Drug Discovery from Natural Products
Natural products are essential in drug discovery and medicine. Their discoveries have cured infections, and saved countless lives. We are interested in identifying biosynthetic pathways that encode new natural products that have not been tested before. These discoveries have the ability to treat new and deadly infections that threaten mankind. The typical approach to natural product drug discovery is to start with the detection of bioactivity from the crude extract of an (micro)organism of interest. Instead, our group targets new biosynthetic enzymes to ensure that a new natural product will be isolated. We then screen the new natural products for bioactivities against infectious diseases and cancer.
Identification of New Biosynthetic Enzymes
Identifying and functional studies for new biosynthetic enzymes is a key aspect of our research, allowing the production and bioassay of new natural products. We are particularly interested in enzymes from the radical SAM superfamily as a source for new biosynthetic enzymes. These enzymes are involved in the biosynthesis of ribosomally-synthesized and posttranslationally modified peptide (RiPP) natural products. Our love for radical SAM enzymes comes from their ability to catalyze unique, chemically difficult, and unpredictable reactions. We are continually surprised by the interesting reactions that rSAM enzymes can accomplish, and these modifications lead to new and bioactive peptides. The pathways that we study have additional modifying enzymes in addition to the radical SAM enzyme that further decorate the peptide scaffold and are a source of additional new enzyme families. Our objective is to characterize the enzyme activities for the radical SAM enzyme, tailoring enzymes, and produce the natural products for biological evaluation.
Defining a New Class of RiPPs - Triceptides
We functionally characterized the radical SAM enzymes identified by genome mining by expression of selected precursor peptides with their cognate radical SAM enzymes by heterologous expression in Escherichia coli. Characterization of the products by nuclear magnetic resonance (NMR) showed that these enzymes are unified in their ability to catalyze formation of a cyclophane ring. RiPP classes are defined by an unique enzymatic reaction for each class. The unique transfromation for the enzymes above is an aromactic to C-beta C(sp2)-C(sp3) bond. We have termed this class of RiPPs as triceptides. Triceptides represent a new modality with the potential to treat various diseases and cancer.
Triceptides as a Platform for Discovery
Triceptide biosynthetic enzymes and natural products are largely unexplored. This represents a unique opportunity to extensively study the natural products and biosynthetic enzymes from this class. Some areas of interest involve producing the end products to test for antibacterial activity. Exploiting the promiscuity of the enzymes to create libraries of triceptides. Studying the enzyme structure, mechanism, and engineering. Exploring the local sequence space to identify the boundaries of triceptide formation. The biosynthetic gene clusters contain a variety of tailoring enzymes and these are interesting to further decorate the triceptide scaffolds as well as lead to unique families of modifying enzymes that can lead to new classes of RiPPs. Our long-term goal is to identify and develop lead peptides for the treatment of infectious diseases and cancer.