Rescue of Glycosylphosphatidylinositol-Anchored Protein Biosynthesis Using Synthetic Glycosylphosphatidylinositol Oligosaccharides.
Rescue of Glycosylphosphatidylinositol-Anchored Protein Biosynthesis Using Synthetic Glycosylphosphatidylinositol Oligosaccharides.
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DOI：
10.1021/acschembio.1c00465
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发表时间：
2021-11-19
影响因子：
4
通讯作者：
Varón Silva D
中科院分区：
文献类型：
--
作者：
Guerrero PA;Murakami Y;Malik A;Seeberger PH;Kinoshita T;Varón Silva D
使用糖基磷脂酰肌醇（GPI）锚将蛋白质附着到细胞膜是真核细胞中普遍存在的过程。GPIs生物合成的缺陷和伴随的GPIs锚定蛋白的产生导致了一系列与人类遗传性GPI缺陷（IGD）相关的罕见和复杂的疾病。目前，对于患有IGD的患者没有治疗方法。在这里，我们报告的设计，合成和使用GPI片段，以挽救生物合成的GPI锚定蛋白（GPI-AP）所造成的突变基因参与的GPI-糖脂在细胞中的组装。我们证明了具有两条（3）和三条脂质链（4）的合成片段GlcNAc-PI（1）、Man-GlcN-PI（5）和GlcN-PI在体外挽救了缺乏PIGA、PIGL和PIGW基因的细胞中GPI生物合成的缺失。该化合物允许GPI生物合成的浓度依赖性恢复，并且在内质网膜的细胞质面上具有高度活性。这些合成分子是开发IGD治疗方法的先导，也是研究GPI-AP生物合成的工具。
The attachment of proteins to the cell membrane using a glycosylphosphatidylinositol (GPI) anchor is a ubiquitous process in eukaryotic cells. Deficiencies in the biosynthesis of GPIs and the concomitant production of GPI-anchored proteins lead to a series of rare and complicated disorders associated with inherited GPI deficiencies (IGDs) in humans. Currently, there is no treatment for patients suffering from IGDs. Here, we report the design, synthesis, and use of GPI fragments to rescue the biosynthesis of GPI-anchored proteins (GPI-APs) caused by mutation in genes involved in the assembly of GPI-glycolipids in cells. We demonstrated that the synthetic fragments GlcNAc-PI (1), Man-GlcN-PI (5), and GlcN-PI with two (3) and three lipid chains (4) rescue the deletion of the GPI biosynthesis in cells devoid of the PIGA, PIGL, and PIGW genes in vitro. The compounds allowed for concentration-dependent recovery of GPI biosynthesis and were highly active on the cytoplasmic face of the endoplasmic reticulum membrane. These synthetic molecules are leads for the development of treatments for IGDs and tools to study GPI-AP biosynthesis.
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DOI：
10.1038/nrdp.2017.28
发表时间：
2017-05-18
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Hill A;DeZern AE;Kinoshita T;Brodsky RA
通讯作者：
Brodsky RA
影响因子：
56.9
作者：
FERGUSON, MAJ;HOMANS, SW;RADEMACHER, TW
通讯作者：
RADEMACHER, TW
影响因子：
3.7
作者：
Kano F;Nakatsu D;Noguchi Y;Yamamoto A;Murata M
通讯作者：
Murata M
影响因子：
6.5
作者：
Houjou, Toshiaki;Hayakawa, Jun;Taguchi, Ryo
通讯作者：
Taguchi, Ryo
影响因子：
15
作者：
Lu, J;Jayaprakash, KN;Fraser-Reid, B
通讯作者：
Fraser-Reid, B