Biosynthetic Engineering

Polyketides are one of the largest classes of known bacterial natural products. Examples of bacterial polyketides that found applications in biomedicine include antibiotic erythromycin, immunosuppressant FK506, and anticancer epothilone. Type I, bacterial polyketide synthases (PKSs) are giant, multi-modular molecular machines that have been referred to as “molecular lego”. Individual catalytic units or domains are organized into modules, with each module being responsible for incorporation and processing of a particular building block in an assembly-line fashion. Structural diversity comes from the combinatorial use of i) the type and number of building blocks (activated carboxylic acid monomers); ii) the presence or absence of optional catalytic activities; and iii) the action of post-PKS, tailoring enzymes.

The modularity of polyketide biosynthesis offers tremendous opportunities for engineering further structural diversity and generating chemical novelty (1). In addition, polyketides are notoriously difficult to obtain synthetically, another argument for engineering and producing them by microbial fermentation.