Mark D. Distefano
University of Minnesota
Protein Prenylation: New Tools Reveal New Biology
SESSION 2: PROTEIN MODIFICATIONS FOR ENABLING BIOLOGY
Sunday, June 25, 2023, at 11:40 am - 12:00 pm
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. 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 describe the development of new chemical tools and how they have been used to probe the biology of protein prenylation as well as streamline the development of new protein-based therapeutics. 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 reveal dysregulated prenylation in a range of systems ranging from human cancer cells to Alzheimer’s disease. 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.
Mark Distefano was born in Baton Rouge, LA, and grew up in California and Paris, France. He received his B.A. degree in Chemistry and Biochemistry from the University of California at Berkeley in 1985 and his Ph.D. degree from Massachusetts Institute of Technology in 1989, where he worked with Professor Christopher T. Walsh. He was a postdoctoral fellow in the laboratory of Peter B. Dervan at California Institute of Technology. He is currently Distinguished McKnight Professor of Chemistry and Medicinal Chemistry at the University of Minnesota.
Work in the Distefano Group on protein prenylation is focused in two areas: Chemical Biology and Biotechnology Applications. In pursuit of those studies, members of the group perform a variety of different types of experiments including chemical synthesis, biochemistry, proteomics and cell culture and animal-based work. The goal of this work is to gain insight into protein prenylation that can be used to advance biology and develop new therapeutic approaches for a broad range of diseases including cancer, Alzheimer’s disease and infectious disease.