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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Enzymatic aminoacylation of tRNA with unnatural amino acids
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Enzymatic aminoacylation of tRNA with unnatural amino acids

机译：非天然氨基酸对tRNA的酶促氨酰化作用

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摘要

The biochemical flexibility of the cellular translation apparatus offers, in principle, a simple route to the synthesis of drug-like modified peptides and novel biopolymers. However, only ≈75 unnatural building blocks are known to be fully compatible with enzymatic tRNA acylation and subsequent ribosomal synthesis of modified peptides. Although the translation system can reject substrate analogs at several steps along the pathway to peptide synthesis, much of the specificity resides at the level of the aminoacyl-tRNA synthetase (AARS) enzymes that are responsible for charging tRNAs with amino acids. We have developed an AARS assay based on mass spectrometry that can be used to rapidly identify unnatural monomers that can be enzymatically charged onto tRNA. By using this assay, we have found 59 previously unknown AARS substrates. These include numerous side-chain analogs with useful functional properties. Remarkably, many β-amino acids, N-methyl amino acids, and α,α-disubstituted amino acids are also AARS substrates. These previously unidentified AARS substrates will be useful in studies of the specificity of subsequent steps in translation and may significantly expand the number of analogs that can be used for the ribosomal synthesis of modified peptides.
机译：原则上，细胞翻译装置的生物化学灵活性为合成药物样修饰肽和新型生物聚合物提供了一条简单的途径。然而，已知只有约75个非天然构件与酶促tRNA酰化作用和随后的核糖体合成修饰肽完全相容。尽管翻译系统可以在肽合成途径的多个步骤中拒绝底物类似物，但许多特异性存在于负责将tRNA充入氨基酸的氨酰基tRNA合成酶（AARS）酶的水平。我们已经开发了一种基于质谱的AARS分析方法，可用于快速鉴定可酶促地掺入tRNA的非天然单体。通过使用该测定法，我们发现了59种以前未知的ARS底物。这些包括许多具有有用功能特性的侧链类似物。显着地，许多β-氨基酸，N-甲基氨基酸和α，α-二取代氨基酸也是AARS底物。这些先前未鉴定的AARS底物可用于研究后续翻译步骤的特异性，并可显着扩大可用于修饰肽的核糖体合成的类似物的数量。

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