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

有了这个奖项，化学部门的生命过程化学项目正在资助博士。佐治亚理工学院的Vinayak Agarwal和James C. Gumbart，以及犹他大学的Eric W. Schmidt博士一起研究大自然是如何利用基因和酶来构建环状吡咯分子的。吡咯环存在于许多分子中，在生物学中起着各种作用，并作为药物分子和候选药物的组成部分。关于酶如何协调吡咯环的构造以及吡咯环如何被其他裁剪酶识别以提供更复杂的化学结构，还有几个问题仍然存在。这些问题由一群研究生、博士后科学家和接受基因组学、酶化学、有机合成和计算化学跨学科培训的研究科学家来回答。此外，还为太平洋岛民学生提供化学和生物科学方面的动手实验教学，太平洋岛民是STEM教育中服务最欠缺的社区之一。本研究项目对参与提供由蛋白质氨基酸l -脯氨酸衍生的硫模板吡咯环的酶进行了生化和结构表征。此外，利用x射线晶体学生成了如何在酶活性位点内识别吡咯环的原子描述。这两种努力都是基于使用机制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。利用宏基因组测序和对其中发现的候选基因编码酶的合成生物学验证相结合，扩大了从复杂全息生物群落中发现基于吡咯的天然产物生物合成基因簇的努力。综上所述，该研究为杂环吡咯环的酶学构建以及该合成子如何参与天然产物的生物合成途径提供了新的分子见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.