Identification of targets and inhibitors of protein palmitoylation.

Importance of the field: Palmitoylation is the post-translational addition of a 16-carbon fatty acid, palmitate, to specific cysteines of proteins via a labile thioester bond. The transfer of palmitate to a substrate is mediated by palmitoyl acyltransferases (PATs). Nearly a third of the 23 genes that encode PATs are linked to human diseases, in particular cancer, and as such represent important targets for drug development. Area covered in this review: In this review, we summarize recent technical advances in the field of palmitoylation, how they will affect our ability to understand palmitoylation-related signaling, and outline a general strategy for the discovery of selective and potent palmitoylation inhibitors. What the reader will gain: The goals of this review are to increase awareness of the importance of palmitoylation in disease as well as our general lack of understanding of the complexity of the fundamental mechanisms of PAT regulation and specificity, and finally to suggest general strategies for the development of PAT inhibitors. Take home message: Any reasonable hope of developing therapeutically useful, pharmacological modulators of palmitoylation will require that they be developed within the context of PAT-related signaling systems that are more extensively characterized than any we currently know. The successful creation of potent, specific drugs in other similarly complex systems suggests that development of useful drugs targeting PATs is certain.