Nonribosomal peptide synthesis

Sieber, S.A. and Marahiel, M.A. (2005) Molecular mechanisms underlying nonribosomal peptide synthesis approaches to new antibiotics. Chemical Reviews, 105, 715. 

The binding affinity of carbohydrate-mimetic peptides can be quite high, often higher than the natural carbohydrate ligand. Carbohydrate-mimetic peptides do not share any general chemical features, and all amino acid residues are represented there is no evidence for an unusual importance of aromatic residues in mimicry. In several cases, o-amino acids have been incorporated, and unusual amino acids (derived from nonribosomal peptide synthesis) have been found in naturally occurring carbohydrate-mimetic peptides. 

Marahiel MA, Stachelhaus T and Mootz HD (1997) Modular peptide synthetases involved in nonribosomal peptide synthesis. Chem Rev 97, 2651-2673. 

P Belshaw, CT Walsh, T Stachelhaus. Aminoacyl-CoAs as probes of condensation domain selectivity in nonribosomal peptide synthesis. Science 284 486 489, 1999. 

Figure 1 Comparison of ribosomal and nonribosomal peptide synthesis.

Stein DB, Linne U, Hahn M, Marahiel MA. Impact of epimer- 24. ization domains on the intermodular transfer of enzyme-bound intermediates in nonribosomal peptide synthesis. ChemBioChem. 2006 7 1807-1814. 

Bergendahl, V., Linne, U., and Marahiel, M.A. (2002) Mutational analysis of the C-domain in nonribosomal peptide synthesis. Eur. 

CPs are integral components of various primary and secondary metabolic pathways, including fatty acid synthesis (FAS), nonribosomal peptide synthesis (NRPS), polyketide synthesis (PKS), and lysine biosynthesis. All CPs harbor... 

Each case will provide important advances and significant obstacles. As we will see, progress toward true combinatorial biosynthesis continues to advance and with it, our understanding of polyketide and nonribosomal peptide synthesis on the whole. 

The isolated TE domain from the tyrocidine (tyc) NRPS has recently been shown to catalyze the macrocyclization of unnatural substrates to generate a variety of cyclic peptides. In conjunction with standard solid-phase peptide synthesis, Walsh and coworkers demonstrated a broad substrate tolerance for peptidyl-N-acetylcysteamine thioesters by the tyrocidine TE [41,42], Cyclization of peptide analogs, where individual amino acids were replaced with ethylene glycol units, was observed with high efficiency. In addition, hydroxyacid starter units were readily cyclized by the isolated TE domain to form nonribosomal peptide-derived macrolactones. More recently, Walsh and coworkers have demonstrated effective cyclization of PEGA resin-bound peptide/polyketide hybrids by the tyrocidine TE domain [43], Utilization of a pantetheine mimic for covalent attachment of small molecules to the resin, serves as an appropriate recognition domain for the enzyme. As peptide macrocyclizations remain challenging in the absence of enzymatic assistance, this approach promises facile construction of previously unattainable structures. 

S. McLoughlin, N. Kelleher, Kinetic and regiospecific interrogation of covalent intermediates in the nonribosomal peptide synthesis of yersiniabactin, J. Am. Chem. Soc. 2004, 126,13265-13275. 

Marahiel M A, Stachelhaus T, Mootz H D (1997). Modular peptide synthases involved in nonribosomal peptide synthesis. Chem. Rev. 97 2651-2673. 

Figure 7. General scheme of nonribosomal peptide synthesis (NRPS). Each NRPS module incorporates one amino acid into the growing peptide chain. The modules are composed of several domains Adenylation domain (red) is responsible for substrate selectivity, peptidyl carrier protein domain (orange) and condensation domain (green) work synergistically to form the peptide bond, and thioester domain (blue) which terminates the reaction, resulting in either a linear or cyclic polypeptide.

Amides and esters are particularly important in biological systems. The phosphate and pyrophosphate derivatives found in DNA and RNA were illustrated in Section 20.12. The structure and chemistry of these compounds will be elaborated upon in Chapter 28. Peptides (discussed in Chapter 27, Section 27.4) are polymers composed of discrete amino acid units. They are joined together by so-called peptide bonds, which are actually amide bonds. Many natural peptides are produced by bacteria via nonribosomal peptide synthesis. Bacillus subtilis produces the heptapeptide surfactin (224), which has antibiotic and antifungal activity. ... 

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