Mapping the structural basis for mechanistic diversity in metalloenzyme superfamilies

Pennsylvania State University, The, University Park PA

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Abstract

Project Summary The parent grant for this supplement aims to discover novel enzymatic cofactors involved in DNA biosynthesis in pathogens. The overarching goal is to enable new routes to enzyme inhibition in bacteria that cause infectious disease. Here we will investigate the mechanism of assembly of an essential tyrosine-derived post-translationally modified radical cofactor found in a subclass of microbial ribonucleotide reductases through incorporation of non- native amino acids. This approach will allow us to identify aspects of cofactor assembly that could be targeted for disruption by therapeutic interventions. In a second aim, we will characterize the cofactor used by this enzyme subclass in a native host organism. The project as a whole will set the stage for understanding how this enzyme subclass is used inside the cell, ultimately allow us to test the impact of disruption of cofactor assembly in a relevant biological context. The project provides an excellent training opportunity for the Ph.D. candidate supported by the supplement in work at the interface between chemistry and microbiology. A collaborative mentoring team is in place with expertise in non-native amino acid methodology, structural and biochemical characterization of proteins, and cultivation of pathogenic and commensal microbes.