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工程吡咯赖氨酸系统用于遗传密码扩展和重编程。

Engineering Pyrrolysine Systems for Genetic Code Expansion and Reprogramming.

机构信息

Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, England, United Kingdom.

Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany.

出版信息

Chem Rev. 2024 Oct 9;124(19):11008-11062. doi: 10.1021/acs.chemrev.4c00243. Epub 2024 Sep 5.

DOI:10.1021/acs.chemrev.4c00243
PMID:39235427
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11467909/
Abstract

Over the past 16 years, genetic code expansion and reprogramming in living organisms has been transformed by advances that leverage the unique properties of pyrrolysyl-tRNA synthetase (PylRS)/tRNA pairs. Here we summarize the discovery of the pyrrolysine system and describe the unique properties of PylRS/tRNA pairs that provide a foundation for their transformational role in genetic code expansion and reprogramming. We describe the development of genetic code expansion, from to all domains of life, using PylRS/tRNA pairs, and the development of systems that biosynthesize and incorporate ncAAs using pyl systems. We review applications that have been uniquely enabled by the development of PylRS/tRNA pairs for incorporating new noncanonical amino acids (ncAAs), and strategies for engineering PylRS/tRNA pairs to add noncanonical monomers, beyond α--amino acids, to the genetic code of living organisms. We review rapid progress in the discovery and scalable generation of mutually orthogonal PylRS/tRNA pairs that can be directed to incorporate diverse ncAAs in response to diverse codons, and we review strategies for incorporating multiple distinct ncAAs into proteins using mutually orthogonal PylRS/tRNA pairs. Finally, we review recent advances in the encoded cellular synthesis of noncanonical polymers and macrocycles and discuss future developments for PylRS/tRNA pairs.

摘要

在过去的 16 年中，通过利用吡咯赖氨酰-tRNA 合成酶（PylRS）/tRNA 对的独特性质的进展，活生物体中的遗传密码扩展和重编程发生了转变。在这里，我们总结了吡咯赖氨酸系统的发现，并描述了 PylRS/tRNA 对的独特性质，这些性质为它们在遗传密码扩展和重编程中的变革作用提供了基础。我们描述了遗传密码扩展的发展，从到所有生命领域，使用 PylRS/tRNA 对，以及使用 pyl 系统生物合成和掺入 ncAA 的系统的发展。我们回顾了由于 PylRS/tRNA 对用于掺入新的非典型氨基酸（ncAA）的开发而得以独特实现的应用，并回顾了用于工程化 PylRS/tRNA 对的策略，以将非典型单体（超出 α--氨基酸）添加到活生物体的遗传密码中。我们回顾了在发现和可扩展生成互斥的 PylRS/tRNA 对方面的快速进展，这些对可以响应不同的密码子来指导掺入不同的 ncAA，我们还回顾了使用互斥的 PylRS/tRNA 对将多个不同的 ncAA 掺入蛋白质中的策略。最后，我们回顾了最近在非典型聚合物和大环的细胞内合成方面的进展，并讨论了 PylRS/tRNA 对的未来发展。

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