研究人员描述了对几种细菌非核糖体肽合成酶（NRPS）的详细系统发育分析，结果发现了可用于NRPS工程的硫醇化（T）结构域内尚未被描述的重组位点。
然后，研究人员开发了一种受演化启发的“T结构域之间的交换单元”（XUT）方法，这种方法允许在广泛的GC含量、蛋白质相似性和扩展单元特异性范围内组装NRPS片段。
据悉，许多临床用药都来自细菌天然产物或受细菌天然产物的启发，这些天然产物通常是通过NRPS产生的，这种大型合成酶能以流水线方式激活和连接单个氨基酸。
附：英文原文
Title: Evolution-inspired engineering of nonribosomal peptide synthetases
Author: Kenan A. J. Bozhüyük, Leonard Prve, Carsten Kegler, Leonie Schenk, Sebastian Kaiser, Christian Schelhas, Yan-Ni Shi, Wolfgang Kuttenlochner, Max Schreiber, Joshua Kandler, Mohammad Alanjary, T. M. Mohiuddin, Michael Groll, Georg K. A. Hochberg, Helge B. Bode
Issue&Volume: 2024-03-22
Abstract: Many clinically used drugs are derived from or inspired by bacterial natural products that often are produced through nonribosomal peptide synthetases (NRPSs), megasynthetases that activate and join individual amino acids in an assembly line fashion. In this work, we describe a detailed phylogenetic analysis of several bacterial NRPSs that led to the identification of yet undescribed recombination sites within the thiolation (T) domain that can be used for NRPS engineering. We then developed an evolution-inspired “eXchange Unit between T domains” (XUT) approach, which allows the assembly of NRPS fragments over a broad range of GC contents, protein similarities, and extender unit specificities, as demonstrated for the specific production of a proteasome inhibitor designed and assembled from five different NRPS fragments.
DOI: adg4320
Source: https://www.science.org/doi/10.1126/science.adg4320