Collaborative Research: Constructing and Employing Pyrroles in Natural Product Biosynthetic Pathways

合作研究：在天然产物生物合成途径中构建和使用吡咯

• 批准号: 2003756
• 负责人: Eric Schmidt
• 金额: $ 13.2万
• 依托单位: University of Utah
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2003756&HistoricalAwards=false
• 关键词: Collaborative; Research; Constructing; Employing; Pyrroles

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Drs. Vinayak Agarwal and James C. Gumbart from Georgia Institute of Technology, and Dr. Eric W. Schmidt from the University of Utah to investigate how nature uses genes and enzymes to construct the ring shaped pyrrole molecule. The pyrrole ring is present in many molecules that serve various roles in biology, and as a component of pharmaceutical molecules and drug candidates. Several questions remain regarding how enzymes orchestrate the construction of the pyrrole ring and how the pyrrole ring is recognized by other tailoring enzymes to furnish more elaborate chemical structures. These questions are answered by a cohort of graduate students, postdoctoral scientists, and research scientists receiving interdisciplinary training in genomics, enzyme chemistry, organic synthesis, and computational chemistry. In addition, hands-on experimental instruction in chemical and biological sciences are provided to Pacific Islander students, one of the most underserved communities in STEM education.This research project undertakes a biochemical and structural characterization of enzymes involved in furnishing the thiotemplated pyrrole ring derived from the proteinogenic amino acid L-proline. Also, an atomistic description of how the pyrrole ring is recognized within enzymological active sites is generated using X-ray crystallography. Both these efforts are based on stabilizing small molecule-protein and protein-protein intramolecular interactions using mechanistic covalent inhibitors. Efforts are extended to discover pyrrole-based natural product biosynthetic gene clusters from complex holobiont communities using a combination of metagenomic sequencing and synthetic biological validation of candidate gene-encoded enzymes discovered therein. Taken together, this study provides new molecular insights into the enzymological construction of the heterocyclic pyrrolic ring and how this synthon participates in natural product biosynthetic pathways.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.

有了这个奖项，化学部门的化学过程计划是资助DRS。佐治亚理工学院的Vinayak Agarwal和James C. Gumbart，以及犹他大学的Eric W. Schmidt博士研究自然如何使用基因和酶来构建环形吡咯分子。吡咯环存在于许多在生物学中起各种作用的分子中，并且是药物分子和候选药物的组成部分。关于酶如何编排吡咯环的结构以及其他裁缝酶如何识别吡咯环以提供更精细的化学结构的几个问题。这些问题由研究生，博士后科学家以及接受基因组学，酶化学，有机合成和计算化学的跨学科培训的研究科学家回答。此外，向太平洋岛民学生提供了化学和生物学科学的实验指导，这是STEM教育中最不受欢迎的社区之一。该研究项目对提供蛋白质氨基氨基酸L-富含蛋白质的吡咯环的酶的生化和结构表征进行了生化和结构性表征。同样，使用X射线晶体学生成酶促活性位点中如何在酶促活性位点识别吡咯环的原子描述。这两种努力均基于使用机械共价抑制剂稳定小分子 - 蛋白质和蛋白质 - 分子内相互作用。努力进行了努力，以发现基于复杂Holobiont群落的基于吡咯的天然产物生物合成基因簇，结合了其发现的候选基因基因编码酶的合成生物学验证。综上所述，这项研究为杂环吡吡那环的酶学结构提供了新的分子见解，以及该合成如何参与天然产品生物合成途径。该奖项反映了NSF的法定任务，并被认为是通过基金会的智力优点和广泛的影响来评估Criteria的智力功能和广泛影响。