Enzymatic Cross-Linking of Side Chains Generates a Modified Peptide with Four Hairpin-like Bicyclic Repeats
Enzymatic Cross-Linking of Side Chains Generates a Modified Peptide with Four Hairpin-like Bicyclic Repeats
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DOI：
10.1021/acs.biochem.7b00808
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发表时间：
2017-09-19
期刊：
影响因子：
2.9
通讯作者：
Kim, Seokhee
中科院分区：
文献类型：
--
作者：
Lee, Hyunbin;Park, Youngseon;Kim, Seokhee
多肽的大环化反应在天然产物的生物合成和药物开发中具有重要的应用价值。肽中两条侧链通过酯或酰胺的酶促交联具有制备拓扑多样性环肽的高潜力，但在天然产物的微绿素类中仅发现单一共有序列。在这里，我们报告，一个新的序列模式的肽可以酶促交联，使一种新的microviridin样肽，plesiocin，其中包含四个重复的一个独特的发夹样双环结构，并显示出强烈的抑制蛋白酶。单个ATP-抓取酶与前导肽结合，其中仅需要13个残基进行结合，并在核心肽上进行8次酯化反应。我们还表明，串联质谱和酯特异性反应的组合大大促进了连接性的测定。我们认为肽侧链的酶促交联可以在自然界或通过工程产生更多样化的结构。
Macrocyclization of peptides is often employed to generate novel structures and biological activities in the biosynthesis of natural products and drug discovery. The enzymatic cross-linking of two side chains in a peptide via an ester or amide has a high potential for making topologically diverse cyclic peptides but is found with only a single consensus sequence in the microviridin class of natural products. Here, we report that a peptide with a new sequence pattern can be enzymatically cross linked to make a novel microviridin-like peptide, plesiocin, which contains four repeats of a distinct hairpin-like bicyclic structure and shows strong inhibition of proteases. A single ATP-grasp enzyme binds to a leader peptide, of which only 13 residues are required for binding, and performs eight esterification reactions on the core peptide. We also demonstrate that the combination of tandem mass spectrometry and an ester-specific reaction greatly facilitates the determination of connectivity. We suggest that the enzymatic cross-linking of peptide side chains can generate more diverse structures in nature or by engineering.