Synthesis of Nε-acetyl-L-homolysine by the Lossen rearrangement and its application for probing deacetylases and binding modules of acetyl-lysine,Journal of Peptide Science

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Synthesis of Nε-acetyl-L-homolysine by the Lossen rearrangement and its application for probing deacetylases and binding modules of acetyl-lysine
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2022-11-23 , DOI: 10.1002/psc.3462
Luisa Rehkopf ₁ , Julian Seidel _{1,

2} , Julia Sindlinger _{1,

3} , Mary Wang ₁ , Sören Kirchgäßner ₁ , Dirk Schwarzer ₁

Affiliation

Lysine acetylation is a posttranslational protein modification mediating protein–protein interactions by recruitment of bromodomains. Investigations of bromodomains have focused so far on the sequence context of the modification site and acyl-modifications installed at lysine side chains. In contrast, there is only little information about the impact of the lysine residue that carries the modification on bromodomain binding. Here, we report a synthesis strategy for L-acetyl-homolysine from L-2-aminosuberic acid by the Lossen rearrangement. Peptide probes containing acetylated homolysine, lysine, and ornithine were generated and used for probing the binding preferences of four bromodomains from three different families. Tested bromodomains showed distinct binding patterns, and one of them bound acetylated homolysine with similar efficiency as the native substrate containing acetyl-lysine. Deacetylation assays with a bacterial sirtuin showed a strong preference for acetylated lysine, despite a broad specificity for N-acyl modifications.

中文翻译：

洛森重排合成 Nε-乙酰-L-高赖氨酸及其在乙酰赖氨酸脱乙酰酶和结合模块检测中的应用

赖氨酸乙酰化是一种翻译后蛋白质修饰，通过募集溴结构域介导蛋白质-蛋白质相互作用。迄今为止，对溴结构域的研究主要集中在修饰位点的序列背景和安装在赖氨酸侧链上的酰基修饰上。相比之下，关于携带修饰的赖氨酸残基对溴结构域结合的影响的信息很少。在这里，我们报告了通过洛森重排从 L-2-氨基辛二酸合成 L-乙酰基-高赖氨酸的策略。生成了含有乙酰化高赖氨酸、赖氨酸和鸟氨酸的肽探针，并用于探测来自三个不同家族的四个溴结构域的结合偏好。测试的溴结构域显示出不同的结合模式，其中之一以与含有乙酰赖氨酸的天然底物相似的效率结合乙酰化高赖氨酸。尽管对 N-酰基修饰具有广泛的特异性，但使用细菌 sirtuin 的脱乙酰化测定显示出对乙酰化赖氨酸的强烈偏好。

更新日期：2022-11-23

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