RUI: BIOPOLYMER - BIObricks POLYketide Metabolic EngineeRing platform

土壤细菌会产生一种名为蒽环酮(ACS)的化合物，其中一些具有很强的治疗活性。ACS具有复杂的结构，这些结构是由细菌中发现的酶产生的。该项目将“混合搭配”这些酶，以使新型的ACS有望具有抗生素和抗癌活性。作为一个本科院校研究项目(RUI)，它将通过让本科生参与完成研究目标来吸引他们投身于理工科职业。教授和学生将通过播客与公众交流。该项目的总体目标是表征聚酮合成酶(PKS)的遗传部分。这些部分将在一个平台(生物聚合物)中结合在一起，形成有效的体内生物合成途径。生物聚合物将促进合理的组合生物合成。中心假设是，选择的PKS和PKS后的酶的组合生物合成将促进合理设计的蒽环酮类药物的生产。这一假说将在两个特定的目标下得到验证：(1)通过在放线菌中异源表达三环并芳香酮类化合物，鉴定和开发用于这些成分的代谢工程的PKS BioBricks部分；(2)鉴定和开发用于四环和氧化修饰的放线菌代谢工程的后PKS BioBricks部分。在这些研究完成后，将确定PKS和后PKS基因组，它们构成了合成新药物或商品化学品的“新的”生物合成途径。在此项目期间开发的菌株和媒介将与更广泛的天然产品社区共享。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Soil bacteria make compounds called anthracyclinones (ACs), some of which have powerful therapeutic activity. ACs have complicated structures that are produced by enzymes found in the bacteria. This project will “mix-and-match” these enzymes to make novel ACs expected to have antibiotic and anticancer activity. As a Research in Undergraduate Institutions (RUI) project, it will attract undergraduate students to careers in science and engineering by involving them in the completion of the research aims. The professor and students will communicate to the public through a podcast. The overall objective of the project is to characterize polyketide synthase (PKS) genetic parts. These parts will be brought together in a platform (BIOPOLYMER) to form productive in vivo biosynthetic pathways. BIOPOLYMER will facilitate rational combinatorial biosynthesis. The central hypothesis is that combinatorial biosynthesis of selected PKS and post-PKS enzymes will facilitate the production of rationally designed anthracyclinones. The hypothesis will be tested in two specific aims: (1) characterize and develop PKS BioBricks parts for metabolic engineering of tricyclic anthracyclinones via heterologous expression of these components in actinomycetes; (2) characterize and develop post-PKS BioBricks parts for metabolic engineering of tetracyclic and oxidatively modified anthracyclinones in actinomycetes. At the completion of these studies, PKS and post-PKS gene sets will be identified that compose “new-to-nature” biosynthetic pathways for synthesizing new pharmaceuticals or commodity chemicals. The strains and vectors that are developed in this project period will be shared with the broader natural products community.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.