The Promiscuity of EpoC Towards Polymer Bound Substrates

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DESCRIPTION (provided by applicant): Small molecule peptide, polyketide and hybrid polyketide/polypeptide natural products are characterized by their potent biological activities and modular biosyntheses. These compounds typically are generated by modular polyketide synthase (PKS), nonribosomal peptide synthetase (NRPS) and hybrid NRPS/PKS enzymes. To date, there has been limited study of the NRPS/PKS interface of hybrid NRPS/PKS enzymes. This proposal seeks to examine the NRPS/PKS interface of epothilone synthase by exploring the promiscuity of the ketosynthase (KS) domain of epoC towards solid phase bound peptide substrates. EpoC, which sits at the hybrid NRPS/PKS interface of epothilone synthase, was chosen for this study because of the pharmaceutical significance of the epothilones and the extensive body of work regarding their biosynthesis. By applying this technology to libraries of peptide substrates a detailed understanding of the substrate specificity of epoC will be developed, opening the door to reengineering epothilone biosynthesis to generation of novel epothilone derivatives. Also, by fusing epoC to additional PKS modules, combinatorial libraries of hybrid polypeptide/polyketide molecules can be accessed for drug discovery by semibiosynthesis.