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Reinvigorating natural product combinatorial biosynthesis with synthetic biology

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.

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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.

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.

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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.

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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

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