ZDHHC24 Inhibitors

Chemical inhibitors of ZDHHC24 can exert their inhibitory effects through various biochemical mechanisms. NSC 625987 and Palmostatin B target the palmitoylation cycle; NSC 625987 does this by impeding the cleavage of thioester bonds in palmitoylated proteins, thus restricting the substrates available for ZDHHC24 to modify. Similarly, Palmostatin B prevents depalmitoylation, leading to an accumulation of palmitoylated proteins, which can affect ZDHHC24 by saturating its substrate pool. Another inhibitor, 2-Bromopalmitate, acts as an alkylating agent that modifies the cysteine residues within ZDHHC24's active site, inhibiting its enzymatic activity directly. Cerulenin's role is more upstream; it inhibits fatty acid synthase, thereby decreasing the production of free fatty acids like palmitate, which are necessary substrates for ZDHHC24's palmitoyltransferase activity. Tunicamycin disrupts the folding and membrane localization of ZDHHC24 through inhibiting N-linked glycosylation, a post-translational modification necessary for its activity.

Continuing with the theme of metabolic interference, PF-429242 inhibits S1P protease, thereby blocking SREBP processing and subsequently the biosynthesis of lipids, which may lead to reduced palmitate availability for ZDHHC24. ML348 and ML349 selectively inhibit APT1 and APT2, respectively, which are thioesterases involved in depalmitoylating proteins; their inhibition could result in reduced ZDHHC24 substrate availability due to increased competition. The alteration of the lipid environment is a common theme, as Fumonisin B1 inhibits ceramide synthase, impacting sphingolipid metabolism and the membrane microenvironment where ZDHHC24 operates. Tipifarnib inhibits farnesyltransferase, potentially changing the localization and availability of proteins for ZDHHC24 to palmitoylate. Indomethacin affects the metabolism of arachidonic acid, altering the lipid milieu and possibly impacting ZDHHC24 activity. Lastly, Perhexiline inhibits carnitine palmitoyltransferase-1, which could lead to a decrease in palmitoyl-CoA levels, a direct substrate for ZDHHC24, thus inhibiting its function.