic actions [ 17 ] . Furthermore, o -Tyr and m -Tyr levels were found to be signifi cantly higher in the aortic tissue of hyperglycemic cynomolgus monkeys and that of rats with aortic banding-induced hypertension [ 11 , 18 ] .…”

Section: Elevated Vascular Level Of Ortho -Tyrosine Contributes To Thmentioning

confidence: 54%

Untitled

2014

Horm Metab Res

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Elevated Vascular Level of ortho -Tyrosine Contributes to the Impairment of Insulin-Induced Arterial Relaxationothers -can modify phenylalanine residues to form para -, meta -and ortho -tyrosines ( p -, m -and o -Tyr) [ 11 -14 ] . Modifi ed amino acids could originate from protein-bound amino acids [ 11 ] or may be incorporated into proteins during their synthesis resulting in a polypeptide without direct oxidative damage of the protein itself [ 15 -17 ] . In line with these fi ndings, free m -Tyr was shown to be incorporated into cellular proteins, possibly via protein synthesis, which then can exert cytotoxic actions [ 17 ] . Furthermore, o -Tyr and m -Tyr levels were found to be signifi cantly higher in the aortic tissue of hyperglycemic cynomolgus monkeys and that of rats with aortic banding-induced hypertension [ 11 , 18 ] . Misincorporation of o -Tyr and mTyr into structural or catalytic proteins could also contribute to impaired cellular function, such as erythropoietin-hyporesponsiveness in erythroblasts and inhibition of tumor growth in vivo, possibly by interfering with MAP/ERK signaling [ 19 , 20 ] . Of note, cytotoxicity of m -Tyr can be blocked in vitro with phenylalanine [ 15 ] , suggesting that L -phenylalanine tRNA synthase recognizes m -Tyr to aff ect incorporation of ROS-damaged amino acids into cellular proteins [ 15 ] . However,

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“…The water molecule W23 generates an extensive HB network with the amide group of Valβ324 (2.8 Å) and the main chain carbonyl oxygen of Alaβ262 (17,23,24). The aromatic rings of the ligands are rotated relative to each other, and slightly shifted (Fig.…”

Section: Resultsmentioning

confidence: 99%

Universal pathway for posttransfer editing reactions: Insights from the crystal structure of Tt PheRS with puromycin

Tworowski

Klipcan

Peretz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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At the amino acid binding and recognition step, phenylalanyltRNA synthetase (PheRS) faces the challenge of discrimination between cognate phenylalanine and closely similar noncognate tyrosine. Resampling of Tyr-tRNA Phe to PheRS increasing the number of correctly charged tRNA molecules has recently been revealed. Thus, the very same editing site of PheRS promotes hydrolysis of misacylated tRNA species, associated both with cis-and trans-editing pathways. Here we report the crystal structure of Thermus thermophilus PheRS (TtPheRS) at 2.6 Å resolution, in complex with phenylalanine and antibiotic puromycin mimicking the A76 of tRNA acylated with tyrosine. Starting from the complex structure and using a hybrid quantum mechanics/molecular mechanics approach, we investigate the pathways of editing reaction catalyzed by TtPheRS. We show that both 2′ and 3′ isomeric esters undergo mutual transformation via the cyclic intermediate orthoester, and the editing site can readily accommodate a model of Tyr-tRNA Phe where deacylation occurs from either the 2′-or 3′-OH. The suggested pathway of the hydrolytic reaction at the editing site of PheRS is of sufficient generality to warrant comparison with other class I and class II aminoacyl-tRNA synthetases.biosynthesis | aminoacyl-tRNA synthetases | tRNA | puromycin | editing

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Eukaryotic cytosolic and mitochondrial phenylalanyl-tRNA synthetases catalyze the charging of tRNA with the meta -tyrosine

Cited by 67 publications

References 32 publications

Translation quality control is critical for bacterial responses to amino acid stress

Translation quality control is critical for bacterial responses to amino acid stress

Untitled

Universal pathway for posttransfer editing reactions: Insights from the crystal structure of Tt PheRS with puromycin

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