ACSS3 Inhibitors

Chemical inhibitors of ACSS3 disrupt its function by interfering with various metabolic pathways that supply or regulate the availability of its substrate, acetyl-CoA. Sulfo-N-succinimidyl oleate impairs fatty acid metabolism by inhibiting fatty acid transport proteins, leading to decreased acetyl-CoA levels, which is essential for ACSS3 activity. Similarly, Triclosan curtails fatty acid synthesis, thus reducing acetyl-CoA production and consequently limiting the enzyme's function. C75, by inhibiting fatty acid synthase, alters the equilibrium between malonyl-CoA and fatty acyl-CoA, resulting in a reduced acetyl-CoA pool. Etomoxir and Perhexiline target carnitine palmitoyltransferase 1 and 2, respectively, leading to a decrease in the β-oxidation of fatty acids, which in turn limits the availability of acetyl-CoA for ACSS3. AICAR activates AMP-activated protein kinase, which inhibits acetyl-CoA carboxylase and lowers malonyl-CoA levels, indirectly restricting the substrate supply for ACSS3.

Continuing with the theme of limiting substrate availability, Cerulenin and TOFA also inhibit fatty acid synthase and acetyl-CoA carboxylase, respectively, thus reducing malonyl-CoA levels and concomitantly decreasing the acetyl-CoA concentration. CPI-613 interferes with the tricarboxylic acid cycle by inhibiting lipoamide dehydrogenase, which can influence acetyl-CoA levels and consequently ACSS3 activity. Orlistat inhibits gastrointestinal lipases, which reduces the hydrolysis and absorption of triglycerides, leading to a decrease in fatty acids available for β-oxidation and ultimately resulting in lower acetyl-CoA levels. Direct inhibition of acetyl-CoA synthetase is achieved by ST1326 and GSK2837808A, both of which prevent the conversion of acetate into acetyl-CoA, thereby depleting the substrate necessary for ACSS3 to function. These inhibitors collectively undermine the activity of ACSS3 by curtailing the production or availability of acetyl-CoA through various metabolic interventions.