Nonribosomal peptides are a large family of naturally occurring compounds enzymatically synthesized from amino acids without a nucleic acid template. Many of these peptides have useful pharmacological properties. Vancomycin, for example, inhibits bacterial cell wall synthesis. Cyclosporin and precursors of penicillin are also nonribosomal peptides. These compounds are typically secreted by filamentous fungi, although their biological role in the producing organism is not known.
Nonribosomal peptide synthetases (NRPSs) are large modular proteins that assemble the amino acid units of the metabolites. Each module is responsible for a single catalytic step, such as activating an amino acid to its adenylate, forming a peptide bond, or modifying a functional group. The growing peptide is covalently attached to each module in turn, and the N- to C-terminal order of modules determines the organization of the final peptide product. For example, the penicillin precursor ACV is synthesized from modules specific for adenylate formation and attachment of amino adipate, cysteine, and valine, in that order. As more genes for NRPSs are identified, it should be possible to rationally construct novel nonribosomal peptides by genetic manipulation of modules.
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