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.

A new cyclodipeptide from the cultures of Geotrichum candidum

A new cyclodipeptide, cyclo(phenylalanyl-N-methyltyrosyl) 1, was isolated from the mycelial solid cultures of Geotrichum candidum. Its structure was elucidated by spectroscopic methods. The antifungal activity of the new compound against Peronophythora litchii was assessed by microplate Alamar blue assay (MABA).

Fungal arginine-containing cyclodipeptide synthases are finally revealed

Biosynthetic pathways without any identifiable core enzymes may encode unknown(biosynthetic route)-unknown(molecular structure)natural products.However,bioinformatics-guided mining for such unknown-unknown metabolites is challenging.Recently,an unknown-unknown biosynthetic route has been deciphered in fungi.It was found that a class of enzymes previously annotated as hypothetical proteins catalyze the biosynthesis of arginine-containing cyclodipeptides(CDPs).This advances the understanding of the biosynthesis of CDPs and highlights the vast potential of unknown-unknown natural products encoded by microbial genomes.

A Convenient Approach to the Enantiopure (1S,2S,4S,5S)-and (1R,2S,4R,5S)-2,5-Bis(phenylmethyl)-1,4-diazabicyclo[2.2.2]-octane

Cyclodipeptide (3 S,6S ) bis(phenylmethyl)piperazine 2,5 dione was prepared in high yield by heating phenylalanine methyl ester in toluene under reflux. The reduction of this cyclodipeptide with sodium NaBH 4 BF 3 in DME gave the (2 S,5S ) bis(phenylmethyl)piperazine, which, on heating with ethylene bromide and triethylamine, afforded the title compounds. This method was proved to be generally applicable to the synthesis of C 2 symmetric 2,5 disubstituted 1,4 diazabicyclo[2.2.2]octane from the corresponding natural or unnatural amino acid esters.