Physical Sciences and Mathematics Commons^™

Substrate-Assisted And Enzymatic Pretransfer Editing Of Nonstandard Amino Acids By Methionyl-Trna Synthetase, Grant B. Fortowsky, Daniel J. Simard, Mohamed M. Aboelnga, James W. Gauld

Chemistry and Biochemistry Publications

Aminoacyl-tRNA synthetases (aaRSs) are cen- tral to a number of physiological processes, including protein biosynthesis. In particular, they activate and then transfer their corresponding amino acid to the cognate tRNA. This is achieved with a generally remarkably high fidelity by editing against incorrect standard and nonstandard amino acids. Using docking, molecular dynamics (MD), and hybrid quantum mechanical/molecular mechanics methods, we have inves- tigated mechanisms by which methionyl-tRNA synthetase (MetRS) may edit against the highly toxic, noncognate, amino acids homocysteine (Hcy) and its oxygen analogue, homo- serine (Hse). Substrate-assisted editing of Hcy-AMP in which its own phosphate acts as the mechanistic …