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Nonribosomal peptideNonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacteria inside these organisms.[citation needed] While there exist a wide range of peptides which are not synthesized by 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 ribosomes, are independent of messenger RNA. Each nonribosomal peptide synthetase can synthesize only one type of peptide. Nonribosomal peptides often have a cyclic and/or branched structures, can contain non-proteinogenic amino acids including D-amino acids, carry modifications like N-methyl and N-formyl groups, or are glycosylated, acylated, halogenated, or hydroxylated. Cyclization of amino acids against the peptide "backbone" is often performed, resulting in oxazolines and thiazolines; these can be further oxidized or reduced. Occasionally dehydration is performed on serines, resulting in 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, siderophores, or pigments. Nonribosomal peptide antibiotics, cytostatics, and immunosuppressants are in commercial use. Additional recommended knowledge
Examples
BiosynthesisNonribosomal peptides are synthesized by one or more specialized nonribosomal peptide-synthetase (NRPS) enzymes. The NRPS genes for a certain peptide are usually organized in one 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 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. ModulesThe order of modules and domains of a complete nonribosomal peptide synthetase is as follows:
(Order: N-terminus to C-terminus; []: optionally; (): alternatively) Domains
Starting stage
Elongation stages
Termination stage
ProcessingThe final peptide is often modified, e.g. by glycosylation, acylation, halogenation, or hydroxylation. The responsible enzymes are usually associated to the synthetase complex and their genes are organized in the same operons or gene clusters. Priming and DeblockingTo 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 S-attached acyl group has to be removed by specialized associated thioesterases (TE-II) (Deblocking). Substrate specificitiesMost domains have a very broad substrate specificity and usually only the A-domain determines which amino acid is incorporated in a module. Ten amino acids have been identified that control substrate specificity and can be considered the 'codons' of nonribosomal peptide synthesis. The condensation C-domain is also believed to have substrate specificity, especially if located behind an epimerase E-domain containing module where it functions as a 'filter' for the epimerized isomer. Mixed with PolyketidesDue 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 alsoLiterature
Categories: Molecular biology | Enzymes | Glycopeptide antibiotics | Antibiotics | Peptides |
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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. |