Discovery of Selective and Potent Inhibitors of Palmitoylation

Palmitoylation is a reversible, post-translational modification of a protein through the addi‐ tion of the 16-carbon fatty acid, palmitate, to a cysteine residue. There are two types of pal‐ mitoylation, one called thioor S-palmitoylation in which palmitate is added to the thiol side chain of a cysteine residue via a labile thioester bond [1]. The other type, N-palmitoyla‐ tion, is the addition of palmitate to an N-terminal cysteine via a stable amide bond [2]. The two forms of palmitoylation are regulated by different families of palmitoyl acyltransferases (PATs)—S-palmitoylation via a family of multi-pass transmembrane proteins called DHHC (Asp-His-His-Cys) proteins [3] and N-palmitoylation via a family of multi-pass transmem‐ brane proteins termed membrane-bound O-acyltransferase [4]. S-palmitoylation, the focus of this chapter, is more common and because of the labile thioester bond, can dynamically regulate protein sorting and function.