ZDHHC25 Inhibitors

ZDHHC25 inhibitors are a class of chemical compounds that specifically target and inhibit the activity of the enzyme ZDHHC25, a member of the DHHC family of proteins. ZDHHC25 is a palmitoyltransferase, an enzyme responsible for catalyzing the post-translational modification known as S-palmitoylation. This modification involves the attachment of a palmitoyl group (a 16-carbon saturated fatty acid) to cysteine residues of proteins, which influences their membrane association, trafficking, stability, and function. ZDHHC25, like other DHHC proteins, contains a DHHC (Asp-His-His-Cys) domain that plays a central role in its enzymatic activity. Inhibitors of ZDHHC25 function by interfering with this palmitoyltransferase activity, preventing the enzyme from catalyzing the palmitoylation of target proteins, which affects various cellular signaling pathways and protein functions that depend on this modification.

The mechanisms by which ZDHHC25 inhibitors operate can involve direct interference with the active site of the enzyme or blocking the interaction between ZDHHC25 and its substrate proteins. Some inhibitors may mimic the structure of palmitoyl-CoA, the substrate for the palmitoylation reaction, thereby competitively inhibiting the enzyme by occupying its active site. This prevents ZDHHC25 from catalyzing the attachment of palmitoyl groups to target proteins. Other inhibitors might target the DHHC domain specifically, destabilizing its structure or blocking the catalytic cysteine residue required for the enzymatic reaction. By inhibiting ZDHHC25, these compounds can disrupt the palmitoylation and subsequent cellular localization or function of key proteins, offering insights into how palmitoylation influences various cellular processes. Understanding ZDHHC25 inhibitors sheds light on the broader role of palmitoyltransferases in cellular regulation, protein function, and intracellular signaling.