Palmitoyltransferasen

Palmitoyltransferasen, or palmitoyltransferases, are enzymes that catalyze the covalent attachment of palmitoyl groups to proteins, forming S-palmitoyl thioester bonds with cysteine residues. The reaction uses palmitoyl-CoA as the acyl donor and is reversible, allowing dynamic regulation of protein localization and function.

The best characterized group among eukaryotes is the DHHC family, also known as zDHHC palmitoyltransferases. They are integral membrane proteins, typically with four transmembrane segments and a conserved cysteine-rich DHHC motif that is essential for catalytic activity. These enzymes operate through an autoacylation step, forming a palmitoyl-enzyme intermediate before transferring the palmitoyl group to substrate cysteines.

Localization and substrates of DHHC enzymes are diverse. They reside in membranes of the Golgi, endoplasmic reticulum, plasma membrane, endosomes, lysosomes, and sometimes mitochondria. Their substrate repertoire includes signaling proteins, receptors, ion channels, and trafficking factors. The combination of DHHC enzyme and substrate determines the specific palmitoylation pattern within a cell.

Function and regulation: Palmitoylation modulates membrane association, subcellular localization, stability, and protein–protein interactions, thereby influencing trafficking, signaling, and synaptic function. The modification is dynamic and reversible; depalmitoylation is carried out by thioesterases such as acyl-protein thioesterases and related enzymes. DHHC activity is regulated by expression levels, subcellular localization, protein interactions, and the cellular lipid environment.

Clinical relevance and research: Dysregulation of palmitoylation is linked to neurological disorders, cancer, and metabolic diseases. Mutations or altered expression of specific DHHC genes associate with intellectual disability, epilepsy, or neurodegeneration. Research relies on methods including acyl-biotin exchange, acyl-RAC, metabolic labeling, and mass spectrometry to identify palmitoylated substrates and enzyme activities.