S-palmitoylation describes the post-translational modification of cysteine residues with a long-chain fatty acid (palmitic acid), and facilitates membrane association of diverse proteins. A dynamic cycle of palmitoylation and de-palmitoylation is critical for plasma membrane localization and activity of many signaling proteins, including Ras and G-proteins. Acyl protein thioesterases (APTs) are serine hydrolases that participate in de-palmitoylation of substrate proteins, releasing them from cell membranes. The two human APT enzymes (APT1 and APT2) share 65% sequence homology. Recently, isoform selective inhibitors have been identified for each APT1 and APT2 (Adibekian et al. JACS 2012, 134, 10345-10348). In efforts to increase the potency of APT2 inhibitors, we have synthesized novel derivatives based on the initially identified APT2 inhibitor scaffold. Also, we have determined the crystal structure of each APT1 and APT2 in the presence of their respective selective inhibitors. These structures reveal each APT inhibitor binds similarly to their respective target enzymes, near the catalytic Ser residues. This information will enable design of more potent APT inhibitors for use as probes to study palmitoylation pathways. Based on these crystal structures, future studies will include mutagenesis of key residues to promote inhibitor selectivity.

Structure and inhibition of acyl protein thioesterases

249th National Meeting (2015)

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