palmitoyltransferases

Palmitoyltransferases are a class of enzymes that catalyze the covalent attachment of palmitic acid to proteins, a reversible post-translational modification known as S-palmitoylation. This modification increases the hydrophobicity of target proteins, promoting membrane association and influencing localization, trafficking, stability, and function.

Most studies focus on the DHHC family (also called zDHHC), named for their conserved Asp-His-His-Cys motif in the active site within a cysteine-rich domain. DHHC enzymes are integral membrane proteins with multiple transmembrane segments and are found in compartments such as the endoplasmic reticulum, Golgi apparatus, and plasma membrane. They act as palmitoyltransferases using palmitoyl-CoA as the donor.

Mechanistically, DHHC enzymes form a transient palmitoyl-enzyme intermediate at the catalytic cysteine and transfer the palmitate to substrate cysteines, creating a thioester linkage. Palmitoylation is reversible: depalmitoylation is carried out by acyl-protein thioesterases (such as APT1, APT2) and other thioesterases, allowing dynamic regulation of protein localization and activity.

Substrate specificity varies among DHHC enzymes; some substrates are palmitoylated by multiple DHHCs, while others show selectivity. The system coordinates various cellular processes, including membrane targeting, trafficking through organelles, protein stability, and signaling. In the nervous system, palmitoylation influences synaptic function and development.

Dysregulation of palmitoylation has been linked to cancer, neurodegenerative diseases, and certain infectious diseases, reflecting the broad importance of DHHC enzymes in cell biology. DHHC palmitoyltransferases are active areas of research for understanding disease mechanisms and exploring therapeutic targeting.