Biosynthesis, discovery, and biocatalytic production of halogenated nucleosides and nucleoside-sulfamates.

About This Grant

Project Summary. Nucleoside analogs are an important class of pharmaceutical compounds that serve as the cornerstone for antiviral therapy. Beyond viral infections, various nucleoside analogs have also shown antitumor, antibacterial, antifungal, and herbicidal activity. Though synthetic chemists can design new nucleoside analogs de novo, a large fraction of our pharmaceuticals are inspired by bioactive compounds made by bacteria. The proposed work will investigate the biosynthesis of a cryptic family of natural product nucleoside analogs that contain ‘rare’ functional groups. This work will be enabled by the research group’s expertise on non-standard nucleoside biochemistry, chemical biology, genetics, and analytical chemistry. Initial work will combine genetic engineering with comparative genomic/comparative metabolomics to identify key enzymes involved in halogenation and sulfamate formation. Since these perform valuable transformations, they make promising candidates as biocatalysts for pharmaceutical synthesis. Notably, kinetic and substrate/reaction characterization of these enzymes will be explored test the feasibly of using these enzymes for alternative synthesis of existing nucleoside analog therapeutics. As a subsequent goal, this work will also explore how ‘modular’ biosynthesis of these nucleoside natural products can be used to rapidly synthesize inhibitors of a wide-range of enzymes. Key innovations here will include combinatorial assays with ribozyme components. Finally, this work will look to integrate bioinformatic/metabolomic/genetic approaches to discover unknown nucleoside analogs made by various bacteria. Specifically, we highlight existing evidence of hybrid gene clusters that make unknown nucleosides. As a general vision, this research program poses that elucidating nucleoside biosynthesis pathways, characterizing enzymes that perform rare biochemistry, and discovering new bioactive nucleosides will expand the repertoire of biocatalytic tools available for making life-saving nucleoside analogs.