Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan.
Chem Commun (Camb). 2020 Apr 21;56(31):4265-4272. doi: 10.1039/d0cc01291b. Epub 2020 Apr 8.
Ribosomal peptide synthesis begins almost exclusively with the amino acid methionine, across all domains of life. The ubiquity of methionine initiation raises the question; to what extent could polypeptide synthesis be realized with other amino acids, proteinogenic or otherwise? This highlight describes the breadth of building blocks now known to be accepted by the ribosome initiation machinery, from subtle methionine analogues to large exotic non-proteinogenic structures. We outline the key methodological developments that have enabled these discoveries, including the exploitation of methionyl-tRNA synthetase promiscuity, synthetase and tRNA engineering, and the utilization of artificial tRNA-loading ribozymes, flexizymes. Using these methods, the number and diversity of validated initiation building blocks is rapidly expanding permitting the use of the ribosome to synthesize ever more artificial polymers in search of new functional molecules.
核糖体肽合成几乎完全从生命所有领域的氨基酸甲硫氨酸开始。甲硫氨酸起始的普遍性提出了一个问题：在多大程度上可以用其他氨基酸，包括蛋白质或非蛋白质的氨基酸来实现多肽合成？这篇重点介绍了现在已知的被核糖体起始机制接受的构建块的广泛范围，从微妙的甲硫氨酸类似物到大型外来非蛋白质结构。我们概述了实现这些发现的关键方法学进展，包括对甲硫氨酰-tRNA 合成酶的简并性、合成酶和 tRNA 工程以及人工 tRNA 加载核酶、flexizymes 的利用。使用这些方法，经过验证的起始构建块的数量和多样性正在迅速扩大，这使得核糖体能够合成越来越多的人工聚合物，以寻找新的功能分子。
