Synthesis of Lipidated Peptides

One of the main reasons of the high diversity and complexity of the human proteome compared to the human genome is the extensive work performed by the posttranslational machinery to incorporate numerous different functionalities on proteins. The covalent attachment of chemical moieties in proteins after translation is known as posttranslational modification (PTM) and has a crucial role in controlling protein localization and activity. Relevant modifications include phosphorylation, carboxymethylation, glycosylation, acetylation, or lipidation. Despite their essential role on protein function, the synthesis of fully posttranslationally modified proteins has been challenging. However, important advances on chemical biology have enabled the synthesis of fully posttranslationally modified peptides and proteins. As a result of this, peptides bearing, i.e., phosphorylated amino acids, C-terminal methylations, lipid modifications, or nonnatural tags have become accessible. These peptides, as well as the corresponding proteins obtained using ligation techniques, have been invaluable tools in biochemical and biophysical studies. As an example of these advances, this chapter describes the methods developed for the synthesis of lipidated peptides from the Ras and Rab families.