Exploring Protein -Palmitoylation: Mechanisms, Detection, and Strategies for Inhibitor Discovery.

-palmitoylation is a reversible and dynamic process that involves the addition of long-chain fatty acids to proteins. This protein modification regulates various aspects of protein function, including subcellular localization, stability, conformation, and biomolecular interactions. The zinc finger DHHC (ZDHHC) domain-containing protein family is the main group of enzymes responsible for catalyzing protein -palmitoylation, and 23 members have been identified in mammalian cells. Many proteins that undergo -palmitoylation have been linked to disease pathogenesis and progression, suggesting that the development of effective inhibitors is a promising therapeutic strategy. Reducing the protein -palmitoylation level can target either the PATs directly or their substrates. However, there are rare clinically effective -palmitoylation inhibitors. This review aims to provide an overview of the -palmitoylation field, including the catalytic mechanism of ZDHHC, -palmitoylation detection methods, and the functional impact of protein -palmitoylation. Additionally, this review focuses on current strategies for expanding the chemical toolbox to develop novel and effective inhibitors that can reduce the level of -palmitoylation of the target protein.