Microorganisms are not only the most abundant form of life on Earth, but they also possess the greatest diversity of metabolic functions. Gaining access to their collective chemical arsenal would significantly enhance our ability to produce essential small molecules ranging from commodity chemicals to life-saving pharmaceuticals. Recent advances in DNA sequencing technologies have delivered a wealth of microbial genomes that provide an unprecedented opportunity for the discovery of new enzymes. The goal of this project is to identify unusual and potentially useful enzymatic chemistry encoded in these genomic data. The discovery of previously uncharacterized enzymatic activity and its introduction into our reaction repertoire will ultimately lead to more efficient and environmentally friendly routes for small molecule synthesis. The specific C-C bond forming enzymes described in this work will be important additions to the synthetic toolkits of both organic chemists and synthetic biologists. These research efforts will also be integrated into a new laboratory-based freshman seminar course that will engage students in the discovery of new enzymes from human gut microbes.
With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Emily Balskus from Harvard University to discover and characterize enzymes that mediate an unusual C-C bond-forming macrocyclizing dimerization step used in the biosynthesis of the cylindrocyclophane family of cyanobacterial natural products. Using a genome mining approach that is guided by chemical knowledge, the PI has uncovered the biosynthetic gene cluster encoding the enzymes responsible for this reaction. The functions and mechanisms of these enzymes will now be elucidated using in vivo and in vitro biochemical characterization methods, an effort that will be enabled by chemical synthesis of crucial substrates. Important mechanistic insights will also be obtained by solving the crystal structures of the enzymes in collaboration with structural biologists. The central educational objective of this proposal is to create a new research-based course for first-year undergraduates focused on using a screening approach to discover novel enzymes from the human gut microbiota. This class will bring the most exciting aspects of scientific training to the forefront of the college curriculum, encouraging interest in further undergraduate research and scientific careers. Overall, the work detailed in this proposal represents an integrated research and education effort at the interface of chemistry and biology.
