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

• Published in: Nature communications 2017-12, Vol.8 (1), p.2281-8, Article 2281
• Main Authors: Song, Youngzee, Zhou, Huihao, Vo, My-Nuong, Shi, Yi, Nawaz, Mir Hussain, Vargas-Rodriguez, Oscar, Diedrich, Jolene K., Yates, John R., Kishi, Shuji, Musier-Forsyth, Karin, Schimmel, Paul
• Format: Article
• Language: English
• Subjects: 631/337/574/1793; 631/45/173; 631/45/612; 631/535/1266; Alanine; Alanine-tRNA Ligase - metabolism; Amino Acids; Amino Acyl-tRNA Synthetases - metabolism; Aminoacyl-tRNA ligase; Azetidinecarboxylic Acid - metabolism; Biocompatibility; Carboxylic acids; Cell Death; Crystal structure; Editing; Food; HeLa Cells; Humanities and Social Sciences; Humans; Inserts; Mimicry; Molecular Mimicry; multidisciplinary; Plants (botany); Proline; Protein Biosynthesis; Protein synthesis; Proteins; RNA Editing; RNA, Transfer - metabolism; Science; Science (multidisciplinary); tRNA; Vegetables
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02201-z

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. Non-proteinogenic (np) amino acids in the food chain present challenges for the human translation machinery. Here the authors show that, while AlaRS and ProRS activate toxic np azetidine-2-carboxylic acid (Aze) present in sugar beets and lilies, only the AlaRS editing system rejects Aze.