The Department of Chemistry and Physics continues its Seminar series. Details for this week’s talk are given below.
Friday, Feb. 9
3-4 p.m. Eastern
Grote Hall 411
Joshua Baccile, assistant professor at UTK
Chemical probes for interrogating five-carbon metabolism in diverse organisms
Joshua Baccile
Abstract: Isoprenoids are structurally diverse metabolites with an array of critical bioactivities which include cell membrane integrity (e.g., cholesterol), glycoprotein synthesis (e.g., the dolichols), steroid hormone signaling (e.g., androgens, estrogens, and cortisol), and mitochondrial health (e.g., coenzyme Q). Human isoprenoids derive from the mevalonic acid (MVA) pathway, whereas many plants and bacteria utilize the methyl erythritol phosphate MEP pathway. Both MVA and MEP pathways converge on the same two structurally related five-carbon precursors, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are chain extended to form higher order isoprenoids. Therefore, IPP and DMAPP are the central five-carbon precursors for all isoprenoids in all organisms. Beyond their role as precursors, IPP and DMAPP also directly modify other small molecules (ATP) and macromolecules (37A tRNA) in a process known as prenylation. Levels of IPP and DMAPP are directly involved in cardiovascular disease and have recently been implicated in cancer, cystic fibrosis, and nonalcoholic fatty liver disease. Despite this importance to human health, the mechanisms responsible for both the clinical effects observed by modulating the intracellular concentration of IPP and DMAPP and the distinct bioactivity of IPP and DMAPP are relatively poorly understood. This talk will be focused on our efforts to bridge this scientific gap through the development of a suite of IPP and DMAPP based chemical probes and methods for the metabolic labeling of isoprenoids and prenylated molecules. I will discuss our synthetic approach for access to a wide variety of IPP and DMAPP analogs. Currently, we are leveraging these compounds to do metabolic labeling studies, and to study the independent biochemical activity of IPP and DMAPP in mammalian cancer cells, as well as bacteria. Lastly, I will discuss the future of metabolic labeling in the prenylome, which is to develop cell-permeant inhibitors of the isomerase that inhibits IPP and DMAPP, enabling distinct isotopic enrichment in their respective downstream metabolic pools.