Structural Biochemistry/Non Ribosomal Peptide Synthesis (NPRS)

Non Ribosomal Peptide Synthesis (NPRS) utilizes a large monomer pool including all the amino acids and several unnatural amino acids along with aryl acid substrates to produce small molecule metabolites by a series of loading and condensation of peptides. Unlike ribosomal peptide synthesis, they do not involve the translation of mRNA in order to begin the synthesis. Because of this there is a very large degree of diversity and gives rise to an extremely varied host of possible products. NRPS is especially relevant because many secondary metabolites produced by this process are of medical importance, creating numerous antibiotics, antibiotic precursors, and immunosuppressant drugs. NRPS is similar to polyketide synthesis and fatty acid synthesis but NRPS multienzymes do not bind covalently to acyl carrier protein intermediates, instead utilizing only a peptidyl carrier protein (PCP). The PCP has a conserved serine group on an alpha helix replaced by a 4'-phosphopantetheine prosthetic group, which allows it to convert to the holo form, and consequently allows for the thiol group at the end of the prosthetic group to attach to other peptides. NRPS begins with the loading of an activated aminoacyl–adenylate onto the PCP, and then undergoes a process of adenylation and condensation until the thiostearase domain completes the polypeptide chain and the synthesis is completed. [1]

key of domains in NRPS

type I NRPS production of the antibiotic tyrocidine [edit]Domains found in NRPS: 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: Cylization 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)

After the peptide chain is synthesized, it can then be modified by halogenation, hydroxylation, acylation or glycosylation, which is typically carried out by an enzyme coded for in the same operon or gene cluster that was associated with the carrier protein. Since NRPS is similar to PKS and FAS, components of the other methods of metabolite synthesis are often cross-linked to each other and combine to form natural products. --A08954805 (discuss • contribs) 22:32, 15 November 2011 (UTC)