ORIGIN OF STARTER UNITS FOR ERYTHROMYCIN BIOSYNTHESIS

Modular polyketide synthases (PKSs), such as the 6-deoxyerythronolide B synthase (DEBS), are multifunctional proteins that govern the synthe sis of a number of clinically important natural products. The modular arrangement of active sites within these enzymes suggests the possibil ity of a combinatorial approach to the synthesis of novel bioactive po lyketides. The efficacy of combinatorial strategies toward altering th e starter unit specificity of polyketide synthases critically depends on controlling the supply of competing endogenous starter acids. Using DEBS 1-TE, a bimodular derivative of DEBS,we aimed to determine wheth er the beta-ketosynthase (KS) domain responsible for condensation in t he first module also has the ability to prime its own biosynthesis by catalyzing the decarboxylation of methylmalonyl-CoA to produce propion yl-CoA. In contrast to earlier reports with a closely similar mini-PKS DEBS 1+TE, we have found that rigorously purified DEBS 1-TE does not catalyze the decarboxylation of methylmalonyl-CoA.