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Recent Advances in Re-engineering Modular PKS and NRPS Assembly Lines

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Abstract

Polyketides such as the antibiotic erythromycin or the immunosuppressant rapamycin, and non-ribosomal peptides, such as the antibiotics penicillin or vancomycin, are important classes of natural products. The core of these molecules are biosynthesized by large polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS), respectively. The modular architecture of these enzymatic assembly lines makes them interesting candidates for synthetic biology approaches. The re-engineering efforts aim to understand the molecular structure, produce new compounds, produce analogs of known compounds, tag the products or improve activity and/or yield. Here, we first consider the definition of PKS and NRPS modules, then give an overview of different strategies for re-engineering and finally review recent examples of PKS and NRPS reengineering.

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References

  1. Weber, T., P. Charusanti, E. M. Musiol-Kroll, X. Jiang, Y. Tong, H. U. Kim, and S. Y. Lee (2015) Metabolic engineering of antibiotic factories: new tools for antibiotic production in actinomycetes. Trends Biotechnol. 33: 15–26.

    Article  CAS  PubMed  Google Scholar 

  2. Palazzotto, E., Y. Tong, S. Y. Lee, and T. Weber (2019) Synthetic biology and metabolic engineering of actinomycetes for natural product discovery. Biotechnol. Adv. 37: 107366.

    Article  CAS  PubMed  Google Scholar 

  3. Robertsen, H. L., T. Weber, H. U. Kim, and S. Y. Lee (2018) Toward systems metabolic engineering of streptomycetes for secondary metabolites production. Biotechnol. J. 13: 1700465.

    Article  CAS  Google Scholar 

  4. Donadio, S., M. J. Staver, J. B. Mcalpine, S. J. Swanson, and L. Katz (1991) Modular organization of genes required for complex polyketide biosynthesis. Science. 252: 675–679.

    Article  CAS  PubMed  Google Scholar 

  5. Mach, B., E. Reich, and E. L. Tatum (1963) Separation of the biosynthesis of the antibiotic polypeptide tyrocidine from protein biosynthesis. Proc. Natl. Acad. Sci. USA. 50: 175–181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hertweck, C. (2009) The biosynthetic logic of polyketide diversity. Angew. Chem. Int. Ed. Engl. 48: 4688–4716.

    Article  CAS  PubMed  Google Scholar 

  7. Süssmuth, R. D. and A. Mainz (2017) Nonribosomal peptide synthesis-Principles and prospects. Angew. Chem. Int. Ed. Engl. 56: 3770–3821.

    Article  PubMed  CAS  Google Scholar 

  8. Gulick, A. M. (2009) Conformational dynamics in the Acyl-CoA synthetases, adenylation domains of non-ribosomal peptide synthetases, and firefly luciferase. ACS Chem. Biol. 4: 811–827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Keatinge-Clay, A. T. (2012) The structures of type I polyketide synthases. Nat. Prod. Rep. 29: 1050–1073.

    Article  CAS  PubMed  Google Scholar 

  10. Stein, T., J. Vater, V. Kruft, A. Otto, B. Wittmann-Liebold, P. Franke, M. Panico, R. McDowell, and H. R. Morris (1996) The multiple carrier model of nonribosomal peptide biosynthesis at modular multienzymatic templates. J. Biol. Chem. 271: 15428–15435.

    Article  CAS  PubMed  Google Scholar 

  11. Kornfuehrer, T. and A. S. Eustáquio (2019) Diversification of polyketide structures via synthase engineering. Med. Chem. Commun. 10: 1256–1272.

    Article  CAS  Google Scholar 

  12. Alanjary, M., C. Cano-Prieto, H. Gross, and M. H. Medema (2019) Computer-aided re-engineering of nonribosomal peptide and polyketide biosynthetic assembly lines. Nat. Prod. Rep. 36: 1249–1261.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang, L., T. Hashimoto, B. Qin, J. Hashimoto, I. Kozone, T. Kawahara, M. Okada, T. Awakawa, T. Ito, Y. Asakawa, M. Ueki, S. Takahashi, H. Osada, T. Wakimoto, H. Ikeda, K. Shin-Ya, and I. Abe (2017) Characterization of giant modular PKSs provides insight into genetic mechanism for structural diversification of aminopolyol polyketides. Angew. Chem. Int. Ed. Engl. 56: 1740–1745.

    Article  CAS  PubMed  Google Scholar 

  14. Keatinge-Clay, A. T. (2017) Polyketide synthase modules redefined. Angew. Chem. Int. Ed. Engl. 56: 4658–4660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nivina, A., K. P. Yuet, J. Hsu, and C. Khosla (2019) Evolution and diversity of assembly-line polyketide synthases. Chem. Rev. 119: 12524–12547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vander Wood, D. A. and A. T. Keatinge-Clay (2018) The modules of trans-acyltransferase assembly lines redefined with a central acyl carrier protein. Proteins. 86: 664–675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bozhüyük, K. A. J., A. Linck, A. Tietze, J. Kranz, F. Wesche, S. Nowak, F. Fleischhacker, Y. N. Shi, P. Grün, and H. B. Bode (2019) Modification and de novo design of non-ribosomal peptide synthetases using specific assembly points within condensation domains. Nat. Chem. 11: 653–661.

    Article  PubMed  CAS  Google Scholar 

  18. Tanovic, A., S. A. Samel, L. O. Essen, and M. A. Marahiel (2008) Crystal structure of the termination module of a nonribosomal peptide synthetase. Science. 321: 659–663.

    Article  CAS  PubMed  Google Scholar 

  19. Bozhüyük, K. A. J., F. Fleischhacker, A. Linck, F. Wesche, A. Tietze, C. P. Niesert, and H. B. Bode (2018) De novo design and engineering of non-ribosomal peptide synthetases. Nat. Chem. 10: 275–281.

    Article  PubMed  CAS  Google Scholar 

  20. Moss, S. J., C. J. Martin, and B. Wilkinson (2004) Loss of colinearity by modular polyketide synthases: a mechanism for the evolution of chemical diversity. Nat. Prod. Rep. 21: 575–593.

    Article  CAS  PubMed  Google Scholar 

  21. Blin, K., S. Shaw, K. Steinke, R. Villebro, N. Ziemert, S. Y. Lee, M. H. Medema, and T. Weber (2019) antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res. 47: W81–W87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Eng, C. H., T. W. H. Backman, C. B. Bailey, C. Magnan, H. García Martín, L. Katz, P. Baldi, and J. D. Keasling (2018) ClusterCAD: a computational platform for type I modular polyketide synthase design. Nucleic Acids Res. 46: D509–D515.

    Article  CAS  PubMed  Google Scholar 

  23. Barajas, J. F., J. M. Blake-Hedges, C. B. Bailey, S. Curran, and J. D. Keasling (2017) Engineered polyketides: Synergy between protein and host level engineering. Synth. Syst. Biotechnol. 2: 147–166.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Birch, A. J. (1963) The biosynthesis of antibiotics. Pure Appl. Chem. 7: 527–538.

    Article  CAS  Google Scholar 

  25. Musiol-Kroll, E. M., F. Zubeil, T. Schafhauser, T. Härtner, A. Kulik, J. McArthur, I. Koryakina, W. Wohlleben, S. Grond, G. J. Williams, S. Y. Lee, and T. Weber (2017) Polyketide bioderivatization using the promiscuous acyltransferase KirCII. ACS Synth. Biol. 6: 421–427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lowden, P. A. S., G. A. Böhm, S. Metcalfe, J. Staunton, and P. F. Leadlay (2004) New rapamycin derivatives by precursor-directed biosynthesis. Chembiochem. 5: 535–538.

    Article  CAS  PubMed  Google Scholar 

  27. Bister, B., D. Bischoff, G. J. Nicholson, S. Stockert, J. Wink, C. Brunati, S. Donadio, S. Pelzer, W. Wohlleben, and R. D. Süssmuth (2003) Bromobalhimycin and chlorobromobalhimycins-illuminating the potential of halogenases in glycopeptide antibiotic biosyntheses. Chembiochem. 4: 658–662.

    Article  CAS  PubMed  Google Scholar 

  28. Rinehart, K. L. (1977) Mutasynthesis of new antibiotics. Pure Appl. Chem. 49: 1361–1384.

    Article  CAS  Google Scholar 

  29. Dutton, C. J., S. P. Gibson, A. C. Goudie, K. S. Holdom, M. S. Pacey, J. C. Ruddock, J. D. Bu’Lock, and M. K. Richards (1991) Novel avermectins produced by mutational biosynthesis. J. Antibiot. 44: 357–365.

    Article  CAS  Google Scholar 

  30. Eustáquio, A. S. and B. S. Moore (2008) Mutasynthesis of fluorosalinosporamide, a potent and reversible inhibitor of the proteasome. Angew. Chem. Int. Ed. Engl. 47: 3936–3938.

    Article  PubMed  CAS  Google Scholar 

  31. Sundermann, U., K. Bravo-Rodriguez, S. Klopries, S. Kushnir, H. Gomez, E. Sanchez-Garcia, and F. Schulz (2013) Enzyme-directed mutasynthesis: a combined experimental and theoretical approach to substrate recognition of a polyketide synthase. ACS Chem. Biol. 8: 443–450.

    Article  CAS  PubMed  Google Scholar 

  32. Challis, G. L., J. Ravel, and C. A. Townsend (2000) Predictive, structure-based model of amino acid recognition by nonribosomal peptide synthetase adenylation domains. Chem. Biol. 7: 211–224.

    Article  CAS  PubMed  Google Scholar 

  33. Stachelhaus, T., H. D. Mootz, and M. A. Marahiel (1999) The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases. Chem. Biol. 6: 493–505.

    Article  CAS  PubMed  Google Scholar 

  34. Musiol-Kroll, E. M. and W. Wohlleben (2018) Acyltransferases as tools for polyketide synthase engineering. Antibiotics (Basel). 7: 62.

    Article  CAS  PubMed Central  Google Scholar 

  35. Wang, F., Y. Wang, J. Ji, Z. Zhou, J. Yu, H. Zhu, Z. Su, L. Zhang, and J. Zheng (2015) Structural and functional analysis of the loading acyltransferase from avermectin modular polyketide synthase. ACS Chem. Biol. 10: 1017–1025.

    Article  CAS  PubMed  Google Scholar 

  36. Thirlway, J., R. Lewis, L. Nunns, M. Al Nakeeb, M. Styles, A. W. Struck, C. P. Smith, and J. Micklefield (2012) Introduction of a non-natural amino acid into a nonribosomal peptide antibiotic by modification of adenylation domain specificity. Angew. Chem. Int. Ed. Engl. 51: 7181–7184.

    Article  CAS  PubMed  Google Scholar 

  37. Koryakina, I., C. Kasey, J. B. McArthur, A. N. Lowell, J. A. Chemler, S. Li, D. A. Hansen, D. H. Sherman, and G. J. Williams (2017) Inversion of extender unit selectivity in the erythromycin polyketide synthase by acyltransferase domain engineering. ACS Chem. Biol. 12: 114–123.

    Article  CAS  PubMed  Google Scholar 

  38. Villiers, B. and F. Hollfelder (2011) Directed evolution of a gatekeeper domain in nonribosomal peptide synthesis. Chem. Biol. 18: 1290–1299.

    Article  CAS  PubMed  Google Scholar 

  39. Kalkreuter, E., J. M. CroweTipton, A. N. Lowell, D. H. Sherman, and G. J. Williams (2019) Engineering the substrate specificity of a modular polyketide synthase for installation of consecutive non-natural extender units. J. Am. Chem. Soc. 141: 1961–1969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kushnir, S., U. Sundermann, S. Yahiaoui, A. Brockmeyer, P. Janning, and F. Schulz (2012) Minimally invasive mutagenesis gives rise to a biosynthetic polyketide library. Angew. Chem. Int. Ed. Engl. 51: 10664–10669.

    Article  CAS  PubMed  Google Scholar 

  41. Watanabe, K., K. Hotta, A. P. Praseuth, M. Searcey, C. C. C. Wang, H. Oguri, and H. Oikawa (2009) Rationally engineered total biosynthesis of a synthetic analogue of a natural quinomycin depsipeptide in Escherichia coli. Chembiochem. 10: 1965–1968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Koch, A. A., D. A. Hansen, V. V. Shende, L. R. Furan, K. N. Houk, G. Jiménez-Osés, and D. H. Sherman (2017) A single active site mutation in the pikromycin thioesterase generates a more effective macrocyclization catalyst. J. Am. Chem. Soc. 139: 13456–13465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hopwood, D. A., F. Malpartida, H. M. Kieser, H. Ikeda, J. Duncan, I. Fujii, B. A. M. Rudd, H. G. Floss, and S. Omura (1985) Production of ‘hybrid’ antibiotics by genetic engineering. Nature. 314: 642–644.

    Article  CAS  PubMed  Google Scholar 

  44. Petkovic, H., R. E. Lill, R. M. Sheridan, B. Wilkinson, E. L. McCormick, H. A. I. McArthur, J. Staunton, P. F. Leadlay, and S. G. Kendrew (2003) A novel erythromycin, 6-desmethyl erythromycin D, made by substituting an acyltransferase domain of the erythromycin polyketide synthase. J. Antibiot. 56: 543–551.

    Article  CAS  Google Scholar 

  45. Calcott, M. J., J. G. Owen, I. L. Lamont, and D. F. Ackerley (2014) Biosynthesis of novel pyoverdines by domain substitution in a nonribosomal peptide synthetase of Pseudomonas aeruginosa. Appl. Environ. Microbiol. 80: 5723–5731.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Tripathi, A., S. S. Choi, D. H. Sherman, and E. S. Kim (2016) Thioesterase domain swapping of a linear polyketide tautomycetin with a macrocyclic polyketide pikromycin in Streptomyces sp. CK4412. J. Ind. Microbiol. Biotechnol. 43: 1189–1193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Annaval, T., C. Paris, P. F. Leadlay, C. Jacob, and K. J. Weissman (2015) Evaluating ketoreductase exchanges as a means of rationally altering polyketide stereochemistry. Chembiochem. 16: 1357–1364.

    Article  CAS  PubMed  Google Scholar 

  48. Marsden, A. F. A., B. Wilkinson, J. Cortés, N. J. Dunster, J. Staunton, and P. F. Leadlay (1998) Engineering broader specificity into an antibiotic-producing polyketide synthase. Science. 279: 199–202.

    Article  CAS  PubMed  Google Scholar 

  49. Kim, M. S., W. J. Cho, M. C. Song, S. W. Park, K. Kim, E. Kim, N. Lee, S. J. Nam, K. H. Oh, and Y. J. Yoon (2017) Engineered biosynthesis of milbemycins in the avermectin high-producing strain Streptomyces avermitilis. Microb. Cell Fact. 16: 9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Mootz, H. D., N. Kessler, U. Linne, K. Eppelmann, D. Schwarzer, and M. A. Marahiel (2002) Decreasing the ring size of a cyclic nonribosomal peptide antibiotic by in-frame module deletion in the biosynthetic genes. J. Am. Chem. Soc. 124: 10980–10981.

    Article  CAS  PubMed  Google Scholar 

  51. Butz, D., T. Schmiederer, B. Hadatsch, W. Wohlleben, T. Weber, and R. D. Süssmuth (2008) Module extension of a non-ribosomal peptide synthetase of the glycopeptide antibiotic balhimycin produced by Amycolatopsis balhimycina. Chembiochem. 9: 1195–1200.

    Article  CAS  PubMed  Google Scholar 

  52. Reeves, C. D., S. L. Ward, W. P. Revill, H. Suzuki, M. Marcus, O. V. Petrakovsky, S. Marquez, H. Fu, S. D. Dong, and L. Katz (2004) Production of hybrid 16-membered macrolides by expressing combinations of polyketide synthase genes in engineered Streptomyces fradiae hosts. Chem. Biol. 11: 1465–1472.

    Article  CAS  PubMed  Google Scholar 

  53. Miao, V., M. F. Coëffet-Le Gal, K. Nguyen, P. Brian, J. Penn, A. Whiting, J. Steele, D. Kau, S. Martin, R. Ford, T. Gibson, M. Bouchard, S. K. Wrigley, and R. H. Baltz (2006) Genetic engineering in Streptomyces roseosporus to produce hybrid lipopeptide antibiotics. Chem. Biol. 13: 269–276.

    Article  CAS  PubMed  Google Scholar 

  54. Hahn, M. and T. Stachelhaus (2004) Selective interaction between nonribosomal peptide synthetases is facilitated by short communication-mediating domains. Proc. Natl. Acad. Sci. USA. 101: 15585–15590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Werneburg, M., B. Busch, J. He, M. E. A. Richter, L. Xiang, B. S. Moore, M. Roth, H. M. Dahse, and C. Hertweck (2010) Exploiting enzymatic promiscuity to engineer a focused library of highly selective antifungal and antiproliferative aureothin analogues. J. Am. Chem. Soc. 132: 10407–10413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Olano, C., C. Méndez, and J. A. Salas (2010) Post-PKS tailoring steps in natural product-producing actinomycetes from the perspective of combinatorial biosynthesis. Nat. Prod. Rep. 27: 571–616.

    Article  CAS  PubMed  Google Scholar 

  57. Yin, X., Y. Chen, L. Zhang, Y. Wang, and T. M. Zabriskie (2010) Enduracidin analogues with altered halogenation patterns produced by genetically engineered strains of Streptomyces fungicidicus. J. Nat. Prod. 73: 583–589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yuzawa, S., K. Deng, G. Wang, E. E. K. Baidoo, T. R. Northen, P. D. Adams, L. Katz, and J. D. Keasling (2017) Comprehensive in vitro analysis of acyltransferase domain exchanges in modular polyketide synthases and its application for short-chain ketone production. ACS Synth. Biol. 6: 139–147.

    Article  CAS  PubMed  Google Scholar 

  59. Kendrew, S. G., H. Petkovic, S. Gaisser, S. J. Ready, M. A. Gregory, N. J. Coates, M. Nur-E-Alam, T. Warneck, D. Suthar, T. A. Foster, L. McDonald, G. Schlingman, F. E. Koehn, J. S. Skotnicki, G. T. Carter, S. J. Moss, M. Q. Zhang, C. J. Martin, R. M. Sheridan, and B. Wilkinson (2013) Recombinant strains for the enhanced production of bioengineered rapalogs. Metab. Eng. 15: 167–173.

    Article  CAS  PubMed  Google Scholar 

  60. Zhu, X., J. Liu, and W. Zhang (2015) De novo biosynthesis of terminal alkyne-labeled natural products. Nat. Chem. Biol. 11: 115–120.

    Article  CAS  PubMed  Google Scholar 

  61. Porterfield, W. B., N. Poenateetai, and W. Zhang (2020) Engineered biosynthesis of alkyne-tagged polyketides by type I PKSs. iScience. 23: 100938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Miyazawa, T., M. Hirsch, Z. Zhang, and A. T. Keatinge-Clay (2020) An in vitro platform for engineering and harnessing modular polyketide synthases. Nat. Commun. 11: 80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dutta, S., J. R. Whicher, D. A. Hansen, W. A. Hale, J. A. Chemler, G. R. Congdon, A. R. H. Narayan, K. Håkansson, D. H. Sherman, J. L. Smith, and G. Skiniotis (2014) Structure of a modular polyketide synthase. Nature. 510: 512–517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Whicher, J. R., S. Dutta, D. A. Hansen, W. A. Hale, J. A. Chemler, A. M. Dosey, A. R. H. Narayan, K. Håkansson, D. H. Sherman, J. L. Smith, and G. Skiniotis (2014) Structural rearrangements of a polyketide synthase module during its catalytic cycle. Nature. 510: 560–564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Risser, F., S. Collin, R. Dos Santos-Morais, A. Gruez, B. Chagot, and K. J. Weissman (2020) Towards improved understanding of intersubunit interactions in modular polyketide biosynthesis: Docking in the enacyloxin IIa polyketide synthase. J. Struct. Biol. 212: 107581.

    Article  CAS  PubMed  Google Scholar 

  66. Niquille, D. L., D. A. Hansen, and D. Hilvert (2019) Reprogramming nonribosomal peptide synthesis by surgical mutation. Synlett. 30: 2123–2130.

    Article  CAS  Google Scholar 

  67. Calcott, M. J., J. G. Owen, and D. F. Ackerley (2020) Efficient rational modification of non-ribosomal peptides by adenylation domain substitution. Nat. Commun. 11: 4554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yan, F., C. Burgard, A. Popoff, N. Zaburannyi, G. Zipf, J. Maier, H. S. Bernauer, S. C. Wenzel, and R. Müller (2018) Synthetic biology approaches and combinatorial biosynthesis towards heterologous lipopeptide production. Chem. Sci. 9: 7510–7519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bozhüyük, K. A., J. Micklefield, and B. Wilkinson (2019) Engineering enzymatic assembly lines to produce new antibiotics. Curr. Opin. Microbiol. 51: 88–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Yu, D., F. Xu, S. Zhang, and J. Zhan (2017) Decoding and reprogramming fungal iterative nonribosomal peptide synthetases. Nat. Commun. 8: 15349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Steiniger, C., S. Hoffmann, A. Mainz, M. Kaiser, K. Voigt, V. Meyer, and R. D. Süssmuth (2017) Harnessing fungal nonribosomal cyclodepsipeptide synthetases for mechanistic insights and tailored engineering. Chem. Sci. 8: 7834–7843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Awakawa, T., T. Fujioka, L. Zhang, S. Hoshino, Z. Hu, J. Hashimoto, I. Kozone, H. Ikeda, K. Shin-Ya, W. Liu, and I. Abe (2018) Reprogramming of the antimycin NRPS-PKS assembly lines inspired by gene evolution. Nat. Commun. 9: 3534.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Samel, S. A., G. Schoenafinger, T. A. Knappe, M. A. Marahiel, and L. O. Essen (2007) Structural and functional insights into a peptide bond-forming bidomain from a nonribosomal peptide synthetase. Structure. 15: 781–792.

    Article  CAS  PubMed  Google Scholar 

  74. Tarry, M. J., A. S. Haque, K. H. Bui, and T. M. Schmeing (2017) X-ray crystallography and electron microscopy of cross- and multi-module nonribosomal peptide synthetase proteins reveal a flexible architecture. Structure. 25: 783–793.e4.

    Article  CAS  PubMed  Google Scholar 

  75. Reimer, J. M., M. Eivaskhani, I. Harb, A. Guarné, M. Weigt, and T. M. Schmeing (2019) Structures of a dimodular nonribosomal peptide synthetase reveal conformational flexibility. Science. 366: eaaw4388.

    Article  CAS  PubMed  Google Scholar 

  76. Liu, H., L. Gao, J. Han, Z. Ma, Z. Lu, C. Dai, C. Zhang, and X. Bie (2016) Biocombinatorial synthesis of novel lipopeptides by COM domain-mediated reprogramming of the plipastatin NRPS complex. Front. Microbiol. 7: 1801.

    PubMed  PubMed Central  Google Scholar 

  77. Hacker, C., X. Cai, C. Kegler, L. Zhao, A. K. Weickhmann, J. P. Wurm, H. B. Bode, and J. Wöhnert (2018) Structure-based redesign of docking domain interactions modulates the product spectrum of a rhabdopeptide-synthesizing NRPS. Nat. Commun. 9: 4366.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Cai, X., L. Zhao, and H. B. Bode (2019) Reprogramming promiscuous nonribosomal peptide synthetases for production of specific peptides. Org. Lett. 21: 2116–2120.

    Article  CAS  PubMed  Google Scholar 

  79. Kegler, C. and H. B. Bode (2020) Artificial splitting of a non-ribosomal peptide synthetase by inserting natural docking domains. Angew. Chem. Int. Ed. Engl. 59: 13463–13467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Tong, Y., T. Weber, and S. Y. Lee (2019) CRISPR/Cas-based genome engineering in natural product discovery. Nat. Prod. Rep. 36: 1262–1280.

    Article  CAS  PubMed  Google Scholar 

  81. Klaus, M., A. D. D’Souza, A. Nivina, C. Khosla, and M. Grininger (2019) Engineering of chimeric polyketide synthases using SYNZIP docking domains. ACS Chem. Biol. 14: 426–433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bozhüyük, K. A. J., J. Watzel, N. Abbood, and H. B. Bode (2020) Synthetic zippers as an enabling tool for engineering of non-ribosomal peptide synthetases. bioRxiv.https://doi.org/10.1101/2020.05.06.080655.

  83. Huang, H. M., P. Stephan, and H. Kries (2020) Engineering DNA templated nonribosomal peptide synthesis. bioRxiv.https://doi.org/10.1101/2020.07.27.223297.

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Acknowledgments

The work of the authors is supported by grants of the Novo Nordisk Foundation [NNF10CC1016517, NNF16OC0021746]. The authors declare no conflict of interest.

Neither ethical approval nor informed consent was required for this study.

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  1. The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet, Building 220, 2800, Kgs. Lyngby, Denmark

    Charlotte Beck, Jaime Felipe Guerrero Garzón & Tilmann Weber

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Beck, C., Garzón, J.F.G. & Weber, T. Recent Advances in Re-engineering Modular PKS and NRPS Assembly Lines. Biotechnol Bioproc E 25, 886–894 (2020). https://doi.org/10.1007/s12257-020-0265-5

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