Nonribosomal peptide



Nonribosomal peptides (NRP) are a class of ribosomes, the term nonribosomal peptide typically refers to a very specific set of these as discussed in this article.

Nonribosomal peptides are synthesized by nonribosomal peptide synthetases, which, unlike the dehydroalanine. This is just a sampling of the various manipulations and variations that nonribosomal peptides can perform. Nonribosomal peptides are often dimers or trimers of identical sequences chained together or cyclized, or even branched.

Nonribosomal peptides are structurally a very diverse family of natural products with an extremely broad range of biological activities and pharmacological properties. They are often toxins, cytostatics, and immunosuppressants are in commercial use.

Examples

Biosynthesis

Nonribosomal peptides are synthesized by one or more specialized nonribosomal peptide-synthetase (NRPS) operon in bacteria and in gene clusters in eukaryotes. The enzymes are organized in modules that are responsible for the indroduction of one additional amino acid. Each module consists of several domains with defined functions, separated by short spacer regions of about 15 amino acids.

The biosynthesis of nonribosomal peptides shares similarities with the propionate derived subunits into the peptide chain.

Modules

The order of modules and domains of a complete nonribosomal peptide synthetase is as follows:

  • Initiation or Starting module: [F/NMe]-A-PCP-
  • Elongation or Extending modules: -(C/Cy)-[NMe]-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-pantethein (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)
  • TE: Termination by a thio-esterase (only found once in a NRPS)
  • R: Reduction to terminal aldehyde or alcohol (optional)

Starting stage

  • Loading: The first amino acid is activated with serine-attached 4'-phospho-pantethein (4'PP) sidechain of the PCP-domain catalyzed by the PCP-domain (thiolation) .
  • Sometimes the amino group of the bound amino acid is formylated by an F-domain or methylated by an NMe-domain.

Elongation stages

  • Loading: Analogous to the starting stage, each module loads its specific amino acid onto its PCP-domain.
  • 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.
  • Epimerization: Sometimes an E-domain epimerizes the innermost amino acid of the peptide chain into the D-configuration.
  • This cycle is repeated for each elongation module.

Termination stage

  • Termination: The TE-domain (thio-esterase domain) lactones).
  • Alternatively, the peptide can be released by an R-domain that aldehyde or alcohol.

Processing

The final peptide is often modified, e.g. by operons or gene clusters.

Priming and Deblocking

To become functional, the 4'-phospho-pantethein sidechain of acyl-CoA molecules has to be attached to the PCP-domain by 4'PP transferases (Priming) and the acyl group has to be removed by specialized associated thioesterases (TE-II) (Deblocking).

Substrate specificities

Most domains have a very broad isomer.

Mixed with Polyketides

Due to the similarity with polyketide synthetases (PKS), many secondary metabolites are in fact fusions of NRPs and polyketides. This essentially occurs when PK modules follow NRP modules, and vice versa. There is high degree of similarity between the PCP domains of both types of sythetases, although the mechanism of condensation is different from a chemical standpoint (claisen vs. transamidation).

See also

Literature

  • "Nonribosomal peptides: from genes to products" by Dirk Schwarzer, Robert Finking, and Mohamed A. Marahiel in Nat. Prod. Rep. 20(3):275-287 (2003) DOI: 10.1039/b111145k
  • "Modular Peptide Synthetases Involved in Nonribosomal Peptide Synthesis" by Mohamed A. Marahiel, Torsten Stachelhaus, and Henning D. Mootz in Chem. Rev. 97(7):2651-2673 (1997) DOI: 10.1021/cr960029e
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Nonribosomal_peptide". A list of authors is available in Wikipedia.