in regards to erythromycin derivatives as well as completely new polyketides generated by various means of engineering the modular complex. There are five general methods in which DEBS is regularly modified: 1. Deletion or inactivation of active sites and modules 2. Substitution or addition of active sites and modules 3. Precursor-directed biosynthesis 4. KR replacement for altered stereospecificity 5. Tailoring enzyme modifications Deletion or inactivation of active sites and modules The first reported instance of genetic engineering of DEBS came in 1991 from the Katz group who deleted the activity of the KR in module 5 of DEBS which produced a 5-keto macrolide instead of the usual 5-hydroxy macrolide. Since then, deletion or inactivation (often via introduction of point mutations) of many active sites to skip reduction and/or dehydration reactions have been created. Such modifications target the various KR, DH, ER active sites seen on different modules in DEBS. In fact, whole modules can be deleted in order to reduce the chain-length of the polyketides and alter the cycle of reduction/dehydration normally seen. Substitution or addition of active sites and modules In one of the first reorganizations of DEBS, a copy of the terminal TE was placed at the end of each module in separate trials, which as predicted resulted in the cleavage and release of the correspondingly shortened products. Following this, ever more complex methods were devised for the addition or substitution of single or multiple active sites to the DEBS complex. The most common method of engineering DEBS as of 2005 is AT substitution, in which the native AT domain is replaced with an AT specific for a different primer or extender molecule. Under normal circumstances, DEBS has a “loading” or priming AT specific for predominantly propionyl-CoA while all six subsequent AT are specific for the extender molecule, methylmalonyl-CoA. The native AT of DEBS have all been successfully substituted with AT from other modular PKS such as the PKS that produces rapamycin; which replaces the methylmalonyl-CoA specific AT with malonyl-CoA AT and produces a non-methylated erythromycin derivative. This mode of engineering in particular shows the versatility that can be achieved as both the priming molecule and the extender molecule can be changed to produce many new products. In addition to the AT sites, any of the reductive/dehydrating enzyme active sites may be replaced with one or more additional reductive/dehydrating enzyme active sites. For example, in one study, the