nonribosomally

Nonribosomally refers to the biosynthesis of peptides by nonribosomal peptide synthetases (NRPS) rather than by ribosomes. This pathway generates a large and diverse class of peptides, often containing nonproteinogenic amino acids, unusual linkages, and complex three-dimensional structures. Nonribosomal peptide production is widespread in bacteria and fungi and underpins the biosynthesis of many medically important compounds.

Nonribosomal peptide synthetases are large, multi-module enzymes that operate in an assembly-line fashion. Each module typically activates a specific amino acid via an adenylation domain, tethers it to a peptidyl carrier protein (also called a thiolation domain), and then participates in a condensation step to form a peptide bond with the growing chain. The order of modules determines the sequence of amino acids in the final product. Many NRPS systems include optional domains that modify residues, such as epimerization domains that convert l- to d-amino acids, N-methyltransferases, oxidoreductases, or enzymes that introduce glycosyl or lipid moieties. A thioesterase domain often releases and cyclizes the finished peptide.

The products of NRPS pathways are diverse, including antibiotics (for example, vancomycin and bacitracin), immunosuppressants (cyclosporine), siderophores (enterobactin), and other bioactive cyclopeptides. These compounds frequently exhibit macrocyclic structures and unusual amino acid compositions not typically produced by ribosomal synthesis.

Compared with ribosomal peptide synthesis, nonribosomal pathways do not rely on messenger RNA templates and ribosomal decoding. They inherently enable greater chemical diversity, structural complexity, and the inclusion of noncanonical amino acids. Researchers study NRPS systems to discover new natural products and to engineer modules for the production of novel therapeutics.