Cracking the Code: Reprogramming the Genetic Script in Prokaryotes and Eukaryotes to Harness the Power of Noncanonical Amino Acids,Chemical Reviews

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Cracking the Code: Reprogramming the Genetic Script in Prokaryotes and Eukaryotes to Harness the Power of Noncanonical Amino Acids
Chemical Reviews ( IF 51.4 ) Pub Date : 2024-08-09 , DOI: 10.1021/acs.chemrev.3c00878
Cosimo Jann _{1,

2} , Sabrina Giofré _{1,

2} , Rajanya Bhattacharjee _{1,

3} , Edward A Lemke _{1,

4}

Affiliation

Over 500 natural and synthetic amino acids have been genetically encoded in the last two decades. Incorporating these noncanonical amino acids into proteins enables many powerful applications, ranging from basic research to biotechnology, materials science, and medicine. However, major challenges remain to unleash the full potential of genetic code expansion across disciplines. Here, we provide an overview of diverse genetic code expansion methodologies and systems and their final applications in prokaryotes and eukaryotes, represented by Escherichia coli and mammalian cells as the main workhorse model systems. We highlight the power of how new technologies can be first established in simple and then transferred to more complex systems. For example, whole-genome engineering provides an excellent platform in bacteria for enabling transcript-specific genetic code expansion without off-targets in the transcriptome. In contrast, the complexity of a eukaryotic cell poses challenges that require entirely new approaches, such as striving toward establishing novel base pairs or generating orthogonally translating organelles within living cells. We connect the milestones in expanding the genetic code of living cells for encoding novel chemical functionalities to the most recent scientific discoveries, from optimizing the physicochemical properties of noncanonical amino acids to the technological advancements for their in vivo incorporation. This journey offers a glimpse into the promising developments in the years to come.

中文翻译：

破解密码：重编程原核生物和真核生物的遗传脚本以利用非经典氨基酸的力量

在过去的二十年中，已经对 500 多种天然和合成氨基酸进行了基因编码。将这些非经典氨基酸掺入蛋白质中可实现许多强大的应用，从基础研究到生物技术、材料科学和医学。然而，要释放跨学科遗传密码扩展的全部潜力，仍然存在重大挑战。在这里，我们概述了不同的遗传密码扩展方法和系统及其在原核生物和真核生物中的最终应用，以大肠杆菌和哺乳动物细胞为代表，是主要的主力模型系统。我们强调了新技术如何首先在简单中建立，然后转移到更复杂的系统中的力量。例如，全基因组工程在细菌中提供了一个极好的平台，可以在转录组中实现转录本特异性遗传密码扩展，而不会脱靶。相比之下，真核细胞的复杂性带来了挑战，需要全新的方法，例如努力建立新的碱基对或在活细胞内产生正交翻译的细胞器。我们将扩展活细胞遗传密码以编码新化学功能的里程碑与最新的科学发现联系起来，从优化非经典氨基酸的物理化学性质到其体内掺入的技术进步。这段旅程让我们得以一窥未来几年的前景发展。

更新日期：2024-08-09

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