Aspartate-histidine-histidine-cysteine protein acyltransferase (ZDHHC)

Aspartate-histidine-histidine-cysteine (DHHC) protein acyltransferases, also known as ZDHHC proteins, are a family of 23 multi-pass transmembrane enzymes in humans that catalyze S-palmitoylation (UniProt, 2023). This reversible post-translational modification involves the attachment of a 16-carbon palmitate fatty acid to cysteine residues, which significantly influences a protein's membrane affinity, sub-cellular localization, and stability (PubMed: 30108230). These enzymes are vital for various physiological processes, including the regulation of ion channels, G-protein coupled receptors, and synaptic proteins like PSD-95 (Wikipedia, 2024). Dysregulation of ZDHHC enzymes is implicated in several diseases; for instance, ZDHHC17 is linked to Huntington's disease, while ZDHHC20 and ZDHHC9 are associated with oncogenic signaling in various cancers (NCBI, 2023). While no drugs targeting this family are currently FDA-approved, small molecule inhibitors like 2-bromopalmitate are widely used in research to study the therapeutic potential of modulating palmitoylation (PubMed: 33504540). The family represents an emerging class of drug targets, with current efforts focused on achieving isoform selectivity to minimize off-target effects in the central nervous system and other tissues.

Other names

Protein S-acyltransferasePATZinc finger DHHC domain-containing proteinDHHC-PATS-palmitoyltransferase

Inhibition of the DHHC catalytic motif to prevent the covalent attachment of long-chain fatty acids (typically palmitate) to cysteine residues of substrate proteins, thereby disrupting their membrane association and function (PubMed: 29305543).