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

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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.