Nonribosomal Peptides Produced by Minimal and Engineered Synthetases with Terminal Reductase Domains

Nonribosomal peptide synthetases (NRPSs) use terminal reductase domains for 2‐electron reduction of the enzyme‐bound thioester releasing the generated peptides as C‐terminal aldehydes. Herein, we reveal the biosynthesis of a pyrazine that originates from an aldehyde‐generating minimal NRPS termed ATRed in entomopathogenic Xenorhabdus indica. Reductase domains were also investigated in terms of NRPS engineering and, although no general applicable approach was deduced, we show that they can indeed be used for the production of similar natural and unnatural pyrazinones. Peptide aldehyde production: An aldehyde‐releasing reductase (R) domain has been identified as part of a minimal nonribosomal peptide synthetase (NRPS) in X. indica. We also show that the R domain from the tilivalline‐producing NRPS can be used in engineered synthetases to introduce an aldehyde group and subsequently produce natural and unnatural pyrazinones.