CAREER: Peptidic Natural Products in Research and Education

在化学系生命过程化学项目的支持下，来自格鲁吉亚理工学院的Vinayak Agarwal正在研究将肽酶促修饰为生物活性有机分子。修饰的肽类有机分子在化学、药理学和农业中的重要性怎么强调都不过分。这些肽分子通常由作用于底物肽的遗传编码酶产生。该项目旨在发现和研究肽修饰酶，并了解这些酶如何识别和结合底物肽。这种追求将使研究生获得遗传学，生物化学，分子生物学和分析化学程序的宝贵培训。该项目还旨在在主办机构进行综合课程创新，其中本科生将接受微生物学和分析化学实验的理论和实践培训，旨在激励他们继续攻读科学研究生课程，从而丰富国家未来的技术培训劳动力。肽和蛋白质的酶改性继续提供新的化学反应。本项目将从细菌基因组和宏基因组的挖掘入手，重构生物合成酶的生化活性，查询肽修饰酶催化的反应和底物范围。特别令人感兴趣的是原子水平的理解分子间肽-蛋白质相互作用的基础，上述化学修饰。使用各种生物物理技术，纯化的底物肽和纯化的修饰酶之间的相互作用的机制将被查询。生物物理学研究将与生物化学实验相结合，目的是加深对分子间识别规则的理解。这些努力有可能提供新的通用生物催化剂，允许肽底物的定制修饰。同时，在主办机构的物质和人员支持下，将为本科生开发新的课程，这将提供最先进的基于质谱的工作流程的指导，旨在从细菌来源发现肽类天然产物，该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的学术价值和更广泛的影响审查标准。

With the support of the Chemistry of Life Processes Program in the Division of Chemistry, Vinayak Agarwal from Georgia Institute of Technology is studying the enzymatic modification of peptides into bioactive organic molecules. The importance of modified peptidic organic molecules in chemistry, pharmacology, and agriculture cannot be overstated. These peptidic molecules are typically produced by genetically encoded enzymes acting upon a substrate peptide. The proposed project is aimed at the discovery and biochemical study of peptide modifying enzymes, and understanding how these enzymes recognize and bind to the substrate peptides. This pursuit will allow graduate students to gain valuable training in genetics, biochemistry, molecular biology, and analytical chemistry procedures. This project also aims at integrated curriculum innovation at the host institution wherein undergraduate students will receive theoretical and hands-on training in microbiology and analytical chemistry experiments with the aim to motivate their retention in postgraduate programs in science, thusly enriching the nation’s future technically trained workforce.The enzymatic modification of peptides and proteins continues to furnish new chemical reactions. Starting with the mining of bacterial genomes and metagenomes, this project will reconstitute the biochemical activities of biosynthetic enzymes and query the reactions catalyzed by and the substrate scope for the peptide modifying enzymes. Of particular interest is the atomistic-level understanding of intermolecular peptide-protein interactions that underlie the above-mentioned chemical modifications. Using a variety of biophysical techniques, the mechanism of interactions between purified substrate peptides and purified modification enzymes will be queried. The biophysical studies will be corroborated with biochemical experiments, with the aim to develop a deeper understanding of the rules of intermolecular recognition. These efforts have the potential to provide new general-purpose biocatalysts that allow for tailored modification of peptidic substrates. Concomitantly, with material and personnel support from the host institution, new coursework for undergraduate students will be developed which will provide instruction in state-of-the-art mass spectrometry-based workflows aimed towards the discovery of peptidic natural products from bacterial sources, together with training in scientific communication and writing.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.