Protein prenylation is a post-translational modification that consists of the addition of C<sub>15</sub> or C<sub>20</sub> isoprenoid groups to a variety of proteins. Because many proteins involved in signal transduction processes contain this modification, considerable interest exists in understanding the chemistry and biology of this phenomenon. 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 have been, or are currently, in clinical trials for cancer therapy and other diseases. In this presentation, experiments using peptide libraries will show how the protein specificity of these enzymes and mutants thereof can be rapidly evaluated. Metabolic labeling with isoprenoid analogues containing bioorthogonal functional groups is being used to identify prenylated proteins and which ones change in response to prenylation inhibitors. Those same analogues are also being employed for selective protein labeling to create modified proteins for therapeutic applications.

Protein prenylation: From enzymology to biotechnology and therapeutic application

249th National Meeting (2015)

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