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

职业：通过天然产物合成酶的表征和重新设计获得化学多样性

• 批准号: 1652424
• 负责人: Louise Charkoudian
• 金额: $ 56.07万
• 依托单位: Haverford College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1652424&HistoricalAwards=false
• 关键词: CAREER; Accessing; Chemical; Diversity; through

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.

有了这个奖项，化学部门的化学过程计划是为哈弗福德学院的路易丝·查库（Louise Charkoudian）博士提供资金，以吸引本科生通过学习和从自然中学习课程，从而发现新的途径到化学多样性。 大自然已经发展出非常简单的途径，以制造出非常复杂的分子，其中许多分子太复杂，无法在实验室中容易合成。 这项资助的研究重点是表征最古老，最独特的生物合成途径的化学，科学家尚待探索。 实验程序导致鉴定由大自然编码的新化合物和酶，以及新工具，以实现自然途径的工程，以构建新型结构和功能的分子。 该项目还集成了专业发展系列，以使本科生在化学科学领域的毕业后职业机会，以及生物ART宣传活动，这些活动采用色素细菌来说明化学和生物学的基本概念。该研究使研究不足以通过新生物体的多样性综合型物质综合（clocke contienters contiments contince covery）酶。来自不同门的孤立的II型（多野生）聚酮基因簇的特征是阐明由古代非肌肉菌种编码的化学多样性。 这些细菌物种被评估为可以在可牵引的异源宿主中表达的PKS酶来源，以使知识较差的II型PKS的体外表征能够体外表征。 最后，使用传统和创新的生化和生物物理学方法的组合来表征代表PKS进化阶段的不同阶段的酰基载体蛋白（ACP）。结果将导致鉴定由自然界编码的新化学多样性，以及新的工具，以实现混合PKS的生物合成工程。 这项工作还包括学生主导的未表征生物合成基因簇的注释，这是一个专业发展系列，旨在使学生在科学领域接触毕业后的职业机会，以及生物ART外展活动，以利用多吉尔·促成细菌的有色性性质。 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了化学和生物学的概念。

项目成果

Widening the bottleneck: Heterologous expression, purification, and characterization of the Ktedonobacter racemifer minimal type II polyketide synthase in Escherichia coli

• DOI: 10.1016/j.bmc.2020.115686
• 发表时间: 2020-10-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Klein, Joshua G.;Wu, Yang;Charkoudian, Louise K.
• 通讯作者: Charkoudian, Louise K.

MIBiG 2.0: a repository for biosynthetic gene clusters of known function

• DOI: 10.1093/nar/gkz882
• 发表时间: 2020-01-08
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Kautsar, Satria A.;Blin, Kai;Medema, Marnix H.
• 通讯作者: Medema, Marnix H.