Production of Diketopiperazine Derivatives by Pathway Engineering with Different Cyclodipeptide Synthases from Various Streptomyces Strains

Cyclodipeptides from fungi and bacteria are often modified by different tailoring enzymes. They display various biological and pharmacological activities, and some derivatives are used as drugs. In a previous study, we elucidated the function of the silent guatrypmethine gene cluster from Streptomyces cinnamoneus containing a cyclodipeptide synthase (CDPS) core gene gtmA and four genes gtmB–gtmE for tailoring enzymes. The latter are used in this study for the design of modified cyclodipeptides by genetic engineering. Addition of six different cyclodipeptides to the Streptomyces albus transformant harboring gtmB–gtmE led to the detection of different pathway products. Coexpression of five CDPS genes from four Streptomyces strains with gtmB–gtmE resulted in the formation of diketopiperazine derivatives, differing in their modification stages. Our results demonstrate the potential of rational gene combination to increase structural diversity.