Insights into auto--fatty acylation: targets, druggability, and inhibitors.

Posttranslational -fatty acylation (or -palmitoylation) modulates protein localization and functions, and has been implicated in neurological, metabolic, and infectious diseases, and cancers. Auto--fatty acylation involves reactive cysteine residues in the proteins which directly react with fatty acyl-CoA through thioester transfer reactions, and is the first step in some palmitoyl acyltransferase (PAT)-mediated catalysis reactions. In addition, many structural proteins, transcription factors and adaptor proteins might possess such "enzyme-like" activities and undergo auto--fatty acylation upon fatty acyl-CoA binding. Auto--fatty acylated proteins represent a new class of potential drug targets, which often harbor lipid-binding hydrophobic pockets and reactive cysteine residues, providing potential binding sites for covalent and non-covalent modulators. Therefore, targeting auto--fatty acylation could be a promising avenue to pharmacologically intervene in important cellular signaling pathways. Here, we summarize the recent progress in understanding the regulation and functions of auto--fatty acylation in cell signaling and diseases. We highlight the druggability of auto--fatty acylated proteins, including PATs and other proteins, with potential and rationalized drug design approaches. We also highlight structural analysis and examples of currently known small molecules targeting auto--fatty acylation, to gain insights into targeting this class of proteins, and to expand the "druggable" proteome.