zDHHC

zDHHC refers to a family of zinc finger DHHC-type palmitoyltransferases, a group of integral membrane enzymes that catalyze S-palmitoylation, the reversible attachment of palmitate to cysteine residues on substrate proteins. Palmitoylation modulates protein membrane association, trafficking, stability and signaling, and zDHHC enzymes contribute to the spatial and temporal control of this modification across cellular compartments.

Structurally, zDHHC enzymes contain the conserved DHHC (Asp-His-His-Cys) catalytic motif within a cysteine-rich domain and multiple transmembrane segments. The catalytic cysteine forms an acyl-enzyme intermediate with palmitoyl-CoA, enabling transfer of palmitate to substrate proteins. Substrate specificity is determined by factors such as subcellular localization, scaffolding interactions, and variable cytosolic extensions; many members are palmitoylated themselves and/or regulated by auto- or trans-palmitoylation.

In humans the zDHHC family comprises numerous members (commonly labeled ZDHHC1 through ZDHHC24), each with distinct tissue expression and substrate repertoires. Notable examples include ZDHHC9, implicated in Ras palmitoylation and X-linked intellectual disability; ZDHHC17 (HIP14), involved in neuronal protein trafficking; and ZDHHC8, studied in the context of schizophrenia risk in 22q11.2 deletions.

Research on zDHHC enzymes employs genetic knockouts, substrate identification by acyl-biotin exchange or click chemistry, and analyses of palmitoylation dynamics. Abnormal zDHHC activity has been linked to neurodevelopmental disorders, cancer and metabolic conditions, making the family a focus for studies on post-translational lipid modification and therapeutic modulation.