CAREER: Peptidic Natural Products in Research and Education

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.