Saturday, May 17, 2025
5/17/2025
Biosynthesis of Unusual Bio-Orthogonal Functionalities in Natural Products - SUMMARY Natural products are important small molecules for studying, treating, and even causing human diseases, and they typically have unique functional groups that are critical for their biological activities. By exploiting the biosynthetic machinery by which these functionalities are synthesized, it is possible to enhance, vary or diminish the biological activities of parent compounds and apply the biosynthetic machinery to new systems for functional group installation. Toward this goal, the chemical logic and enzymatic machinery underlying natural product biosynthesis need to be fully characterized and understood. Our lab has been focused on the biosynthesis of unusual pharmacophores of natural products, including but not limited to terminal alkene, alkyne, isonitrile, and N-hydroxytriazene. These moieties often serve as the warhead of bioactive NPs and have distinct physical properties that enable molecular tracking such as Raman- or IR-imaging based cellular uptake and dynamic studies. More importantly, they are often called “clickable” and utilized in bio-orthogonal chemical transformations for various chemical biology applications. Specifically, our program has and will continue to make contributions in the following four areas: 1) Novel enzyme discovery. “Bio-orthogonal” suggests that these functionalities are rare in nature, but structures of a few rare NPs have already indicated the prospect of novel enzyme discovery for these functionalities. 2) Enzyme mechanism interrogation. New and fundamental insights into the catalytic mechanisms of these new enzymes will be obtained. 3) Biocatalysis and biosynthetic pathway engineering. We plan to examine the substrate scope of new enzymes in detail and explore the utilization of these biosynthetic machinery to install “clickable” functionalities on various biomolecules on demand. 4) Leveraging the unique properties of these functionalities to promote natural product research, such as visualization, identification, enrichment, quantification, diversification, and biological target identification. Our program employs multidisciplinary approaches including bioinformatics, genetics, heterologous reconstitution, organic synthesis, biochemical and structural analysis, spectroscopic analysis, bio-orthogonal chemistry, protein engineering, and pathway engineering, with support from world-renowned collaborators providing complementary expertise in structural biology, bioinorganic chemistry, computational chemistry, enzymology, chemical biology, biophysics, and microbiology.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).