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

有了这个奖项，化学部的生命过程化学项目资助了Vinayak Agarwal博士和James C。来自格鲁吉亚理工学院的Gumbart和Eric W.犹他州大学的施密特研究自然界如何利用基因和酶来构建环状吡咯分子。吡咯环存在于许多分子中，在生物学中发挥各种作用，并作为药物分子和候选药物的组分。关于酶如何协调吡咯环的构建以及吡咯环如何被其他剪裁酶识别以提供更精细的化学结构，仍存在一些问题。这些问题是由一群研究生，博士后科学家和研究科学家回答的，他们接受基因组学，酶化学，有机合成和计算化学的跨学科培训。此外，还为STEM教育中最缺乏服务的社区之一的太平洋岛民学生提供化学和生物科学的实践实验指导。该研究项目对参与提供来自蛋白质氨基酸L-脯氨酸的硫代模板吡咯环的酶进行生物化学和结构表征。此外，吡咯环是如何识别酶活性位点内的原子描述产生使用X射线晶体学。这些努力都是基于使用机械共价抑制剂稳定小分子-蛋白质和蛋白质-蛋白质分子内相互作用。努力延伸到发现吡咯为基础的天然产物生物合成基因簇从复杂的全生物群落使用宏基因组测序和合成生物学验证的候选基因编码的酶中发现的组合。综上所述，这项研究提供了新的分子见解的酶结构的杂环吡咯环，以及如何这种合成子参与天然产物的生物合成pathways.This奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。

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.