Studying the Anchor of Life: the Chemical Biology of Protein Prenylation
Professor Mark Distefano, Erskine Visitor
Department of Chemistry and Medicinal Chemistry, University of Minnesota
Time & Place
Wed, 20 Mar 2019 12:00:00 NZDT in Room 701, West Building
All are welcome
Protein lipid-modification involves the attachment of hydrophobic groups to polypeptides within cells after they are synthesized by ribosomes. The purpose of these modifications is to anchor specific proteins to the cell membrane where they can relay chemical messages from the exterior to the cellular interior. Protein prenylation is one example of lipid modification and consists of the addition of either C15 or C20 isoprenoid groups to a variety of proteins; such proteins play key roles in regulating processes within cells including cell division, shape, differentiation and memory. Of particular note is the observation that protein prenylation is required for the transforming activity of mutant Ras oncoproteins; inhibition of the enzyme farnesyltransferase (which catalyzes protein prenylation) arrests the growth of transformed cells in a variety of models. A number of inhibitors of this enzyme and others in the protein prenylation pathway are currently in clinical trials for cancer therapy and other diseases. This presentation will illustrate how chemical synthesis has driven discovery in this field. New methodology for the synthesis of peptide libraries has enabled the specificity of prenyltransferases to be probed in detail and illuminated new types of proteins that may carry this modification. Synthetic isoprenoid probes have been used to identify prenylated proteins in a range of systems ranging from the malaria parasite to human cancer cells. These molecules can also be used for selective protein labeling to create new protein nanostructures. New photoremovable protecting groups for thiols, that can be activated via two photon excitation, have been used to trigger or inhibit protein lipid modification in living cells. Those protecting groups have also been used to 3D create patterns within hydrogels that should be useful for guiding cell migration. Ultimately, new discoveries from these fundamental studies should reveal new targets and strategies for therapeutic applications.
Top Left: Heat map showing results of screening a 380-member peptide library for farnesyltransferase activity. Top Right: Metabolic labeling with isoprenoid analogues identifies over 100 prenylated proteins. Bottom Left: Structure of a photoactivatable inhibitor of protein prenylation. Bottom Right: Migration of lipid-modified peptides to cell membrane upon photodeprotection of thiol group.
Read more about Mark Distefano here.