Natural and engineered cyclodipeptides: Biosynthesis, chemical diversity, and engineering strategies for diversification and high-yield bioproduction.

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 side 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.