Mining and engineering natural-product biosynthetic pathways

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Abstract

Natural products continue to fulfill an important role in the development of therapeutic agents. In addition, with the advent of chemical genetics and high-throughput screening platforms, these molecules have become increasingly valuable as tools for interrogating fundamental aspects of biological systems. To access the vast portion of natural-product structural diversity that remains unexploited for these and other applications, genome mining and microbial metagenomic approaches are proving particularly powerful. When these are coupled with recombineering and related genetic tools, large biosynthetic gene clusters that remain intractable or cryptic in the native host can be more efficiently cloned and expressed in a suitable heterologous system. For lead optimization and the further structural diversification of natural-product libraries, combinatorial biosynthetic engineering has also become indispensable. However, our ability to rationally redesign biosynthetic pathways is often limited by our lack of understanding of the structure, dynamics and interplay between the many enzymes involved in complex biosynthetic pathways. Despite this, recent structures of fatty acid synthases should allow a more accurate prediction of the likely architecture of related polyketide synthase and nonribosomal peptide synthetase multienzymes.

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Figure 1
Figure 2
Figure 3: Combinatorial assembly of PKS modules through synthetic biology.
Figure 4: The fungal FAS is another biomolecular motor.
Figure 5
Figure 6: General two-step strategy for the transglycosylation of calicheamicin using the native glycosyltransferase CalG1.
Figure 7: Production of the antimalarial drug precursor artemisinic acid in engineered yeast and its chemical conversion to the active species artemisinin.

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Acknowledgements

J.M. thanks the Biotechnology and Biological Sciences Research Council for support of biosynthetic engineering research through grants and studentships (36/B12126 and BB/C503662). S. Moss (Biotica) and M. Gregory (Biotica) are also acknowledged for proofreading the manuscript.

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Competing interests

B.W. works for and has financial interests in Biotica, a drug discovery company that uses biosynthetic engineering technology. J.M. has no competing financial interests.

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Wilkinson, B., Micklefield, J. Mining and engineering natural-product biosynthetic pathways. Nat Chem Biol 3, 379–386 (2007) doi:10.1038/nchembio.2007.7

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