Nonribosomal peptide

Nonribosomal 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.[1] While there exist a wide range of peptides that 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 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. On occasion, 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 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.

Examples

Biosynthesis

Nonribosomal 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. However the first fungal NRP to be found was ciclosporin. It is synthesized by a single 1.6MDa NRPS.[4] The enzymes are organized in modules that are responsible for the introduction 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 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.

Modules

The 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

Processing

The 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 Deblocking

To become functional, the 4'-phospho-pantetheine 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 specificities

Most 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 that control substrate specificity and can be considered the 'codons' of nonribosomal peptide synthesis have been identified. 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 Polyketides

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

See also

Software for Characterization of NRPs

Literature

References

  1. ↑ Dai, Li-Xin (2012). Ding, Kuiling, ed. Organic chemistry : breakthroughs and perspectives. Weinheim, Germany: Wiley-VCH. ISBN 9783527333776.
  2. ↑ J.D. Walton (2006). "HC-toxin". Phytochemistry 67 (14): 1406–1413. doi:10.1016/j.phytochem.2006.05.033. PMID 16839576.
  3. ↑ R.D. Johnson, L. Johnson, Y. Itoh, M. Kodama, H. Otani, and K. Kohmoto (2000). "Cloning and Characterization of a Cyclic Peptide Synthetase Gene from Alternaria alternata Apple Pathotype Whose Product Is Involved in AM-Toxin Synthesis and Pathogenicity". Molecular Plant-Microbe Interactions 13 (7): 742–753. doi:10.1094/MPMI.2000.13.7.742. PMID 10875335.
  4. ↑ K. Turgay, M. Krause and M. A. Marahiel, Mol. Microbiol., 1992, 6, 529.
  5. ↑ Elizabeth A. Felnagle, John J. Barkei, Hyunjun Park, Angela M. Podevels, Matthew D. McMahon, Donald W. Drott, and Michael G. Thomas (2010). "MbtH-Like Proteins as Integral Components of Bacterial Nonribosomal Peptide Synthetases". Biochemistry 49: 8815–8817. doi:10.1021/bi1012854.
  6. ↑ Wenjun Zhang, John R. Heemstra Jr., Christopher T. Walsh, and Heidi J. Imker (2010). "Activation of the Pacidamycin PacL Adenylation Domain by MbtH-like Proteins". Biochemistry 49: 9946–9947. doi:10.1021/bi101539b.
  7. ↑ Novak, Jiri; Lemr, Karel; Schug, Kevin A.; Havlicek, Vladimir (2015). "CycloBranch: De Novo Sequencing of Nonribosomal Peptides from Accurate Product Ion Mass Spectra". J. Am. Soc. Mass Spectrom. 26 (10): 1780–1786. doi:10.1007/s13361-015-1211-1. PMID 26195308.
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