Chapter 13. Nonribosomal Peptide Synthetases Mechanistic and Structural Aspects of Essential Domains

A widespread class of therapeutically important natural products is of peptidic origin. They are produced nonribosomally by large "assembly line"-like multienzyme complexes, the nonribosomal peptide synthetases (NRPS). In contrast to ribosomal peptide synthesis, nonribosomally assembled peptides contain unique structural features such as D-amino acids, N-terminally attached fatty acid chains, N- and C-methylated amino acids, N-formylated residues, heterocyclic elements, glycosylated amino acids, and phosphorylated residues. In recent research using genetic, biochemical, and structural methods, experiments have revealed profound insights into the molecular mechanism of nonribosomal peptide synthesis. Based on this, it was possible to alter existing nonribosomally produced peptides either by changing their biosynthetic templates or by the combined action of chemical peptide synthesis and subsequent enzyme catalysis. An overview of the structural aspects of the NRPS machinery with a focus on mechanistic and structural aspects of essential domains is presented.