The Promiscuity of EpoC Towards Polymer Bound Substrates

描述(由申请人提供)： 小分子多肽、聚酮和杂化聚酮/多肽天然产物具有较强的生物活性和模块化的生物合成。这些化合物通常由模块化聚酮合成酶(PKS)、非核糖体肽合成酶(NRPS)和NRPS/PKS混合酶产生。到目前为止，对NRPS/PKS杂交酶的NRPS/PKS界面的研究还很有限。该建议试图通过探索EPOC的酮合成酶(KS)结构域与固相结合的多肽底物的混杂来检查EPOC的NRPS/PKS界面。EPOC位于Epethilone合成酶的NRPS/PKS杂交界面上，由于EpoC具有药学意义，以及关于其生物合成的大量工作，因此被选为本研究的对象。通过将这项技术应用于多肽底物文库，将详细了解EPOC的底物专一性，从而为重新设计Epothilone的生物合成以产生新的Epothilone衍生物打开大门。此外，通过将EPOC与额外的PKS模块融合，杂化多肽/聚酮分子的组合文库可以通过半生物合成访问用于药物发现。

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.