SSRP Abstract

Board 30: Atypical Key Enzymes in Phosphonate Natural Product Biosynthesis

Student Scientist: Ivan Vore ’25
Research Mentors: Kou-San Ju and Jerry Cui (Department of Microbiology, The Ohio State University)

The rise of drug-resistant pathogens presents an urgent need for new developments in antibiotic research. The Ju Research Group specializes in the study of organically-produced compounds capable of mimicking essential nutrients used in basic metabolism. The goal of our research is to uncover new compounds produced in microorganisms for use in medicine and industry. My work in the lab is focused on the structure and function of a fundamental protein used in the creation of these antibiotic compounds we study.

Phosphonate natural products are antimetabolites defined by their carbon-phosphorus bond. This class of compounds exhibits cytotoxic properties by mimicking common molecules in essential metabolism, making them potent antibiotic, herbicidal, antifungal, and anticancer compounds. The mining of genomic data for phosphonate natural products in microorganisms has provided us with a rich source of newly available compounds in medicine and industry. Genome mining for phosphonate natural product biosynthetic gene clusters (BGCs) is conducted by locating the protein-coding gene PepM. The product of this gene, phosphoenolpyruvate mutase (PepM) is responsible for the first step of all known phosphonate biosynthesis: creating the carbonphosphorus bond that defines all phosphonates. Our analyses of microbial genomes have revealed potential homologs of PepM that lack a defining motif, which has been utilized to distinguish the phosphonate-forming PepM enzyme from ancestral relatives. Yet, their encoding biosynthetic gene clusters contain other known genes for phosphonate biosynthesis within their neighborhoods, suggesting they may indeed catalyze the formation of the carbonphosphorus bond. Here, we test this hypothesis by examining the biochemical function of two atypical PepM homologs from Mesorhizobium sanjuanii and Streptacidiphilus rugosus. Understanding the function of these two enzymes will lead to a greater definition of phosphonate biosynthesis and potentially expand the number of pathways for this family of natural products.