College of Food Science and Engineering, Ningbo University, Ningbo 315800, China.
Mar Drugs. 2024 Jul 29;22(8):349. doi: 10.3390/md22080349.
Nonribosomal peptides (NRPs) are biosynthesized by nonribosomal peptide synthetases (NRPSs) and are widely distributed in both terrestrial and marine organisms. Many NRPs and their analogs are biologically active and serve as therapeutic agents. The adenylation (A) domain is a key catalytic domain that primarily controls the sequence of a product during the assembling of NRPs and thus plays a predominant role in the structural diversity of NRPs. Engineering of the A domain to alter substrate specificity is a potential strategy for obtaining novel NRPs for pharmaceutical studies. On the basis of introducing the catalytic mechanism and multiple functions of the A domains, this article systematically describes several representative NRPS engineering strategies targeting the A domain, including mutagenesis of substrate-specificity codes, substitution of condensation-adenylation bidomains, the entire A domain or its subdomains, domain insertion, and whole-module rearrangements.
非核糖体肽（NRPs）是由非核糖体肽合成酶（NRPSs）生物合成的，广泛分布于陆地和海洋生物中。许多 NRPs 及其类似物具有生物活性，可用作治疗剂。腺苷酰化（A）结构域是一个关键的催化结构域，主要控制 NRPs 组装过程中产物的序列，因此在 NRPs 的结构多样性中起着主要作用。通过工程化 A 结构域来改变底物特异性是获得用于药物研究的新型 NRPs 的一种潜在策略。本文在介绍 A 结构域的催化机制和多种功能的基础上，系统描述了几种针对 A 结构域的代表性 NRPS 工程策略，包括底物特异性密码子的突变、缩合-腺苷酰化双结构域的替换、整个 A 结构域或其亚结构域、结构域插入和整个模块重排。
