The modular nature of these proteins provides an opportunity to replace or substitute individual domains or entire modules to produce a non-natural PKS that will introduce different polyketide units or alter the stereochemistry or functionality in the macrocycle. For instance, the loading domain (AT-ACP) of DEBS1 was replaced by the loading module from the avermectin PKS. This alternative loading module accepts a wider range of starting units such as isobutryrate and 2-methylbutyrate in addition to the acetate and propionyl units accepted by the DEBS1 loading module.
In another example, module 2 from the rapamycin PKS gene cluster was inserted into the eryAI gene that encodes DEBS1. The resulting non-natural synthase produced several new compounds including polyketides with a larger macrolactone, derived from an octaketide.