Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Reinvigorating natural product combinatorial biosynthesis with synthetic biology

Nature Chemical Biology volume 11, pages 649–659 (2015)Cite this article

Subjects

An Erratum to this article was published on 20 October 2015

This article has been updated

Abstract

Natural products continue to play a pivotal role in drug-discovery efforts and in the understanding of human health. The ability to extend nature's chemistry through combinatorial biosynthesis—altering functional groups, regiochemistry and scaffold backbones through the manipulation of biosynthetic enzymes—offers unique opportunities to create natural product analogs. Incorporating emerging synthetic biology techniques has the potential to further accelerate the refinement of combinatorial biosynthesis as a robust platform for the diversification of natural chemical drug leads. Two decades after the field originated, we discuss the current limitations, the realities and the state of the art of combinatorial biosynthesis, including the engineering of substrate specificity of biosynthetic enzymes and the development of heterologous expression systems for biosynthetic pathways. We also propose a new perspective for the combinatorial biosynthesis of natural products that could reinvigorate drug discovery by using synthetic biology in combination with synthetic chemistry.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structures of novel natural products generated by engineering the substrate specificity of biosynthetic enzymes.
Figure 2: General strategies for the combinatorial biosynthesis of PKs and NRPs.
Figure 3: Approaches to assembling natural product biosynthetic pathways.
Figure 4: The structures of novel or cryptic natural products produced by heterologous expression or chemobiosynthesis.
Figure 5: Representative synthetic biology tools for optimization of the expression of combinatorially assembled biosynthetic machineries.
Figure 6: Representative synthetic biology tools for optimization of producing hosts.

Similar content being viewed by others

Change history

  • 23 September 2015

    In the version of this article initially published, there were four typographical errors in the abstract and main text. The errors have been corrected in the HTML and PDF versions of the article.

References

  1. Hopwood, D.A. et al. Production of 'hybrid' antibiotics by genetic engineering. Nature 314, 642–644 (1985).

    Article  CAS  PubMed  Google Scholar 

  2. Newman, D.J. & Cragg, G.M. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75, 311–335 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Robles, O. & Romo, D. Chemo- and site-selective derivatizations of natural products enabling biological studies. Nat. Prod. Rep. 31, 318–334 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Li, J.W. & Vederas, J.C. Drug discovery and natural products: end of an era or an endless frontier? Science 325, 161–165 (2009).

    Article  PubMed  CAS  Google Scholar 

  5. Huang, K.X., Xia, L., Zhang, Y., Ding, X. & Zahn, J.A. Recent advances in the biochemistry of spinosyns. Appl. Microbiol. Biotechnol. 82, 13–23 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Schwarzer, D., Finking, R. & Marahiel, M.A. Nonribosomal peptides: from genes to products. Nat. Prod. Rep. 20, 275–287 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. McDaniel, R. et al. Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel “unnatural” natural products. Proc. Natl. Acad. Sci. USA 96, 1846–1851 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. McDaniel, R., Ebert-Khosla, S., Hopwood, D.A. & Khosla, C. Engineered biosynthesis of novel polyketides. Science 262, 1546–1550 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Nguyen, K.T. et al. Combinatorial biosynthesis of novel antibiotics related to daptomycin. Proc. Natl. Acad. Sci. USA 103, 17462–17467 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Baltz, R.H. Combinatorial biosynthesis of cyclic lipopeptide antibiotics: a model for synthetic biology to accelerate the evolution of secondary metabolite biosynthetic pathways. ACS Synth. Biol. 3, 748–758 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Sugimoto, Y., Ding, L., Ishida, K. & Hertweck, C. Rational design of modular polyketide synthases: morphing the aureothin pathway into a luteoreticulin assembly line. Angew. Chem. Int. Edn Engl. 53, 1560–1564 (2014).

    Article  CAS  Google Scholar 

  13. Wang, P., Kim, W., Pickens, L.B., Gao, X. & Tang, Y. Heterologous expression and manipulation of three tetracycline biosynthetic pathways. Angew. Chem. Int. Edn Engl. 51, 11136–11140 (2012).

    Article  CAS  Google Scholar 

  14. Wilson, M.C. & Moore, B.S. Beyond ethylmalonyl-CoA: the functional role of crotonyl-CoA carboxylase/reductase homologs in expanding polyketide diversity. Nat. Prod. Rep. 29, 72–86 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Giessen, T.W. & Marahiel, M.A. Ribosome-independent biosynthesis of biologically active peptides: Application of synthetic biology to generate structural diversity. FEBS Lett. 586, 2065–2075 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Eustáquio, A.S. et al. Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-L-methionine. Proc. Natl. Acad. Sci. USA 106, 12295–12300 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Mo, S. et al. Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues. J. Am. Chem. Soc. 133, 976–985 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Yan, Y. et al. Multiplexing of combinatorial chemistry in antimycin biosynthesis: expansion of molecular diversity and utility. Angew. Chem. Int. Edn Engl. 52, 12308–12312 (2013).

    Article  CAS  Google Scholar 

  21. Sundermann, U. et al. Enzyme-directed mutasynthesis: a combined experimental and theoretical approach to substrate recognition of a polyketide synthase. ACS Chem. Biol. 8, 443–450 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Koryakina, I. et al. Poly specific trans-acyltransferase machinery revealed via engineered acyl-CoA synthetases. ACS Chem. Biol. 8, 200–208 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Thirlway, J. et al. Introduction of a non-natural amino acid into a nonribosomal peptide antibiotic by modification of adenylation domain specificity. Angew. Chem. Int. Edn Engl. 51, 7181–7184 (2012).

    Article  CAS  Google Scholar 

  24. Kries, H. et al. Reprogramming nonribosomal peptide synthetases for “clickable” amino acids. Angew. Chem. Int. Edn Engl. 53, 10105–10108 (2014).

    Article  CAS  Google Scholar 

  25. Evans, B.S., Chen, Y., Metcalf, W.W., Zhao, H. & Kelleher, N.L. Directed evolution of the nonribosomal peptide synthetase AdmK generates new andrimid derivatives in vivo. Chem. Biol. 18, 601–607 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Piel, J. Biosynthesis of polyketides by trans-AT polyketide synthases. Nat. Prod. Rep. 27, 996–1047 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Walker, M.C. et al. Expanding the fluorine chemistry of living systems using engineered polyketide synthase pathways. Science 341, 1089–1094 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dunn, B.J. & Khosla, C. Engineering the acyltransferase substrate specificity of assembly line polyketide synthases. J. R. Soc. Interface 10, 20130297 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Fischbach, M.A., Lai, J.R., Roche, E.D., Walsh, C.T. & Liu, D.R. Directed evolution can rapidly improve the activity of chimeric assembly-line enzymes. Proc. Natl. Acad. Sci. USA 104, 11951–11956 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Dutta, S. et al. Structure of a modular polyketide synthase. Nature 510, 512–517 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Whicher, J.R. et al. Structural rearrangements of a polyketide synthase module during its catalytic cycle. Nature 510, 560–564 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Johnson, M.N., Londergan, C.H. & Charkoudian, L.K. Probing the phosphopantetheine arm conformations of acyl carrier proteins using vibrational spectroscopy. J. Am. Chem. Soc. 136, 11240–11243 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ross, A.C. et al. Biosynthetic multitasking facilitates thalassospiramide structural diversity in marine bacteria. J. Am. Chem. Soc. 135, 1155–1162 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kapur, S. et al. Reprogramming a module of the 6-deoxyerythronolide B synthase for iterative chain elongation. Proc. Natl. Acad. Sci. USA 109, 4110–4115 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gokhale, R.S., Tsuji, S.Y., Cane, D.E. & Khosla, C. Dissecting and exploiting intermodular communication in polyketide synthases. Science 284, 482–485 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Broadhurst, R.W. et al. The structure of docking domains in modular polyketide synthases. Chem. Biol. 10, 723–731 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Whicher, J.R. et al. Cyanobacterial polyketide synthase docking domains: a tool for engineering natural product biosynthesis. Chem. Biol. 20, 1340–1351 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Ongley, S.E., Bian, X., Neilan, B.A. & Müller, R. Recent advances in the heterologous expression of microbial natural product biosynthetic pathways. Nat. Prod. Rep. 30, 1121–1138 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Charlop-Powers, Z., Milshteyn, A. & Brady, S.F. Metagenomic small molecule discovery methods. Curr. Opin. Microbiol. 19, 70–75 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Bachmann, B.O., Van Lanen, S.G. & Baltz, R.H. Microbial genome mining for accelerated natural products discovery: is a renaissance in the making? J. Ind. Microbiol. Biotechnol. 41, 175–184 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Thaker, M.N. & Wright, G.D. Opportunities for synthetic biology in antibiotics: expanding glycopeptide chemical diversity. ACS Synth. Biol. 4, 195–206 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Cobb, R.E., Ning, J.C. & Zhao, H. DNA assembly techniques for next-generation combinatorial biosynthesis of natural products. J. Ind. Microbiol. Biotechnol. 41, 469–477 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Gibson, D.G. Programming biological operating systems: genome design, assembly and activation. Nat. Methods 11, 521–526 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Zhang, Y., Muyrers, J.P., Testa, G. & Stewart, A.F. DNA cloning by homologous recombination in Escherichia coli. Nat. Biotechnol. 18, 1314–1317 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Fu, J. et al. Full-length RecE enhances linear-linear homologous recombination and facilitates direct cloning for bioprospecting. Nat. Biotechnol. 30, 440–446 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Kouprina, N. & Larionov, V. TAR cloning: insights into gene function, long-range haplotypes and genome structure and evolution. Nat. Rev. Genet. 7, 805–812 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Feng, Z., Kim, J.H. & Brady, S.F. Fluostatins produced by the heterologous expression of a TAR reassembled environmental DNA derived type II PKS gene cluster. J. Am. Chem. Soc. 132, 11902–11903 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Feng, Z., Kallifidas, D. & Brady, S.F. Functional analysis of environmental DNA-derived type II polyketide synthases reveals structurally diverse secondary metabolites. Proc. Natl. Acad. Sci. USA 108, 12629–12634 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yamanaka, K. et al. Direct cloning and refactoring of a silent lipopeptide biosynthetic gene cluster yields the antibiotic taromycin A. Proc. Natl. Acad. Sci. USA 111, 1957–1962 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gust, B., Challis, G.L., Fowler, K., Kieser, T. & Chater, K.F. PCR-targeted Streptomyces gene replacement identifies a protein domain needed for biosynthesis of the sesquiterpene soil odor geosmin. Proc. Natl. Acad. Sci. USA 100, 1541–1546 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shao, Z., Luo, Y. & Zhao, H. Rapid characterization and engineering of natural product biosynthetic pathways via DNA assembler. Mol. Biosyst. 7, 1056–1059 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gibson, D.G. et al. Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat. Methods 6, 343–345 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Li, M.Z. & Elledge, S.J. SLIC: a method for sequence- and ligation-independent cloning. Methods Mol. Biol. 852, 51–59 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Kushnir, S. et al. Minimally invasive mutagenesis gives rise to a biosynthetic polyketide library. Angew. Chem. Int. Edn Engl. 51, 10664–10669 (2012).

    Article  CAS  Google Scholar 

  57. Song, M.C. et al. Microbial biosynthesis of medicinally important plant secondary metabolites. Nat. Prod. Rep. 31, 1497–1509 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Gomez-Escribano, J.P. & Bibb, M.J. Engineering Streptomyces coelicolor for heterologous expression of secondary metabolite gene clusters. Microb. Biotechnol. 4, 207–215 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Komatsu, M., Uchiyama, T., Omura, S., Cane, D.E. & Ikeda, H. Genome-minimized Streptomyces host for the heterologous expression of secondary metabolism. Proc. Natl. Acad. Sci. USA 107, 2646–2651 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhou, M. et al. Sequential deletion of all the polyketide synthase and nonribosomal peptide synthetase biosynthetic gene clusters and a 900-kb subtelomeric sequence of the linear chromosome of Streptomyces coelicolor. FEMS Microbiol. Lett. 333, 169–179 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Komatsu, M. et al. Engineered Streptomyces avermitilis host for heterologous expression of biosynthetic gene cluster for secondary metabolites. ACS Synth. Biol. 2, 384–396 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rodriguez, E. et al. Rapid engineering of polyketide overproduction by gene transfer to industrially optimized strains. J. Ind. Microbiol. Biotechnol. 30, 480–488 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Li, C., Hazzard, C., Florova, G. & Reynolds, K.A. High titer production of tetracenomycins by heterologous expression of the pathway in a Streptomyces cinnamonensis industrial monensin producer strain. Metab. Eng. 11, 319–327 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Pfeifer, B.A., Admiraal, S.J., Gramajo, H., Cane, D.E. & Khosla, C. Biosynthesis of complex polyketides in a metabolically engineered strain of E. coli. Science 291, 1790–1792 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Zhang, H., Wang, Y., Wu, J., Skalina, K. & Pfeifer, B.A. Complete biosynthesis of erythromycin A and designed analogs using E. coli as a heterologous host. Chem. Biol. 17, 1232–1240 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Watanabe, K. et al. Total biosynthesis of antitumor nonribosomal peptides in Escherichia coli. Nat. Chem. Biol. 2, 423–428 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Bian, X. et al. Direct cloning, genetic engineering, and heterologous expression of the syringolin biosynthetic gene cluster in E. coli through Red/ET recombineering. ChemBioChem 13, 1946–1952 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Ross, A.C., Gulland, L.E., Dorrestein, P.C. & Moore, B.S. Targeted capture and heterologous expression of the Pseudoalteromonas alterochromide gene cluster in Escherichia coli represents a promising natural product exploratory platform. ACS Synth. Biol. 4, 414–420 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. Liu, J., Zhu, X., Seipke, R.F. & Zhang, W. Biosynthesis of antimycins with a reconstituted 3-formamidosalicylate pharmacophore in Escherichia coli. ACS Synth. Biol. 4, 559–565 (2015).

    Article  PubMed  CAS  Google Scholar 

  70. Ro, D.K. et al. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440, 940–943 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Brown, S., Clastre, M., Courdavault, V. & O'Connor, S.E. De novo production of the plant-derived alkaloid strictosidine in yeast. Proc. Natl. Acad. Sci. USA 112, 3205–3210 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ma, S.M. et al. Complete reconstitution of a highly reducing iterative polyketide synthase. Science 326, 589–592 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chiang, Y.M. et al. An efficient system for heterologous expression of secondary metabolite genes in Aspergillus nidulans. J. Am. Chem. Soc. 135, 7720–7731 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mutka, S.C., Carney, J.R., Liu, Y. & Kennedy, J. Heterologous production of epothilone C and D in Escherichia coli. Biochemistry 45, 1321–1330 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Oßwald, C. et al. Modular construction of a functional artificial epothilone polyketide pathway. ACS Synth. Biol. 3, 759–772 (2014).

    Article  PubMed  CAS  Google Scholar 

  76. Dueber, J.E. et al. Synthetic protein scaffolds provide modular control over metabolic flux. Nat. Biotechnol. 27, 753–759 (2009).

    Article  CAS  Google Scholar 

  77. Delebecque, C.J., Lindner, A.B., Silver, P.A. & Aldaye, F.A. Organization of intracellular reactions with rationally designed RNA assemblies. Science 333, 470–474 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Conrado, R.J. et al. DNA-guided assembly of biosynthetic pathways promotes improved catalytic efficiency. Nucleic Acids Res. 40, 1879–1889 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Temme, K. et al. Modular control of multiple pathways using engineered orthogonal T7 polymerases. Nucleic Acids Res. 40, 8773–8781 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Salis, H.M., Mirsky, E.A. & Voigt, C.A. Automated design of synthetic ribosome binding sites to control protein expression. Nat. Biotechnol. 27, 946–950 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Siegl, T., Tokovenko, B., Myronovskyi, M. & Luzhetskyy, A. Design, construction and characterisation of a synthetic promoter library for fine-tuned gene expression in actinomycetes. Metab. Eng. 19, 98–106 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Ran, F.A. et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281–2308 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang, H.H. et al. Programming cells by multiplex genome engineering and accelerated evolution. Nature 460, 894–898 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bao, Z. et al. Homology-integrated CRISPR-Cas (HI-CRISPR) system for one-step multigene disruption in Saccharomyces cerevisiae. ACS Synth. Biol. 4, 585–594 (2014).

    Article  PubMed  CAS  Google Scholar 

  86. Jiang, W., Bikard, D., Cox, D., Zhang, F. & Marraffini, L.A. RNA-guided editing of bacterial genomes using CRISPR-Cas systems. Nat. Biotechnol. 31, 233–239 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cobb, R.E., Wang, Y. & Zhao, H. High-efficiency multiplex genome editing of Streptomyces species using an engineered CRISPR/Cas system. ACS Synth. Biol. 4, 723–728 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Uguru, G.C. et al. Synthetic RNA silencing of actinorhodin biosynthesis in Streptomyces coelicolor A3(2). PLoS ONE 8, e67509 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Na, D. et al. Metabolic engineering of Escherichia coli using synthetic small regulatory RNAs. Nat. Biotechnol. 31, 170–174 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Deb Roy, A., Grüschow, S., Cairns, N. & Goss, R.J. Gene expression enabling synthetic diversification of natural products: chemogenetic generation of pacidamycin analogs. J. Am. Chem. Soc. 132, 12243–12245 (2010).

    Article  PubMed  CAS  Google Scholar 

  91. Arnison, P.G. et al. Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature. Nat. Prod. Rep. 30, 108–160 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Park, S.R., Park, J.W., Ban, Y.H., Sohng, J.K. & Yoon, Y.J. 2-Deoxystreptamine-containing aminoglycoside antibiotics: recent advances in the characterization and manipulation of their biosynthetic pathways. Nat. Prod. Rep. 30, 11–20 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Kirby, J. & Keasling, J.D. Metabolic engineering of microorganisms for isoprenoid production. Nat. Prod. Rep. 25, 656–661 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Xu, W., Gavia, D.J. & Tang, Y. Biosynthesis of fungal indole alkaloids. Nat. Prod. Rep. 31, 1474–1487 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Schmidt, E.W. et al. Patellamide A and C biosynthesis by a microcin-like pathway in Prochloron didemni, the cyanobacterial symbiont of Lissoclinum patella. Proc. Natl. Acad. Sci. USA 102, 7315–7320 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ruffner, D.E., Schmidt, E.W. & Heemstra, J.R. Assessing the combinatorial potential of the RiPP cyanobactin tru pathway. ACS Synth. Biol. 4, 482–492 (2015).

    Article  CAS  PubMed  Google Scholar 

  97. Medema, M.H., van Raaphorst, R., Takano, E. & Breitling, R. Computational tools for the synthetic design of biochemical pathways. Nat. Rev. Microbiol. 10, 191–202 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Birmingham, W.R. et al. Bioretrosynthetic construction of a didanosine biosynthetic pathway. Nat. Chem. Biol. 10, 392–399 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank K. Rathwell for critically reading this manuscript. Research in Y.J.Y.'s laboratory has been supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (MISP) (2013R1A2A1A01014230), the Intelligent Synthetic Biology Center of the Global Frontier Project funded by MISP (20110031961), the High Value-added Food Technology Development Program, Ministry of Agriculture, Food and Rural Affairs, Republic of Korea, and the National Research Council of Science and Technology through the Degree & Research Center program (DRC-14-3-KBSI). Combinatorial biosynthetic work in B.S.M.'s laboratory is supported by US National Institutes of Health grants R01-CA127622 and R01-GM085770.

Author information

Authors and Affiliations

  1. Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea

    Eunji Kim & Yeo Joon Yoon

  2. Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California, USA.,

    Bradley S Moore

  3. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California, USA.,

    Bradley S Moore

Authors
  1. Eunji Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bradley S Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yeo Joon Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Bradley S Moore or Yeo Joon Yoon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, E., Moore, B. & Yoon, Y. Reinvigorating natural product combinatorial biosynthesis with synthetic biology. Nat Chem Biol 11, 649–659 (2015). https://doi.org/10.1038/nchembio.1893

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.1893

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research