Widodo Wahyu Setia, Billerbeck Sonja
Department of Molecular Enzymology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
Department of Molecular Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
Eng Microbiol. 2022 Dec 24;3(1):100067. doi: 10.1016/j.engmic.2022.100067. eCollection 2023 Mar.
Cyclodipeptides are diverse chemical scaffolds that show a broad range of bioactivities relevant for medicine, agriculture, chemical catalysis, and material sciences. Cyclodipeptides can be synthesized enzymatically through two unrelated enzyme families, non-ribosomal peptide synthetases (NRPS) and cyclodipeptide synthases (CDPSs). The chemical diversity of cyclodipeptides is derived from the two amino acid chains and the modification of those side-chains by cyclodipeptide tailoring enzymes. While a large spectrum of chemical diversity is already known today, additional chemical space - and as such potential new bioactivities - could be accessed by exploring yet undiscovered NRPS and CDPS gene clusters as well as via engineering. Further, to exploit cyclodipeptides for applications, the low yield of natural biosynthesis needs to be overcome. In this review we summarize current knowledge on NRPS and CDPS-based cyclodipeptide biosynthesis, engineering approaches to further diversity the natural chemical diversity as well as strategies for high-yield production of cyclodipeptides, including a discussion of how advancements in synthetic biology and metabolic engineering can accelerate the translational potential of cyclodipeptides.
环二肽是多种多样的化学支架，具有与医学、农业、化学催化和材料科学相关的广泛生物活性。环二肽可以通过两个不相关的酶家族，即非核糖体肽合成酶（NRPS）和环二肽合成酶（CDPS）进行酶促合成。环二肽的化学多样性源于两条氨基酸链以及环二肽修饰酶对这些侧链的修饰。虽然如今已经知道了大量的化学多样性，但通过探索尚未发现的NRPS和CDPS基因簇以及通过工程手段，仍可以获得更多的化学空间——以及潜在的新生物活性。此外，为了将环二肽用于实际应用，需要克服天然生物合成产量低的问题。在这篇综述中，我们总结了基于NRPS和CDPS的环二肽生物合成的现有知识、进一步拓展天然化学多样性的工程方法以及环二肽高产生产的策略，包括讨论合成生物学和代谢工程的进展如何加速环二肽的转化潜力。
