Life Sciences Institute, Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou 310058, China.
Center for Oncology Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China.
Chem Rev. 2024 Nov 13;124(21):12176-12212. doi: 10.1021/acs.chemrev.4c00419. Epub 2024 Oct 23.
Protein lipidation dramatically affects protein structure, localization, and trafficking via remodeling protein-membrane and protein-protein interactions through hydrophobic lipid moieties. Understanding the biosynthesis of lipidated proteins, whether natural ones or mimetics, is crucial for reconstructing, validating, and studying the molecular mechanisms and biological functions of protein lipidation. In this Perspective, we first provide an overview of the natural enzymatic biosynthetic pathways of protein lipidation in mammalian cells, focusing on the enzymatic machineries and their chemical linkages. We then discuss strategies to biosynthesize protein lipidation in mammalian cells by engineering modification machineries and substrates. Additionally, we explore site-specific protein lipidation biosynthesis via enzyme-mediated ligations and primarily through genetic code expansion strategies. We also discuss the use of small molecule tools to modulate the process of protein lipidation biosynthesis. Finally, we provide concluding remarks and discuss future directions for the biosynthesis and applications of protein lipidation.
蛋白质脂质化通过疏水性脂质部分重塑蛋白质-膜和蛋白质-蛋白质相互作用，极大地影响蛋白质结构、定位和运输。了解脂质化蛋白质的生物合成，无论是天然的还是模拟的，对于重建、验证和研究蛋白质脂质化的分子机制和生物学功能至关重要。在本观点中，我们首先概述了哺乳动物细胞中蛋白质脂质化的天然酶促生物合成途径，重点介绍了酶机制及其化学连接。然后，我们讨论了通过工程化修饰机制和底物来在哺乳动物细胞中生物合成蛋白质脂质化的策略。此外，我们还通过酶介导的连接以及主要通过遗传密码扩展策略探索了蛋白质脂质化的定点生物合成。我们还讨论了使用小分子工具来调节蛋白质脂质化生物合成过程。最后，我们提供了结论并讨论了蛋白质脂质化生物合成和应用的未来方向。
