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Nat Commun. 2017 Dec 22;8(1):2281. doi: 10.1038/s41467-017-02201-z.

Double mimicry evades tRNA synthetase editing by toxic vegetable-sourced non-proteinogenic amino acid.

Author information

1
The Scripps Laboratories for tRNA Synthetase Research and the Department of Molecular Medicine, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 92037, La Jolla, CA, USA.
2
Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, China.
3
Department of Chemistry, New York University, Abu Dhabi, PO Box 129188, United Arab Emirates.
4
Department of Chemistry and Biochemistry, Center for RNA Biology, The Ohio State University, Columbus, OH, 43220, USA.
5
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA.
6
The Scripps Laboratories for tRNA Synthetase Research and Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
7
The Scripps Laboratories for tRNA Synthetase Research and the Department of Molecular Medicine, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 92037, La Jolla, CA, USA. schimmel@scripps.edu.
8
The Scripps Laboratories for tRNA Synthetase Research and Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA. schimmel@scripps.edu.

Abstract

Hundreds of non-proteinogenic (np) amino acids (AA) are found in plants and can in principle enter human protein synthesis through foods. While aminoacyl-tRNA synthetase (AARS) editing potentially provides a mechanism to reject np AAs, some have pathological associations. Co-crystal structures show that vegetable-sourced azetidine-2-carboxylic acid (Aze), a dual mimic of proline and alanine, is activated by both human prolyl- and alanyl-tRNA synthetases. However, it inserts into proteins as proline, with toxic consequences in vivo. Thus, dual mimicry increases odds for mistranslation through evasion of one but not both tRNA synthetase editing systems.

PMID:
29273753
PMCID:
PMC5741666
DOI:
10.1038/s41467-017-02201-z
[Indexed for MEDLINE]
Free PMC Article

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