DHHCpalmitoyltransferases

DHHC palmitoyltransferases, commonly referred to as ZDHHC proteins, constitute a family of integral membrane enzymes that catalyze S-palmitoylation—the reversible attachment of palmitate to cysteine residues on substrate proteins. This modification, which uses palmitoyl-CoA as the donor, regulates protein membrane association, trafficking, stability, and activity.

Most DHHC enzymes are multispanning membrane proteins, typically with four transmembrane helices. The catalytic DHHC motif (Asp-His-His-Cys) resides in a cytosolic loop and is essential for activity. The prevailing mechanism involves auto-palmitoylation of the enzyme, followed by transfer of the palmitoyl group to a substrate cysteine. Palmitoylation is reversible, and depalmitoylation is carried out by thioesterases such as APT1, APT2, and ABHD17 family members, enabling dynamic regulation of substrate function and localization.

Substrate range is broad and varies among family members; individual ZDHHC enzymes display substrate preferences that influence signaling, membrane trafficking, receptor and ion channel localization, and synaptic function. The human genome encodes multiple ZDHHC genes, with tissue- and development-specific expression patterns that reflect diverse biological roles.

Clinical and research relevance: Dysregulation or mutation of specific ZDHHC genes has been linked to neurological disorders, cancer, and metabolic diseases, underscoring the importance of regulated palmitoylation in health. Ongoing research aims to map substrates, regulatory networks, and the structural basis of specificity for this enzyme family.