Palmitoyltransferase

Palmitoyltransferases are enzymes that catalyze the covalent attachment of palmitate, a 16-carbon fatty acid, to substrate proteins in a process known as palmitoylation. The modification is typically a thioester linkage to cysteine residues (S-palmitoylation) and serves to regulate protein membrane association, trafficking, stability, and activity. The term often refers to the DHHC family of palmitoyltransferases, also called zDHHC enzymes, which are integral membrane proteins with a conserved DHHC (Asp-His-His-Cys) catalytic motif.

Most DHHC enzymes reside in cellular membranes such as the endoplasmic reticulum, Golgi apparatus, or plasma membrane. Their catalytic cycle generally involves auto-palmitoylation of the enzyme on the active-site cysteine with palmitoyl-CoA, followed by transfer of the palmitoyl group to substrate cysteine residues. Palmitoylation is a dynamic modification: thioesterases such as APT1 and APT2 can remove palmitoyl groups, enabling rapid cycles of attachment and removal that regulate protein localization and function.

A broad and diverse set of substrates are affected, including small GTPases (e.g., certain Rab and Ras family members), various receptors and signaling adaptors, ion channels, and neuronal proteins. Substrate specificity is influenced by expression patterns of PATs, cellular context, and the availability of palmitoyl-CoA, among other factors. Dysregulation of palmitoylation has been linked to neurological disorders, cancer, and infectious diseases, reflecting its fundamental role in signaling and membrane organization.

Research methods to study palmitoylation include acyl-biotin exchange, acyl-resin-assisted capture, and metabolic labeling with palmitate analogs.