Chapter 10: Engineering Enzymes for Natural Product Biosynthesis and Diversification
Published:31 May 2018
F. Twigg, D. Skyrud, J. Li, and W. Zhang, in Modern Biocatalysis: Advances Towards Synthetic Biological Systems, ed. G. Williams and M. Hall, The Royal Society of Chemistry, 2018, ch. 10, pp. 261-286.
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This chapter covers current approaches to engineering enzymes in natural product biosynthetic pathways. Focus is given to nonribosomal peptide synthetases and polyketide synthases, both of which are known for their assembly line like production of secondary metabolites. Progress towards piecing together new modular systems has the potential to create cellular manufactories with broad access to relevant chemical compounds not readily available by synthetic means due to their complex molecular scaffolds and unique chemical entities. Both in vivo and in vitro approaches are considered in this chapter with their distinct advantages and limitations in rationally designing mutant megasynthases to produce novel natural product derivatives. The concepts crucial for the success of existing engineered systems may be extended towards many different biosynthetic pathways. Additionally, this chapter covers the application of the directed evolution approach to rapidly evolve these megasynthases when rational models are insufficient for design.