The DEBS paradigm for type I modular polyketide synthases and beyond

Polyketides are natural products that form the basis of numerous human and veterinary drugs. The biosynthesis of complex polyketides is carried out by polyketide synthases (PKSs), enzymes composed of multifunctional polypeptides that are assembled into large protein complexes. Nucleotide sequencing revealed that the PKS that produces the polyketide backbone of the antibiotic erythromycin, DEBS (for 6-deoxyerythronolide B synthase), contains a discrete domain for every enzymatic step of the corresponding biochemical pathway, that the domains are organized into modules each corresponding to a single extension (condensation and beta-carbonyl processing) step in the biochemical pathway, that the organization of the domains is consistent from module to module, that faithful production of the polyketide 6-dEB requires that the domains are always used and never bypassed, that the PKS does not contain additional domains that are not used, and that the domains are organized in a linear array in the order of use in the biosynthesis of 6-dEB. Taken together, these properties are often referred to as the DEBS paradigm. In this chapter, the biosyntheses of numerous polyketides will be described to highlight the generalizability of the DEBS paradigm, but also to illustrate the range of deviations from the paradigm so far found in nature that contribute to product versatility.