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Volume 150, Issue 6

Substrate recognition by nonribosomal peptide synthetase multi-enzymes Free

Abstract

Nonribosomal peptide synthetases (NRPSs) are giant multi-domain enzymes that catalyse the biosynthesis of many commercially important peptides produced by bacteria and fungi. Several studies over the last decade have shown that many of the individual domains within NRPSs exhibit significant substrate selectivity, which impacts on our ability to engineer NRPSs to produce new bioactive microbial peptides. Adenylation domains appear to be the primary determinants of substrate selectivity in NRPSs. Much progress has been made towards an empirical understanding of substrate selection by these domains over the last 5 years, but the molecular basis of substrate selectivity in these domains is not yet well understood. Perhaps surprisingly, condensation domains have also been reported to exhibit moderate to high substrate selectivity, although the generality of this observation and its potential impact on engineered biosynthesis experiments has yet to be fully elucidated. The situation is less clear for the thioesterase domains, which seem in certain cases to be dedicated to the hydrolysis/cyclization of their natural substrate, whereas in other cases they are largely permissive.

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2004-06-01
2024-04-23
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References

  1. Ackerley D. F., Caradoc-Davies T. T., Lamont I. L. 2003; Substrate specificity of the non-ribosomal peptide synthetase PvdD from Pseudomonas aeruginosa. J Bacteriol 185:2848–2855 [CrossRef]
     [Google Scholar]
  2. Belshaw P. J., Walsh C. T., Stachelhaus T. 1999; Aminoacyl-CoAs as probes of condensation domain selectivity in nonribosomal peptide synthesis. Science 284:486–489 [CrossRef]
     [Google Scholar]
  3. Bentley S. D., Chater K. F., Cerdeno-Tarraga A. M.40 other authors 2002; Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147 [CrossRef]
     [Google Scholar]
  4. Bruner S. D., Weber T., Kohli R. M., Schwarzer D., Marahiel M. A., Walsh C. T., Stubbs M. T. 2002; Structural basis for the cyclization of the lipopeptide antibiotic surfactin by the thioesterase domain SrfTE. Structure (Camb 10:301–310 [CrossRef]
     [Google Scholar]
  5. Cerdeno A. M., Bibb M. J., Challis G. L. 2001; Analysis of the prodiginine biosynthesis gene cluster of Streptomyces coelicolor A3(2): new mechanisms for chain initiation and termination in modular multienzymes. Chem Biol 8:817–829 [CrossRef]
     [Google Scholar]
  6. Challis G. L., Ravel J. 2000; Coelichelin, a new peptide siderophore encoded by the Streptomyces coelicolor genome: structure prediction from the sequence of its non-ribosomal peptide synthetase. FEMS Microbiol Lett 187:111–114 [CrossRef]
     [Google Scholar]
  7. Challis G. L., Ravel J., Townsend C. A. 2000; Predictive, structure-based model of amino acid recognition by nonribosomal peptide synthetase adenylation domains. Chem Biol 7:211–224 [CrossRef]
     [Google Scholar]
  8. Conti E., Stachelhaus T., Marahiel M. A., Brick P. 1997; Structural basis for the activation of phenylalanine in the non-ribosomal biosynthesis of gramicidin S. EMBO J 16:4174–4183 [CrossRef]
     [Google Scholar]
  9. Doekel S., Marahiel M. A. 2000; Dipeptide formation on engineered hybrid peptide synthetases. Chem Biol 7:373–384 [CrossRef]
     [Google Scholar]
  10. Ehmann D. E., Trauger J. W., Stachelhaus T., Walsh C. T. 2000; Aminoacyl-SNACs as small-molecule substrates for the condensation domains of nonribosomal peptide synthetases. Chem Biol 7:765–772 [CrossRef]
     [Google Scholar]
  11. Eppelmann K., Stachelhaus T., Marahiel M. A. 2002; Exploitation of the selectivity-conferring code of nonribosomal peptide synthetases for the rational design of novel peptide antibiotics. Biochemistry 41:9718–9726 [CrossRef]
     [Google Scholar]
  12. Keating T. A., Marshall C. G., Walsh C. T., Keating A. E. 2002; The structure of VibH represents nonribosomal peptide synthetase condensation, cyclization and epimerization domains. Nat Struct Biol 9:522–526
     [Google Scholar]
  13. Kohli R. M., Trauger J. W., Schwarzer D., Marahiel M. A., Walsh C. T. 2001; Generality of peptide cyclization catalyzed by isolated thioesterase domains of nonribosomal peptide synthetases. Biochemistry 40:7099–7108 [CrossRef]
     [Google Scholar]
  14. Kohli R. M., Walsh C. T., Burkart M. D. 2002a; Biomimetic synthesis and optimization of cyclic peptide antibiotics. Nature 418:658–661 [CrossRef]
     [Google Scholar]
  15. Kohli R. M., Takagi J., Walsh C. T. 2002b; The thioesterase domain from a nonribosomal peptide synthetase as a cyclization catalyst for integrin binding peptides. Proc Natl Acad Sci U S A 99:1247–1252 [CrossRef]
     [Google Scholar]
  16. Linne U., Marahiel M. A. 2000; Control of directionality in nonribosomal peptide synthesis: role of the condensation domain in preventing misinitiation and timing of epimerization. Biochemistry 39:10439–10447 [CrossRef]
     [Google Scholar]
  17. Linne U., Stein D. B., Mootz H. D., Marahiel M. A. 2003; Systematic and quantitative analysis of protein-protein recognition between nonribosomal peptide synthetases investigated in the tyrocidine biosynthetic template. Biochemistry 42:5114–5124 [CrossRef]
     [Google Scholar]
  18. Luo L., Burkart M. D., Stachelhaus T., Walsh C. T. 2001; Substrate recognition and selection by the initiation module PheATE of gramicidin S synthetase. J Am Chem Soc 123:11208–11218 [CrossRef]
     [Google Scholar]
  19. Luo L., Kohli R. M., Onishi M., Linne U., Marahiel M. A., Walsh C. T. 2002; Timing of epimerization and condensation reactions in nonribosomal peptide assembly lines: kinetic analysis of phenylalanine activating elongation modules of tyrocidine synthetase B. Biochemistry 41:9184–9196 [CrossRef]
     [Google Scholar]
  20. Marshall C. G., Burkart M. D., Keating T. A., Walsh C. T. 2001; Heterocycle formation in vibriobactin biosynthesis: alternative substrate utilization and identification of a condensed intermediate. Biochemistry 40:10655–10663 [CrossRef]
     [Google Scholar]
  21. Marshall C. G., Burkart M. D., Meray R. K., Walsh C. T. 2002; Carrier protein recognition in siderophore-producing nonribosomal peptide synthetases. Biochemistry 41:8429–8437 [CrossRef]
     [Google Scholar]
  22. May J. J., Kessler N., Marahiel M. A., Stubbs M. T. 2002; Crystal structure of DhbE, an archetype for aryl acid activating domains of modular nonribosomal peptide synthetases. Proc Natl Acad Sci U S A 99:12120–12125 [CrossRef]
     [Google Scholar]
  23. Peypoux F., Michel G. 1992; Controlled biosynthesis of Val7- and Leu7-surfactins. Appl Microbiol Biotechnol 36:515–517
     [Google Scholar]
  24. Ruttenberg M. A., Mach B. 1966; Studies on amino acid substitution in the biosynthesis of the antibiotic polypeptide tyrocidine. Biochemistry 5:2864–2869 [CrossRef]
     [Google Scholar]
  25. Schwarzer D., Mootz H. D., Marahiel M. A. 2001; Exploring the impact of different thioesterase domains for the design of hybrid peptide synthetases. Chem Biol 8:997–1010 [CrossRef]
     [Google Scholar]
  26. Stachelhaus T., Mootz H. D., Marahiel M. A. 1999; The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases. Chem Biol 6:493–505 [CrossRef]
     [Google Scholar]
  27. Thomas M. G., Burkart M. D., Walsh C. T. 2002; Conversion of l-proline to pyrrolyl-2-carboxyl-S-PCP during undecylprodigiosin and pyoluteorin biosynthesis. Chem Biol 9:171–184 [CrossRef]
     [Google Scholar]
  28. Trauger J. W., Kohli R. M., Mootz H. D., Marahiel M. A., Walsh C. T. 2000; Peptide cyclization catalysed by the thioesterase domain of tyrocidine synthetase. Nature 407:215–218 [CrossRef]
     [Google Scholar]
  29. Trauger J. W., Kohli R. M., Walsh C. T. 2001; Cyclization of backbone-substituted peptides catalyzed by the thioesterase domain from the tyrocidine nonribosomal peptide synthetase. Biochemistry 40:7092–7098 [CrossRef]
     [Google Scholar]
  30. Tseng C. C., Bruner S. D., Kohli R. M., Marahiel M. A., Walsh C. T., Sieber S. A. 2002; Characterization of the surfactin synthetase C-terminal thioesterase domain as a cyclic depsipeptide synthase. Biochemistry 41:13350–13359 [CrossRef]
     [Google Scholar]
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Substrate recognition by nonribosomal peptide synthetase multi-enzymes
Microbiology 150, 1629 (2004); https://doi.org/10.1099/mic.0.26837-0
/content/journal/micro/10.1099/mic.0.26837-0
/content/journal/micro/10.1099/mic.0.26837-0
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