近日,
该研究组描述了一种可移除糖基化修饰(RGM)策略,它可以加速具有多个或甚至链间二硫键的正确折叠蛋白质的化学合成。他们的策略包括在Ser/Thr位点引入简单的O-连接的β-N-乙酰氨基葡萄糖(O-GlcNAc)基团,通过稳定其折叠中间体,有效地促进了富含二硫的蛋白质的折叠。折叠后,O-GlcNAc基团可以用β-N-乙酰氨基葡萄糖酶(OGA)被有效地去除,从而获得正确折叠的蛋白质。
使用这种策略,该研究组完成了正确折叠的铁调素的合成,这是一种含有四组二硫键的铁调节激素。此外,他们还首次实现了正确折叠的白细胞介素5 (IL-5)的全合成,这是一种26 kDa的同型二聚体细胞因子,负责嗜酸性粒细胞的生长和分化。
据介绍,在生物医学研究中,富含二硫的蛋白质是有用的药物或工具分子,但它们的合成由于折叠的困难而变得复杂。
附:英文原文
Title: Total Chemical Synthesis of Correctly Folded Disulfide-Rich Proteins Using a Removable O-Linked β-N-Acetylglucosamine Strategy
Author: Wei-Wei Shi, Chaowei Shi, Tong-Yue Wang, Yu-Lei Li, Yong-Kang Zhou, Xu-Han Zhang, Donald Bierer, Ji-Shen Zheng, Lei Liu
Issue&Volume: January 3, 2022
Abstract: Disulfide-rich proteins are useful as drugs or tool molecules in biomedical studies, but their synthesis is complicated by the difficulties associated with their folding. Here, we describe a removable glycosylation modification (RGM) strategy that expedites the chemical synthesis of correctly folded proteins with multiple or even interchain disulfide bonds. Our strategy comprises the introduction of simple O-linked β-N-acetylglucosamine (O-GlcNAc) groups at the Ser/Thr sites that effectively improve the folding of disulfide-rich proteins by stabilization of their folding intermediates. After folding, the O-GlcNAc groups can be efficiently removed using O-GlcNAcase (OGA) to afford the correctly folded proteins. Using this strategy, we completed the synthesis of correctly folded hepcidin, an iron-regulating hormone bearing four pairs of disulfide-bonds, and the first total synthesis of correctly folded interleukin-5 (IL-5), a 26 kDa homodimer cytokine responsible for eosinophil growth and differentiation.
DOI: 10.1021/jacs.1c10091
Source: https://pubs.acs.org/doi/10.1021/jacs.1c10091
JACS:《美国化学会志》,创刊于1879年。隶属于美国化学会,最新IF:14.612
官方网址:https://pubs.acs.org/journal/jacsat
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