Beyond peptide bond formation: the versatile role of condensation domains in natural product biosynthesis

Covering: up to the end of 2020Nonribosomal peptide synthetases are remarkable molecular machines that produce a wide range of structurally complex peptide natural products with important applications in medicine and agriculture. Condensation domains play a central role in these biosynthetic pathways by catalysing amide bond formation between various aminoacyl substrates. In recent years, however, it has become increasingly clear that the catalytic repertoire of C domains extends far beyond conventional peptide bond formation. C domains have been shown to perform highly diverse functions during nonribosomal peptide assembly, such as β-lactam formation, dehydration, hydrolysis, chain length control, cycloaddition, Pictet-Spengler cyclization, Dieckmann condensation and recruitment of auxiliary enzymes. In this review, a comprehensive overview of the multifaceted role of C domains in the biosynthesis of specialized metabolites in bacteria and fungi is presented. Different perspectives are also offered on how the exceptional functional versatility of C domains may be exploited for bioengineering approaches to expand the chemical diversity of nonribosomal peptides and other natural products.