Metabolic engineering for the production of natural products

Abstract

Natural products and their derivatives play an important role in modern healthcare as frontline treatments for many diseases and as inspiration for chemically synthesized therapeutics. With advances in sequencing and recombinant DNA technology, many of the biosynthetic pathways responsible for the production of these chemically complex yet valuable compounds have been elucidated. With an ever-expanding toolkit of biosynthetic components, metabolic engineering is an increasingly powerful method to improve natural product titers and generate novel compounds. Heterologous production platforms have enabled access to pathways from difficult to culture strains, systems biology and metabolic modeling tools have resulted in increasing predictive and analytic capabilities, advances in expression systems and regulation have enabled the fine-tuning of pathways for increased efficiency, and characterization of individual pathway components has facilitated the construction of hybrid pathways for the production of new compounds. These advances in the many aspects of metabolic engineering not only have yielded fascinating scientific discoveries but also make it an increasingly viable approach for the optimization of natural product biosynthesis.

Figure 1

Major classes of natural products. PK – polyketide, NRP – non-ribosomal peptide.

Figure 2

General metabolic engineering strategies for improvement of product titer.

Figure 3

Examples of pathway engineering and combinatorial biosynthesis to generate new analogs: A. exchange of 6-deoxyerythronolide synthase (DEBS) AT2 and KR6 domains with rapAT2 and rapDH/KR4 domains from rapamycin synthase (RAPS) (123). B. exchange of daptomycin Dpt module 11 and subunit DptD with corresponding module and subunit from A54145 pathway (LptABCD) (128). Loading module and subunit DptA are not shown as it is unchanged and the parent daptomycin structure is shown in Figure 1. C. swapping of tailoring genes clo-hal (halogenase) and novO (methyltransferase) between clorobiocin and novobiocin pathways (110).