Fidelity escape by the unnatural amino acid β-hydroxynorvaline: an efficient substrate for Escherichia coli threonyl-tRNA synthetase with toxic effects on growth

Anand MinajigiChristopher S Francklyn


In all living systems, the fidelity of translation is maintained in part by the editing mechanisms of aminoacyl-tRNA synthetases (ARSs). Some nonproteogenic amino acids, including β-hydroxynorvaline (HNV) are nevertheless efficiently aminoacylated and become incorporated into proteins. To investigate the basis of HNV's ability to function in protein synthesis, the utilization of HNV by Escherichia coli threonyl-tRNA synthetase (ThrRS) was investigated through both in vitro functional experiments and bacterial growth studies. The measured specificity constant (k(cat)/K(M)) for HNV was found to be only 20-30-fold less than that of cognate threonine. The rate of aminoacyl transfer (10.4 s(-1)) was 10-fold higher than the multiple turnover k(cat) value (1 s(-1)), indicating that, as for cognate threonine, amino acid activation is likely to be the rate-limiting step. Like noncognate serine, HNV enhances the ATPase function of the synthetic site, at a rate not increased by nonaminoacylatable (3'-dA76) tRNA. ThrRS also failed to exhibit posttransfer editing activity against HNV. In growing bacteria, the addition of HNV dramatically suppressed growth rates, which indicates either negative phenotypic consequences associated with its inc...Continue Reading


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Related Concepts

Metabolic Process, Cellular
Activation of Amino Acids
Alkalescens-Dispar Group
Adenosine Triphosphatases
Amino Acids, I.V. solution additive
MT-TA gene
Triplet Codon-amino Acid Adaptor Activity
Transfer RNA
Protein Biosynthesis
Threonine-tRNA Ligase

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