Structural Biochemistry/Non Ribosomal Peptide Synthesis

From Wikibooks, open books for an open world
Jump to: navigation, search

Non ribosomal peptide synthesis is an alternative pathway that allows production of polypeptides other than through the traditional translation mechanism. The peptides are created here by enzymatic complexes called synthetases and the resulting peptides are generally short, 2-50 residues.[1] Non ribosomal peptide synthesis produces several pharmacologically important compounds uncluding antibiotics and immunosuppressors. This biosynthesis pathway is found in many bacteria and fungi. Non Ribosomal Peptide Synthesis (NRPS) 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. Peptides produced by NRPS show peculiar features compared to traditional proteins. First, they can contain standard as well as non-standard amino acids.[1] Sencondly, amino acids are linked not only by an amino-peptide, but also by non-conventional links that form a non-linear peptide backbone.Non ribosomal peptide synthesis is a key mechanism responsible for the biosynthesis of bioactive metabolites in bacteria and fungi. Non ribosomal peptide synthetase genes, generally represent a part of multigene clusters, encode NRP synthetase which in turn, biosynthesize peptide products.[1] an NPR synthetase is generally composed of one or more modules and can terminate ina thioesterase domain that releases the newly synthesized peptide from the enzyme.[1] 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 polypeptide 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.[2]

File:Type I NRPS production of the antibiotic tyrocidine.png
type I NRPS production of the antibiotic tyrocidine

Domains found in NRPS[edit]

  • 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 (discusscontribs) 22:32, 15 November 2011 (UTC)


  1. Invalid <ref> tag; no text was provided for refs named Campbell
  2. [1], additional text.