GEORG SCHOENAFINGER AND MOHAMED A. MARAHIEL
Philipps-University of Marburg, FB Chemie/Biochemie, Marburg, Germany
Many microorganisms have evolved an unusual way of producing secondary peptide metabolites. Large multidomain enzymatic machineries, the so-called nonribosomal peptide synthetases (NRPSs), are responsible for the production of this structurally diverse class of peptides with various functions, such as cytostatic, immunosuppressive, antibacterial, or antitumor properties. These secondary metabolites differ from peptides of ribosomal origin in several ways. Their length is limited to a mere 20 building blocks, roughly, and mostly a circular or branched cyclic connectivity is found. Furthermore, aside from the proteinogenic amino acids, a larger variety of chemical groups is found in these bioactive compounds: D-configurated amino acids, fatty acids, methylated, oxidized, halogenated, and glycosylated building blocks. These functional and structural features are known to be important for bioactivity, and often natural defense mechanisms are thus evaded. In this chapter, we describe the enzymatic machineries of NRPSs, the chemical reactions catalyzed by their subunits, and the potential of redesigning or using these machineries to give rise to new nonribosomal peptide antibiotics.