Optimizing the production of and engineering polyketide synthases

Date

2019-05-09

Authors

Shah, Prachi

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Abstract

Polyketide synthases are enormous modular enzymes that synthesize large acyl chains known as polyketides. Common polyketides include pharmaceuticals such as antibiotics, immunosuppressants, and antifungals1. The mechanism of polyketide synthases is analogous to an assembly line. A group of enzymes work together to extend and process an acyl intermediate, forming new carbon-carbon bonds and setting stereocenters. The group of enzymes, a “module”, consists of a set of processing enzymes on its N-terminal end, an acyl carrier protein in its center, and a ketosynthase at its C-terminal end2. Understanding the chemical machinery of and engineering polyketide synthases is useful for future pharmaceutical applications. This work focuses on creating and optimizing the synthesis of two polyketides: venemycin and the first three modules of erythromycin. Erythromycin triketide lactone was produced in vitro and in vivo, and engineering experiments were attempted. Venemycin was produced in vitro, and its production was optimized by modifying various parameters including pH and buffer concentrations.

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