非核糖体肽合成酶催化模块的重构与多肽合成

Reconstitution of Non-ribosomal Peptide Synthetases Catalytic Module and Peptide Synthesis

天然次级代谢产物是重要的药物来源,非核糖体肽(non-ribosomal peptide,NRP)是自然界中广泛存在的次级代谢产物,其多样的化学结构使其具有多种生物活性,如抗炎、抗肿瘤、抗病毒等。基于非核糖体多肽合成酶(nonribosomal peptide synthetases,NRPS)模块化线性合成多肽的原理对其催化模块进行改造、重组,定向设计多肽的生物合成途径以获得目的多肽已成为一个研究热点。然而杂合NRPS存在催化模块无法加载目标氨基酸或多肽合成效率显著降低等诸多问题,限制了其应用。近年来,NRPS腺苷酰化域(adenylation domain,A域)及缩合结构域(condensation domain,C域)的底物选择性、NRPS亚基间对接域(docking domain,DD)和模块间连接区(linker)的研究已取得较大突破。从C域对底物的选择性及以不同融合边界进行催化单元替换两方面进行综述,介绍NRPS催化模块重构的研究进展,并概述了各替换方案的优点与局限性。

Based on the principle of modular linear synthesis of peptides by non-ribosomal peptide synthetases(NRPS),it has become a research hotspot to engineer and recombine its catalytic module and design the biosynthetic pathway of peptides to obtain the target peptides.However,heterozygous NRPS has many problems.For example,the catalytic module cannot load the target amino acids or the synthesis efficiency of peptides is significantly reduced,which limits its application.In recent years,great breakthroughs have been made in the research of substrate selectivity of NRPS adenylation domain(A domain)and condensation domain(C domain),docking domain(DD)between NRPS subunits and linker between modules.This review introduces the research progress of NRPS catalytic module reconsitution from the two aspects of substrate selectivity in C domain and catalytic unit substitution with different fusion boundaries,and summarizes the advantages and limitations of each substitution scheme.