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Information about Nonribosomal Peptide

Nonribosomal peptides (NRP) are a class of secondary metabolites, usually produced by microorganisms like bacteria and fungi. These are also often found in higher organisms, such as nudibranchs but they are thought to be made by bacteria inside these organisms. Note that although there are many peptides which are not made on the ribosome, nonribosomal peptide typically refers to a very specific set of these as discussed in this article.

Unlike polypeptides synthesized on the ribosome, these peptides are synthesized by nonribosomal peptide synthetases (NRPS) from amino acids. NRPS can be thought of as preassembled, modular, molecular factories. Unlike the ribosome, which is fed an mRNA code and can make an arbitrary sequence of peptides, an NRPS does not accept a code and is preset to make one peptide. As a class, NRPS can make a wider diversity of peptides than can ribosomes.

NRPs often have a cyclic and/or branched structure, 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 on dehydroalanine. This is just a sampling of the various manipulations and variations that NRPS can perform. NRPs 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.

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. 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.

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 ATP as a mixed acyl-phosphoric acid anhydride with AMP by the A-domain and loaded onto the 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.
  • Condensation: The C-domain catalyzes the amide bond formation between the 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.
  • Condensation-Cyclization: Sometimes the C-domain is replaced by a Cy-domain which, in addition to the amide bond formation, catalyzes the reaction of the serine, threonine, or cysteine sidechain with the amide-N, thereby forming oxazolidines and thiazolidine, respectively.
  • 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) hydrolyzes the completed polypeptide chain from the ACP-domain of the previous module, thereby often forming cyclic amides (lactams) or cyclic esters (lactones).
  • Alternatively, the peptide can be released by an R-domain that reduces the thioester bond to terminal aldehyde or alcohol.

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-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 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 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 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
Secondary metabolites are organic compounds that are not directly involved in the normal growth, development or reproduction of organisms. Unlike primary metabolites, absence of secondary metabolities results not in immediate death, but in long-term impairment of the organism's
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microorganism (also spelled as microrganism) or microbe is an organism that is microscopic (too small to be seen by the human eye). The study of microorganisms is called microbiology.
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Bacteria

Phyla

Actinobacteria
Aquificae
Chlamydiae
Bacteroidetes/Chlorobi
Chloroflexi
Chrysiogenetes
Cyanobacteria
Deferribacteres
Deinococcus-Thermus
Dictyoglomi
Fibrobacteres/Acidobacteria
Firmicutes
Fusobacteria
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Eukarya
Whittaker & Margulis, 1978
(unranked) Opisthokonta

Kingdom: Fungi
(L., 1753) R.T. Moore, 1980[1]

Subkingdom/Phyla

Chytridiomycota
Blastocladiomycota

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Nudibranchia

Infraorders

Anthobranchia
Cladobranchia
See text for superfamilies.

Nudibranchs (ˈnü-də-ˌbraŋk, ˈnyü-), also known as sea slugs, are soft-bodied marine snails belonging to the suborder
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A ribosome is a small, dense, functional structure found in most known cells that assemble proteins and polypeptides used in cell division. It catalyses the assembly of individual amino acids into polypeptide chains by reading messenger RNAs and binding amino acids that are
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A ribosome is a small, dense, functional structure found in most known cells that assemble proteins and polypeptides used in cell division. It catalyses the assembly of individual amino acids into polypeptide chains by reading messenger RNAs and binding amino acids that are
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Peptides (from the Greek πεπτίδια, "small digestibles") are short polymers formed from the linking, in a defined order, of α-amino acids.
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In biochemistry, a ligase (from the Latin verb ligāre — "to bind" or "to glue together") is an enzyme that can catalyse the joining of two large molecules by forming a new chemical bond, usually with accompanying hydrolysis of a small chemical group pendant to
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amino acid is a molecule that contains both amine and carboxyl functional groups. In biochemistry, this term refers to alpha-amino acids with the general formula H2NCHRCOOH, where R is an organic substituent.
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In organic chemistry, a cyclic compound is one in which a series of carbon atoms are connected together to form a loop or ring. Benzene is a well known example.

The term "polycyclic" is used when more than one ring is combined in a single molecule, and the term "macrocycle"
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Proteinogenic amino acids, also known as standard, normal, or primary amino acids, are those 20 amino acids that are found in proteins and that are coded for in the standard genetic code. Proteinogenic literally means protein building.
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3, 5, 4, 2
(strongly acidic oxide)
Electronegativity 3.04 (Pauling scale)
Ionization energies
(more) 1st: 1402.3 kJmol−1
2nd: 2856 kJmol−1
3rd: 4578.1 kJmol−1

Atomic radius 65 pm
Atomic radius (calc.
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Glycosylation is the process or result of addition of saccharides to proteins and lipids. The process is one of four principal co-translational and post-translational modification steps in the synthesis of membrane and secreted proteins and the majority of proteins synthesized in
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In chemistry, acylation (rarely, but more formally: alkanoylation) is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent.
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Halogenation is a chemical reaction that incorporates a halogen atom into a molecule. More specific descriptions exist that specify the type of halogen: fluorination, chlorination, bromination, and iodination.
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Hydroxylation is any chemical process that introduces one or more hydroxyl groups (-OH) into a compound (or radical) thereby oxidizing it. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases.
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Serine (abbreviated as Ser or S)[1] is an organic compound with the formula HO2CCH(NH2)CH2OH. It is one of the 20 naturally occurring proteinogenic amino acids. Its codons are UCU, UCC, UCA, UCG, AGU and AGC.
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dimer refers to a molecule composed of two identical subunits or monomers linked together.

Chemistry

The molecules in a dimer are connected by covalent bonds or weaker interactions such as hydrogen bonds.
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Trimer might refer to:
  • trimer (chemistry), a reaction product composed of three identical molecules
  • trimer (biochemistry), a compound of three macromolecules non-covalently bound
  • Trimer, a commune of the Ille-et-Vilaine département, in France

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A Siderophore (Greek for iron carrier) is an iron chelating compound secreted by microorganisms. Iron Fe3+ ions have a very low solubility at neutral pH and therefore cannot be utilized by organisms.
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pigment is a material that changes the color of light it reflects as the result of selective color absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which the material itself emits light.
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antibiotic is a chemotherapeutic agent that inhibits or abolishes the growth of micro-organisms, such as bacteria, fungi, or protozoans. The term originally referred to any agent with biological activity against living organisms; however, "antibiotic" now is used to refer to
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Chemotherapy is the use of chemical substances to treat disease. In its modern-day use, it refers to cytotoxic drugs used to treat cancer or the combination of these drugs into a standardized treatment regimen.
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Immunosuppressive drugs or immunosuppressants are drugs that are used in immunosuppressive therapy to inhibit or prevent activity of the immune system. Clinically they are used to:
  • prevent the rejection of transplanted organs and tissues (e.g.

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antibiotic is a chemotherapeutic agent that inhibits or abolishes the growth of micro-organisms, such as bacteria, fungi, or protozoans. The term originally referred to any agent with biological activity against living organisms; however, "antibiotic" now is used to refer to
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Bacitracin is a mixture of related cyclic polypeptides produced by organisms of the licheniformis group of Bacillus subtilis var Tracy. Its unique name derives from the fact that the bacillus producing it was first isolated in 1943 from a knee scrape from
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Vancomycin (INN) (IPA: [ˌvæŋkoˈmaɪsən]) is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria.
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antibiotic is a chemotherapeutic agent that inhibits or abolishes the growth of micro-organisms, such as bacteria, fungi, or protozoans. The term originally referred to any agent with biological activity against living organisms; however, "antibiotic" now is used to refer to
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Penicillin (sometimes abbreviated PCN) is a group of beta-lactam antibiotics used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms.
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