美国麻省理工学院Voigt, Christopher A.团队报道了核糖体合成和翻译后修饰肽的从头设计。相关研究成果发表在2025年1月7日出版的《自然—化学》。

在自然界中，肽被酶修饰以限制其结构并引入功能部分。从头开始的肽结构可以通过组合来自不同途径的酶来构建，但很难确定它们的使用规则。

该文中，研究人员提出了一种生物物理模型，将来自细菌核糖体合成和翻译后修饰肽（RiPP）基因簇的酶结合起来。使用管道评估1000多种肽，该模型在大肠杆菌的统一条件下对不同类别的酶（graspetide, spliceotide, pantocin, cyanobactin, glycocin, lasso peptide 和lanthipeptide)）进行了参数化。

具有最多三种酶识别序列的合成先导肽被设计用于修饰与天然RiPP是、没有同一性的核心序列。根据经验，具有所需修饰的RiPPs占所生产肽总量的7-67%，设计的8种肽有6种被成功修饰。

该项工作是酶修饰肽和库设计的一个例子，使用了一个可以扩展到包括新酶和化学部分的框架。

附：英文原文

Title: De novo design of ribosomally synthesized and post-translationally modified peptides

Author: Glassey, Emerson, Zhang, Zhengan, King, Andrew M., Niquille, David L., Voigt, Christopher A.

Issue&Volume: 2025-01-07

Abstract: In nature, peptides are enzymatically modified to constrain their structure and introduce functional moieties. De novo peptide structures could be built by combining enzymes from different pathways, but determining the rules of their use is difficult. We present a biophysical model to combine enzymes sourced from bacterial ribosomally synthesized and post-translationally modified peptide (RiPP) gene clusters. Using a pipeline to evaluate more than 1,000 peptides, the model was parameterized under uniform conditions in Escherichia coli for enzymes from different classes (graspetide, spliceotide, pantocin, cyanobactin, glycocin, lasso peptide and lanthipeptide). Synthetic leader peptides with recognition sequences for up to three enzymes were designed to modify core sequences sharing no identity to natural RiPPs. Empirically, RiPPs with the desired modifications constituted 7–67% of the total peptides produced, and 6 of our 8 peptide designs were successfully modified. This work is an example of the design of enzyme-modified peptides and libraries, using a framework that can be expanded to include new enzymes and chemical moieties.

DOI: 10.1038/s41557-024-01685-9

Source: https://www.nature.com/articles/s41557-024-01685-9