Peptide synthetases

Figure 11.17 Hypothetical organization of an azinomycin B peptide synthetase.

It is likely that the biosynthesis of 113 is directed by a hybrid polyketide syn-thase/nonribosomal peptide synthetase enzyme system, as indicated in Figure 11.19. 

It is likely that the madurastatins are biosynthesized on a nonribosomal peptide synthetase, from salicylic acid as the starter acid. L-Serine is probably the precursor to the aziridine moiety, with epimerization occurring on the enzyme-bound amino acid as found for other nonribosomal peptides, with aziridine formation occurring at a late stage. Compounds 120 and 123 could therefore be biosynthetic precursors to 119 and 122, respectively. 

Mootz, H.D., Schwarzer, D. and Marahiel, M.A. (2002) Ways of assembling complex natural products on modular nonribosomal peptide synthetases. Chembiochem A European Journal of Chemical Biology, 3, 490. 

Ku, J., Mirmira, R.G., Liu, L. andSanti, D.V. (1997) Expression of a functional non-ribosomal peptide synthetase module in Escherichia coli by coexpression with a phosphopantetheinyl transferase. Chemistry Biology, 4 (3), 203-207. 

Cane, D.E. and Walsh, C.T. (1999) The parallel and convergent universes of polyketide synthases and nonribosomal peptide synthetases. Chemistry Biology, 6 (12), R319—R325. 

Trauger, J.W., Kohli, R.M. and Walsh, C.T. (2001) Cyclization of backbone-substituted peptides catalyzed by the thioesterase domain from the tyrocidine nonribosomal peptide synthetase. Biochemistry, 40 (24), 7092-7098. 

Weber, G., Schorgendorfer, K., Schneider-Scherzer, E. and Leitner, E. (1994) The peptide synthetase catalyzing cyclosporine production in Tolypocladium niveum is encoded by a giant 45.8-kilobase open reading frame. Current Genetics, 26 (2), 120-125. 

The biosynthetic hypothesis commences with the action of a nonribosomal peptide synthetase on natural amino acid precursors. While the incorporation of... 

Bacitracin biosynthesis requires a non-ribosomal peptide synthetase with three major protein components, BacABC. This synthetase has a modular structure. There are associated regulatory and transport systems. Biosynthesis of bacitracin has been engineered in the surrogate host, B. subtilis, by genetic techniques. A strain, B. subtilis KE 350, expresses the entire 49-kb bacitracin... 

Bacterial siderophores are typically small peptidic molecules, which contain side chains and functional groups that can provide high-affinity ligands for coordination of ferric ions. The structures of some siderophores are shown in Drechsel and Jung [142]. Siderophore synthesis occurs via enzymatic assembly by nonribosomal peptide synthetases [144], In bacteria, siderophore synthesis is... 

Acid-amino acid ligases (peptide synthetases)... 

Based on our current understanding of ribosomal protein synthesis, several strategies have been developed to incorporate amino acids other than the 20 standard proteinogenic amino acids into a peptide using the ribosomal machinery . This allows for the design of peptides with novel properties. On the one hand, such a system can be used to synthesize nonstandard peptides that are important pharmaceuticals. In nature, such peptides are produced by nonribosomal peptide synthetases, which operate in complex pathways. On the other hand, non-natural residues are a useful tool in biochemistry and biophysics to study proteins. For example, incorporation of non-natural residues by the ribosome allows for site-specific labeling of proteins with spin labels for electron paramagnetic resonance spectroscopy, with... 

Phosphopantetheine tethering is a posttranslational modification that takes place on the active site serine of carrier proteins - acyl carrier proteins (ACPs) and peptidyl carrier proteins (PCPs), also termed thiolation (T) domains - during the biosynthesis of fatty acids (FAs) (use ACPs) (Scheme 23), polyketides (PKs) (use ACPs) (Scheme 24), and nonribosomal peptides (NRPs) (use T domain) (Scheme 25). It is only after the covalent attachment of the 20-A Ppant arm, required for facile transfer of the various building block constituents of the molecules to be formed, that the carrier proteins can interact with the other components of the different multi-modular assembly lines (fatty acid synthases (FASs), polyketide synthases (PKSs), and nonribosomal peptide synthetases (NRPSs)) on which the compounds of interest are assembled. The structural organizations of FASs, PKSs, and NRPSs are analogous and can be divided into three broad classes the types I, II, and III systems. Even though the role of the carrier proteins is the same in all systems, their mode of action differs from one system to another. In the type I systems the carrier proteins usually only interact in cis with domains to which they are physically attached, with the exception of the PPTases and external type II thioesterase (TEII) domains that act in trans. In the type II systems the carrier proteins selectively interact... 

Introduction Peptide-Based Natural Products Nonribosomal Peptide Natural Products The Canonical Enzymology of NRPS Modules Classes of Nonribosomal Peptide Synthetases... 

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