CAREER: Accessing Chemical Diversity through the Characterization and Redesign of Natural Product Synthases

通过这一奖项，化学系的生命过程化学项目资助哈弗福德学院的Louise Charkoudian博士，让本科生通过学习和应用大自然的教训来发现化学多样性的新途径。自然界已经进化出了非常简单的方法来制造非常复杂的分子，其中许多分子太复杂了，在实验室里很难合成。这项资助的研究重点是描述最古老和最独特的生物合成途径的化学特征，科学家们尚未探索这些途径。实验程序导致了自然编码的新化合物和酶的鉴定，以及能够设计自然途径以构建具有新结构和功能的分子的新工具。这个项目还整合了一系列专业发展，让本科生接触到毕业后在化学科学领域的职业机会，以及生物艺术推广活动，利用着色细菌来说明化学和生物学的基本概念。研究让本科生通过表征未探索的聚酮合成酶(PKS)基因簇和酶来发现新的生物合成途径，从而实现化学多样性。对来自不同门的孤儿II型(多芳香族)聚酮基因簇进行了表征，以阐明古代非放线菌物种编码的化学多样性。这些细菌物种被评估为PKS酶的来源，可以在易处理的异种宿主中表达，从而能够在体外表征鲜为人知的II型PKS。最后，使用传统和创新的生化和生物物理方法相结合的方法来表征代表PKS进化的不同阶段的酰基载体蛋白(ACP)。结果将导致识别新的自然编码的化学多样性，以及使杂交PKS的生物合成工程成为可能的新工具。这项工作还包括由学生主导的对未表征的生物合成基因簇的注释，使学生在毕业后获得科学职业机会的专业发展系列，以及利用产多酮细菌的色素性质的BioArt外联活动。外展活动向来自不同文化和社会经济背景的年轻学生以及智力和发育障碍的成年人介绍化学和生物的概念。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Louise Charkoudian from Haverford College to engage undergraduates in the discovery of new routes to chemical diversity by learning and applying lessons from nature. Nature has evolved remarkably simple routes to make very complicated molecules, many of which are too complex to be readily synthesized in the laboratory. The funded research focuses on characterizing the chemistry of the most ancient and unique biosynthetic pathways, which have yet to be explored by scientists. The experimental procedures lead to the identification of new compounds and enzymes encoded by nature, as well as new tools to enable the engineering of natural pathways to build molecules of novel structure and function. This project also integrates a professional development series to expose undergraduate students to post-graduation career opportunities in the chemical sciences, as well as BioArt outreach activities that employ pigmented bacteria to illustrate fundamental concepts of chemistry and biology.The research engagees undergraduates in the discovery of new biosynthetic routes to chemical diversity through the characterization of unexplored polyketide synthase (PKS) gene clusters and enzymes. Orphaned type II (polyaromatic) polyketide gene clusters from diverse phyla are characterized to elucidate the chemical diversity encoded by ancient non-actinomycete species. These bacterial species are evaluated as a source of PKS enzymes that can be expressed in tractable heterologous hosts to enable in vitro characterization of poorly understood type II PKSs. Finally, acyl carrier proteins (ACPs) representing diverse stages of PKS evolution are characterized using a combination of traditional and innovative biochemical and biophysical methods. Results will lead to the identification of new chemical diversity encoded by nature, as well as new tools to enable the biosynthetic engineering of hybrid PKSs. The work also includes the student-led annotation of uncharacterized biosynthetic gene clusters, a professional development series to expose students to post-graduation career opportunities in the sciences, and BioArt outreach activities that leverage the pigmented nature of polyketide-producing bacteria. The outreach activities introduce concepts of chemistry and biology to young students from diverse cultural and socioeconomic backgrounds, as well as to adults with intellectual and developmental disabilities.