Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark.
Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525AJ, Nijmegen, The Netherlands.
Org Biomol Chem. 2021 Dec 22;20(1):173-181. doi: 10.1039/d1ob02191e.
Histone lysine methyltransferases and acetyltransferases are two classes of epigenetic enzymes that play pivotal roles in human gene regulation. Although they both recognise and posttranslationally modify lysine residues in histone proteins, their difference in histone peptide-based substrates and inhibitors remains to be firmly established. Here, we have synthesised lysine mimics that posses an amide bond linker in the side chain, incorporated them into histone H3 tail peptides, and examined synthetic histone peptides as substrates and inhibitors for human lysine methyltransferases and acetyltransferases. This work demonstrates that histone lysine methyltransferases G9a and GLP do catalyse methylation of the most similar lysine mimic, whereas they typically do not tolerate more sterically demanding side chains. In contrast, histone lysine acetyltransferases GCN5 and PCAF do not catalyse acetylation of the same panel of lysine analogues. Our results also identify potent H3-based inhibitors of GLP methyltransferase, providing a basis for development of peptidomimetics for targeting KMT enzymes.
组蛋白赖氨酸甲基转移酶和乙酰转移酶是两类表观遗传酶，在人类基因调控中发挥着关键作用。尽管它们都能识别和翻译后修饰组蛋白蛋白中的赖氨酸残基，但它们在基于组蛋白肽的底物和抑制剂方面的差异仍有待确定。在这里，我们合成了赖氨酸类似物，其在侧链中具有酰胺键连接子，将其掺入组蛋白 H3 尾部肽中，并将合成的组蛋白肽作为人赖氨酸甲基转移酶和乙酰转移酶的底物和抑制剂进行了研究。这项工作表明，组蛋白赖氨酸甲基转移酶 G9a 和 GLP 确实催化最相似的赖氨酸类似物的甲基化，而它们通常不能容忍更具空间位阻的侧链。相比之下，组蛋白赖氨酸乙酰转移酶 GCN5 和 PCAF 不能催化同一组赖氨酸类似物的乙酰化。我们的结果还确定了 GLP 甲基转移酶的强效 H3 基抑制剂，为开发针对 KMT 酶的肽模拟物提供了基础。
