The interplay between metabolism and the post-translational regulation of proteins and signaling pathways is integral to all cellular processes. In this seminar I will present several research efforts where I have applied emerging technologies, including activity-based protein profiling (ABPP), and mass spectrometry-based metabolomic and proteomic platforms, to discover, characterize and perturb diverse post-translational regulatory mechanisms. First, I will discuss the use of ABPP and metabolomic screening platforms in the discovery of a “quorum sensing-like” metabolic pathway present in cancer cells, as well as the subsequent development of highly specific imaging reagents targeting the critical enzymatic node in this cancer-specific pathway. Second, I will describe the discovery of a new type of protein post-translational modification, phosphoglyceryllysine (pgK), which is formed by the non-enzymatic reaction of specific lysine residues on proteins with the primary glycolytic metabolite 1,3-bisphosphoglycerate. This exciting finding provides the first evidence of a direct connection between glycolytic flux and alterations in the structure and function of key proteins, including glycolytic enzymes themselves, pointing to the existence of an ancient and likely biomedically important intrinsic feedback pathway in mammalian cells. This work also implicates pgK modification as a conduit linking core metabolism with numerous other signaling pathways. Progress on the role of pgK modifications as both a cause and consequence of deregulated metabolism in cancer, as well as their dynamic regulation in cells, will be discussed. Together, these efforts underscore the power of integrating traditional chemical and biochemical approaches with quantitative proteomic and metabolomic platforms to expose and exploit novel post-translational regulatory mechanisms in (patho)physiologic processes.
Prof. Nick Hud (404-385-1162)