Engineering Microbial Cells for the Biosynthesis of Natural Compounds of Pharmaceutical Significance

Figure 2

Biosynthesis of deoxyerythronolide B in the route to erythromycin A (adapted from [19]). Deoxyerythronolide B synthases (DEBS) catalyze iterative claisen-type condensations by progressively associating one propionyl-CoA primer unit with six methylmalonyl-CoA extender units. Each DEBS molecule contains two modules, these modules representing a physical location for a claisen-type condensation. Once loaded onto the ketosynthase (KS) of module 1 by the loading acyl transferase (AT) and the acyl carrier protein (ACP) domains, propionyl-CoA condenses with a methylmalonyl unit loaded onto module 1 ACP by the module 1 AT domain. After that, ketoreductases (KR), specific for each module, reduce the resulting ketone group. The chain then passes in a progressive manner from module 1 ACP (via a phosphopantetheine cofactor) to the KS domain of the next module (module 2). Following these iterative condensations, the polyketide chain grows before being released and cyclized by a thioesterase/claisen cyclase (TE). Other abbreviations: ER are enoyl reductase and DH: dehydratase.