School of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
Nat Prod Rep. 2016 Feb;33(2):317-47. doi: 10.1039/c5np00099h.
Nonribosomal peptides are amongst the most widespread and structurally diverse secondary metabolites in nature with many possessing bioactivity that can be exploited for therapeutic applications. Due to the major challenges associated with total- and semi-synthesis, bioengineering approaches have been developed to increase yields and generate modified peptides with improved physicochemical properties or altered bioactivity. Here we review the major advances that have been made over the last decade in engineering the biosynthesis of nonribosomal peptides. Structural diversity has been introduced by the modification of enzymes required for the supply of precursors or by heterologous expression of tailoring enzymes. The modularity of nonribosomal peptide synthetase (NRPS) assembly lines further supports module or domain swapping methodologies to achieve changes in the amino acid sequence of nonribosomal peptides. We also review the new synthetic biology technologies promising to speed up the process, enabling the creation and optimisation of many more assembly lines for heterologous expression, offering new opportunities for engineering the biosynthesis of novel nonribosomal peptides.
非核糖体肽是自然界中分布最广泛、结构最多样化的次级代谢产物之一，其中许多具有生物活性，可用于治疗应用。由于全合成和半合成所面临的重大挑战，人们已经开发了生物工程方法来提高产量，并生成具有改善的物理化学性质或改变的生物活性的修饰肽。在这里，我们回顾了过去十年中在非核糖体肽生物合成工程方面取得的主要进展。通过修饰合成前体所需的酶或异源表达修饰酶，可以引入结构多样性。非核糖体肽合成酶（NRPS）组装线的模块化进一步支持模块或结构域交换方法学，以实现非核糖体肽的氨基酸序列变化。我们还回顾了新的合成生物学技术，这些技术有望加快这一过程，使更多的组装线能够进行异源表达，为新型非核糖体肽的生物合成工程提供新的机会。
