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J. Biol. Chem., Vol. 279, Issue 17, 17707-17714, April 23, 2004

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Divergence in Noncognate Amino Acid Recognition between Class I and Class II Lysyl-tRNA Synthetases^*

Jeffrey Levengood, Sandro F. Ataide, Hervé Roy, and Michael Ibba

From the Department of Microbiology, Ohio State University, Columbus, Ohio 43210-1292

Lysine insertion during coded protein synthesis requires lysyl-tRNA^Lys, which is synthesized by lysyl-tRNA synthetase (LysRS). Two unrelated forms of LysRS are known: LysRS2, which is found in eukaryotes, most bacteria, and a few archaea, and LysRS1, which is found in most archaea and a few bacteria. To compare amino acid recognition between the two forms of LysRS, the effects of L-lysine analogues on aminoacylation were investigated. Both enzymes showed stereospecificity toward the L-enantiomer of lysine and discriminated against noncognate amino acids with different R-groups (arginine, ornithine). Lysine analogues containing substitutions at other positions were generally most effective as inhibitors of LysRS2. For example, the K_i values for aminoacylation of S-(2-aminoethyl)-L-cysteine and L-lysinamide were over 180-fold lower with LysRS2 than with LysRS1. Of the other analogues tested, only -aminobutyric acid showed a significantly higher K_i for LysRS2 than LysRS1. These data indicate that the lysine-binding site is more open in LysRS2 than in LysRS1, in agreement with previous structural studies. The physiological significance of divergent amino acid recognition was reflected by the in vivo resistance to growth inhibition imparted by LysRS1 against S-(2-aminoethyl)-L-cysteine and LysRS2 against -aminobutyric acid. These differences in resistance to naturally occurring noncognate amino acids suggest the distribution of LysRS1 and LysRS2 contributes to quality control during protein synthesis. In addition, the specific inhibition of LysRS1 indicates it is a potential drug target.

Received for publication, December 15, 2003 , and in revised form, January 26, 2004.

^* This work was supported by Grant 0265004B from the American Heart Association and Grant 65183 from NIGMS, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Microbiology, Ohio State University, 484 West 12th Ave., Columbus, OH 43210-1292. Tel.: 614-292-2120; Fax: 614-292-8120; E-mail: ibba.1{at}osu.edu.

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