scholarly journals Recent advances in engineering nonribosomal peptide assembly lines

2016 ◽  
Vol 33 (2) ◽  
pp. 317-347 ◽  
Author(s):  
M. Winn ◽  
J. K. Fyans ◽  
Y. Zhuo ◽  
J. Micklefield
Keyword(s):  
Assembly Lines ◽  
New Techniques ◽  
Nonribosomal Peptide ◽  
Nonribosomal Peptide Synthetases ◽  
Peptide Synthetases ◽  
Peptide Assembly ◽  
Recent Advances ◽  
Tailoring Enzymes

This reviews summarises progress towards the engineering of nonribosomal peptide synthetases (NRPS) from the expression of heterologous tailoring enzymes to direct modifications of the assembly lines to produce analogues. New techniques/tools for introducing changes are also examined.

scholarly journals In Vivo Production of Artificial Nonribosomal Peptide Products in the Heterologous Host Escherichia coli

2004 ◽  
Vol 70 (6) ◽  
pp. 3282-3291 ◽  
Author(s):  
Stephan Gruenewald ◽  
Henning D. Mootz ◽  
Per Stehmeier ◽  
Torsten Stachelhaus
Keyword(s):  
Escherichia Coli ◽  
Single Amino Acid ◽  
Modular Organization ◽  
Cyclic Dipeptide ◽  
Assembly Lines ◽  
Heterologous Host ◽  
Nonribosomal Peptide ◽  
Nonribosomal Peptide Synthetases ◽  
E Coli ◽  
Peptide Synthetases

ABSTRACT Nonribosomal peptide synthetases represent the enzymatic assembly lines for the biosynthesis of pharmacologically relevant natural peptides, e.g., cyclosporine, vancomycin, and penicillin. Due to their modular organization, in which every module accounts for the incorporation of a single amino acid, artificial assembly lines for the production of novel peptides can be constructed by biocombinatorial approaches. Once transferred into an appropriate host, these hybrid synthetases could facilitate the bioproduction of basically any peptide-based molecule. In the present study, we describe the fermentative production of the cyclic dipeptide d-Phe-Pro-diketopiperazine, as a prototype for the exploitation of the heterologous host Escherichia coli, and the use of artificial nonribosomal peptide synthetases. E. coli provides a tremendous potential for genetic engineering and was manipulated in our study by stable chromosomal integration of the 4′-phosphopantetheine transferase gene sfp to ensure heterologous production of fully active holoenzmyes. d-Phe-Pro-diketopiperazine is formed by the TycA/TycB1 system, whose components represent the first two modules for tyrocidine biosynthesis in Bacillus brevis. Coexpression of the corresponding genes in E. coli gave rise to the production of the expected diketopiperazine product, demonstrating the functional interaction of both modules in the heterologous environment. Furthermore, the cyclic dipeptide is stable and not toxic to E. coli and is secreted into the culture medium without the need for any additional factors. Parameters affecting the productivity were comprehensively investigated, including various genetic setups, as well as variation of medium composition and temperature. By these means, the overall productivity of the artificial system could be enhanced by over 400% to yield about 9 mg of d-Phe-Pro-diketopiperazine/liter. As a general tool, this approach could allow the sustainable bioproduction of peptides, e.g., those used as pharmaceuticals or fine chemicals.

scholarly journals Nonprocessive [2 + 2]e- off-loading reductase domains from mycobacterial nonribosomal peptide synthetases

2012 ◽  
Vol 109 (15) ◽  
pp. 5681-5686 ◽  
Author(s):  
A. Chhabra ◽  
A. S. Haque ◽  
R. K. Pal ◽  
A. Goyal ◽  
R. Rai ◽  
...  
Keyword(s):  
Nonribosomal Peptide ◽  
Nonribosomal Peptide Synthetases ◽  
Peptide Synthetases

scholarly journals Core Assembly Mechanism of Quinocarcin/SF-1739: Bimodular Complex Nonribosomal Peptide Synthetases for Sequential Mannich-type Reactions

2013 ◽  
Vol 20 (12) ◽  
pp. 1523-1535 ◽  
Author(s):  
Tomoshige Hiratsuka ◽  
Kento Koketsu ◽  
Atsushi Minami ◽  
Shunsuke Kaneko ◽  
Chiaki Yamazaki ◽  
...  
Keyword(s):  
Nonribosomal Peptide ◽  
Nonribosomal Peptide Synthetases ◽  
Peptide Synthetases ◽  
Assembly Mechanism

Kinetics Profiling of Gramicidin S Synthetase A, a Member of Nonribosomal Peptide Synthetases

Biochemistry ◽  
2014 ◽  
Vol 53 (50) ◽  
pp. 7983-7989 ◽  
Author(s):  
Xun Sun ◽  
Hao Li ◽  
Jonas Alfermann ◽  
Henning D. Mootz ◽  
Haw Yang
Keyword(s):  
Nonribosomal Peptide ◽  
Nonribosomal Peptide Synthetases ◽  
Peptide Synthetases ◽  
Gramicidin S
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