Chapter 5: Peptide Natural Products II: Nonribosomal Peptides

Peptide natural products assembled by nonribosomal peptide synthetase (NRPS) machinery activate proteinogenic and nonproteinogenic amino acids, install them as thioesters tethered to phosphopantetheinyl prosthetic groups on peptidyl carrier protein domains, and carry out chain elongations by amide bond formations. The growing peptidyl chain, as a series of elongating peptidyl thioesters, is released when it reaches the most downstream NRPS assembly-line module, typically by either hydrolysis, macrolactonization/macrolactamization, reductive elimination, or Dieckmann condensation. A series of dedicated tailoring enzymes act both on assembly lines or as post-assembly-line tailoring catalysts to morph the peptide backbone and side chains into compact, hydrolysis-resistant linear and cyclic end products. NRPS assembly lines build the aminoadipyl-cysteinyl-d-valine tripeptide, which is then bis-cyclized to the 4,5-fused ring system of lactam antibiotics, as well as the heptapeptide scaffold of vancomycin-type glycopeptide antibiotics. Additional nonribosomal peptide biosynthesis products analyzed include didemnin, kutzneride, tyrocidine, polymyxin, ADEPs, daptomycin, enterobactin, yersiniabactin, echinocandin, and obafluorin. Hybrid nonribosomal peptide-polyketide assembly lines lead to rapamycin, bleomycin, and colibactin.