consists of several domains with defined functions, separated by short spacer regions of about 15 amino acids. The biosynthesis of nonribosomal peptides shares characteristics with the polyketide and fatty acid biosynthesis. Due to these structural and mechanistic similarities, some nonribosomal peptide synthetases contain polyketide synthase modules for the insertion of acetate or propionate-derived subunits into the peptide chain. Note that as many as 10% percent of bacterial NRPS are not laid out as large modular proteins, but as separate enzymes. Some NRPS modules deviate from the standard domain structure, and some extra domains have been described. There are also NRPS enzymes that serve as a scaffold for other modifications to the substrate to incorporate unusual amino acids. Modules The order of modules and domains of a complete nonribosomal peptide synthetase is as follows: Initiation or Starting module: [F/NMT]-A-PCP- Elongation or Extending modules: -(C/Cy)-[NMT]-A-PCP-[E]- Termination or Releasing module: -(TE/R) (Order: N-terminus to C-terminus; []: optionally; (): alternatively) Domains F: Formylation (optional) A: Adenylation (required in a module) PCP: Thiolation and peptide carrier protein with attached 4'-phospho-pantetheine (required in a module) C: Condensation forming the amide bond (required in a module) Cy: Cyclization into thiazoline or oxazolines (optional) Ox: Oxidation of thiazolines or oxazolines to thiazoles or oxazoles (optional) Red: Reduction of thiazolines or oxazolines to thiazolidines or oxazolidines (optional) E: Epimerization into D-amino acids (optional) NMT: N-methylation (optional) TE: Termination by a thio-esterase (only found once in a NRPS) R: Reduction to terminal aldehyde or alcohol (optional) X: Recruits cytochrome P450 enzymes (optional) Starting stage Loading: The first amino acid is activated with ATP as a mixed acyl-phosphoric acid anhydride with AMP by the A-domain and loaded onto the serine-attached 4'-phospho-pantethine (4'PP) sidechain of the PCP-domain catalyzed by the PCP-domain (thiolation). Some A domains require interaction with MbtH-like proteins for their activity. Sometimes the amino group of the bound amino acid is formylated by an F-domain or methylated by an NMT-domain. Elongation stages Loading: Analogous to the starting stage, each module loads its specific amino acid onto its PCP-domain. Condensation: The C-domain catalyzes the amide bond formation between the thioester group of the growing peptide chain from the previous module with the amino group of the current module. The extended peptide is now attached to the current PCP-domain. Condensation-Cyclization: Sometimes the C-domain is replaced by a Cy-domain, which, in addition to the amide bond formation, catalyzes the reaction of the serine,