Divergence of Carboxylate-Bridged Diiron Enzymes for Natural Product Biosynthesis

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Dinuclear iron enzymes (DIs) utilize a carboxylate- and histidine-coordinated cofactor to affect synthetically challenging biochemical reactions. The recognized roles for DIs have recently expanded to include several important natural product biosynthetic pathways, including the generation of folate in pathogenic bacteria, the modulation of antibiotic potency via halogen installation, and the synthesis of essential secondary metabolites through carbon-carbon bond scission. To understand the molecular basis for how a very similar cofactor and structural core can perform such diverse functions, we propose to study three newly discovered DIs that contain nearly identical coordination motifs and overall structural scaffolds, but orchestrate chemistry in ways that fundamentally differ from both each other and from well-studied DIs that instead perform the oxygenation of substrates. The proposed work will utilize an array of spectroscopic, kinetic, and genetic tools to identify key sites of the protein, substrate, and cofactor that enable such disparate activities. An elucidation of the structural basis for DI functional reprogramming will provide a biochemical template for the synthesis of new pharmacophores and the molecular basis for pathways that are critical for microbial proliferation and pathogenicity.